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Sample records for r-flurbiprofen reduces neuropathic

  1. R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids.

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    Philipp Bishay

    Full Text Available BACKGROUND: R-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear. METHODOLOGY/PRINCIPAL FINDINGS: We show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB, which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARgamma and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists. CONCLUSION: Our results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain.

  2. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

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    Koo Edward H

    2007-07-01

    Full Text Available Abstract Background Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs is associated with a reduced incidence of Alzheimer's disease (AD. We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice. Results A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning. Conclusion We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition

  3. Placebo manipulations reduce hyperalgesia in neuropathic pain.

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    Petersen, Gitte Laue; Finnerup, Nanna Brix; Nørskov, Kathrine Næsted; Grosen, Kasper; Pilegaard, Hans K; Benedetti, Fabrizio; Price, Donald D; Jensen, Troels Staehelin; Vase, Lene

    2012-06-01

    Several studies have shown that placebo analgesia effects can be obtained in healthy volunteers, as well as patients suffering from acute postoperative pain and chronic pain conditions such as irritable bowel syndrome. However, it is unknown whether placebo analgesia effects can be elicited in chronic pain conditions with a known pathophysiology such as a nerve injury. Nineteen patients who had developed neuropathic pain after thoracotomy were exposed to a placebo manipulation in which they received either open or hidden administrations of lidocaine. Before the treatment, the patients rated their levels of spontaneous pain and expected pain and completed a questionnaire on their emotional feelings (Positive Affect Negative Affect Schedule) and went through quantitative sensory testing of evoked pain (brush and cold allodynia, heat pain tolerance, area of pinprick hyperalgesia, wind-up-like pain after pinprick stimulation). The placebo manipulation significantly reduced the area of pinprick hyperalgesia (P=.027), and this placebo effect was significantly related to low levels of negative affect (P=.008; R(2)=0.362) but not to positive affect or expected pain levels. No placebo effect was observed in relation to spontaneous pain or evoked pain, which is most likely due to low pain levels resulting in floor effects. This is the first study to demonstrate a placebo effect in neuropathic pain. The possible mechanisms underlying the placebo effects in hyperalgesia are discussed, and implications for treatment are outlined.

  4. An examination of the thermodynamics of fusion, vaporization, and sublimation of (R,S)- and (R)-flurbiprofen by correlation gas chromatography.

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    Umnahanant, Patamaporn; Hasty, Darrell; Chickos, James

    2012-06-01

    The vaporization, fusion, and sublimation enthalpies of (R,S)- and (R)-flurbiprofen at T = 298.15 K are reported and compared with literature values when available. Correlation gas chromatography experiments were first performed to identify appropriate standards that could be used for materials containing a single fluorine substituent. Subsequent correlations resulted in a vaporization enthalpy for (R,S)-flurbiprofen and (R)-flurbiprofen, ΔH(vap) (298.15 K), of (127.5 ± 5.5) and (127.4 ± 4.7) kJ mol, respectively. Fusion enthalpies, ΔH(fus) (387 K), of (28.2 ± and, ΔH(fus) (381 K), (22.8 ± kJ mol(-1) were also measured by differential scanning calorimetry for the racemic and chiral forms of flurbiprofen. Adjusted to T = 298.15 K and combined with the vaporization enthalpy resulted in sublimation enthalpies, ΔH(sub) (298.15 K), of (155.6 ± 5.8) and (145.1 ± 5.7) kJ mol(-1) for (R,S)- and (R)-flurbiprofen, respectively. The fusion enthalpy measured for the racemic form was in excellent agreement with the literature value, while the sublimation enthalpy varies substantially from previous work. Two weak solid-solid phase transitions were also observed for (R)-flurbiprofen at T = 353.9 K (0.30 ± 0.1) and 363.2 K (0.21 ± 0.03) kJ · mol(-1).

  5. Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.

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    Rojewska, Ewelina; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy.

  6. Ocimum gratissimum Essential Oil and Its Isolated Compounds (Eugenol and Myrcene) Reduce Neuropathic Pain in Mice.

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    Paula-Freire, Lyvia Izaura Gomes; Molska, Graziella Rigueira; Andersen, Monica Levy; Carlini, Elisaldo Luiz de Araújo

    2016-02-01

    Ocimum gratissimum is used in popular medicine to treat painful diseases. The antihypernociceptive properties of O. gratissimum essential oil and two of its active components (eugenol and myrcene) were tested in a model of neuropathic pain induced by a chronic constriction injury of the sciatic nerve. In tests to determine chronic antinociception, adult male C57BL/6 J mice were treated orally with corn oil (control group), O. gratissimum essential oil at doses of 10, 20, or 40 mg/kg or eugenol or myrcene at doses of 1, 5, or 10 mg/kg for 14 days after surgery. Pregabalin (20 mg/kg) was used as a standard in this study. The treatment with 20 and 40 mg/kg of O. gratissimum essential oil and at doses of 5 and 10 mg/kg of the active components were able to promote antihypernociception in both mechanical (von Frey) and thermal (hot plate) tests. The treatment with the essential oil of the plant or eugenol was effective in reducing the levels of interleukin-1β in the sciatic nerve. Our findings demonstrate that O. gratissimum essential oil and its isolated active components possess antihypernociceptive activity in neuropathic pain models.

  7. Frutalin reduces acute and neuropathic nociceptive behaviours in rodent models of orofacial pain.

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    Damasceno, Marina B M V; de Melo Júnior, José de Maria A; Santos, Sacha Aubrey A R; Melo, Luana T M; Leite, Laura Hévila I; Vieira-Neto, Antonio E; Moreira, Renato de A; Monteiro-Moreira, Ana Cristina de O; Campos, Adriana R

    2016-08-25

    Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor.

  8. Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.

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    Matsuo, Hideaki; Uchida, Kenzo; Nakajima, Hideaki; Guerrero, Alexander Rodriguez; Watanabe, Shuji; Takeura, Naoto; Sugita, Daisuke; Shimada, Seiichiro; Nakatsuka, Terumasa; Baba, Hisatoshi

    2014-09-01

    Although transcutaneous electrical nerve stimulation (TENS) is widely used for the treatment of neuropathic pain, its effectiveness and mechanism of action in reducing neuropathic pain remain uncertain. We investigated the effects of early TENS (starting from the day after surgery) in mice with neuropathic pain, on hyperalgesia, glial cell activation, pain transmission neuron sensitization, expression of proinflammatory cytokines, and opioid receptors in the spinal dorsal horn. Following nerve injury, TENS and behavioral tests were performed every day. Immunohistochemical, immunoblot, and flow cytometric analysis of the lumbar spinal cord were performed after 8 days. Early TENS reduced mechanical and thermal hyperalgesia and decreased the activation of microglia and astrocytes (PEarly TENS decreased p-p38 within microglia (Pearly TENS relieved hyperalgesia in our mouse model of neuropathic pain by inhibiting glial activation, MAP kinase activation, PKC-γ, and p-CREB expression, and proinflammatory cytokines expression, as well as maintenance of spinal opioid receptors. The findings indicate that TENS treatment is more effective when applied as early after nerve injury as possible. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  9. The Edible Brown Seaweed Ecklonia cava Reduces Hypersensitivity in Postoperative and Neuropathic Pain Models in Rats

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    Jae Goo Kim

    2014-06-01

    Full Text Available The current study was designed to investigate whether edible brown seaweed Ecklonia cava extracts exhibits analgesic effects in plantar incision and spared nerve injury (SNI rats. To evaluate pain-related behavior, we performed the mechanical withdrawal threshold (MWT and thermal hypersensitivity tests measured by von Frey filaments and a hot/cold plate analgesia meter. Pain-related behavior was also determined through analysis of ultrasonic vocalization. The results of experiments showed MWT values of the group that was treated with E. cava extracts by 300 mg/kg significantly increased; on the contrary, number of ultrasonic distress vocalization of the treated group was reduced at 6 h and 24 h after plantar incision operation (62.8%, p < 0.05. Moreover, E. cava 300 mg/kg treated group increased the paw withdrawal latency in hot-and cold-plate tests in the plantar incision rats. After 15 days of continuous treatment with E. cava extracts at 300 mg/kg, the treated group showed significantly alleviated SNI-induced hypersensitivity response by MWT compared with the control group. In conclusion, these results suggest that E. cava extracts have potential analgesic effects in the case of postoperative pain and neuropathic pain in rats.

  10. Neuropathic pain

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    Colloca, Luana; Ludman, Taylor; Bouhassira, Didier

    2017-01-01

    Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7-10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing...... to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central...... nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased...

  11. Lateral Hypothalamic Stimulation Reduces Hyperalgesia Through Spinally Descending Orexin-A Neurons in Neuropathic Pain.

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    Wardach, Jacob; Wagner, Monica; Jeong, Younhee; Holden, Janean E

    2016-03-01

    No evidence to date shows that lateral hypothalamic (LH) stimulation produces orexin-A-mediated antinociception in the spinal cord dorsal horn (SCDH) in a model of neuropathic pain. We conducted experiments to examine the effect of orexin-A-mediated LH stimulation in female rats with chronic constriction injury (CCI) on thermal hyperalgesia. Rats receiving carbachol into the LH demonstrated antinociception on both the left CCI and right nonligated paws (p orexin-1 (OX1) receptor antagonist SB-334867, which blocked LH-induced antinociception compared with control groups (p orexin-A connection between the LH and the SCDH. Identification of this pathway may lead to studies using orexins to manage clinical pain.

  12. A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects.

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    Ignatowska-Jankowska, Bogna M; Baillie, Gemma L; Kinsey, Steven; Crowe, Molly; Ghosh, Sudeshna; Owens, Robert A; Damaj, Imad M; Poklis, Justin; Wiley, Jenny L; Zanda, Matteo; Zanato, Chiara; Greig, Iain R; Lichtman, Aron H; Ross, Ruth A

    2015-12-01

    The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Δ(9)-tetrahydrocannabinol and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [(3)H]CP55,940 to the CB1 receptor as well as enhancing AEA-stimulated [(35)S]GTPγS binding in mouse brain membranes and β-arrestin recruitment and ERK phosphorylation in hCB1 cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity, and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB1 receptor-mediated antinociceptive effects in the chronic constriction nerve injury model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB1 PAM and provide the first proof of principle that CB1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects.

  13. Managing Neuropathic Pain in Dogs

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    Moore, Sarah A.

    2016-01-01

    Disorders of the somatosensory system such as neuropathic pain are common in people with chronic neurologic and musculoskeletal diseases, yet these conditions remain an underappreciated morbidity in veterinary patients. This is likely because assessment of neuropathic pain in people relies heavily on self-reporting, something our veterinary patients are not able to do. The development of neuropathic pain is a complex phenomenon, and concepts related to it are frequently not addressed in the standard veterinary medical curriculum such that veterinarians may not recognize this as a potential problem in patients. The goals of this review are to discuss basic concepts in the pathophysiology of neuropathic pain, provide definitions for common clinical terms used in association with the condition, and discuss pharmacological treatment options for dogs with neuropathic pain. The development of neuropathic pain involves key mechanisms such as ectopic afferent nerve activity, peripheral sensitization, central sensitization, impaired inhibitory modulation, and pathologic activation of microglia. Treatments aimed at reducing neuropathic pain are targeted at one or more of these mechanisms. Several drugs are commonly used in the veterinary clinical setting to treat neuropathic pain. These include gabapentin, pregabalin, amantadine, and amitriptyline. Proposed mechanisms of action for each drug, and known pharmacokinetic profiles in dogs are discussed. Strong evidence exists in the human literature for the utility of most of these treatments, but clinical veterinary-specific literature is currently limited. Future studies should focus on objective methods to document neuropathic pain and monitor response to therapy in veterinary patients. PMID:26942185

  14. Managing neuropathic pain in dogs

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    Sarah A Moore

    2016-02-01

    Full Text Available Disorders of the somatosensory system such as neuropathic pain are common in people with chronic neurologic and musculoskeletal diseases, yet these conditions remain an underappreciated morbidity in our veterinary patients. This is likely because assessment of neuropathic pain in people relies heavily on self-reporting, something our veterinary patients are not able to do. The development of neuropathic pain is a complex phenomenon, and concepts related to it are frequently not addressed in the standard veterinary medical curriculum such that veterinarians may not recognize this as a potential problem in patients. The goals of this review are to discuss basic concepts in the pathophysiology of neuropathic pain, provide definitions for common clinical terms used in association with the condition, and discuss available medical treatment options for dogs with neuropathic pain. The development of neuropathic pain involves key mechanisms such as ectopic afferent nerve activity, peripheral sensitization, central sensitization, impaired inhibitory modulation, and activation of microglia. Treatments aimed at reducing neuropathic pain are targeted at one or more of these mechanisms. Several drugs are commonly used in the veterinary clinical setting to treat neuropathic pain. These include gabapentin, pregabalin, amantadine, and amitriptyline. Proposed mechanisms of action for each drug, and known pharmacokinetic profiles in dogs are discussed. Strong evidence exists in the human literature for the utility of most of these treatments, but clinical veterinary-specific literature is currently limited. Future studies should focus on objective methods to document neuropathic pain and monitor response to therapy in our veterinary patients.

  15. Managing Neuropathic Pain in Dogs.

    Science.gov (United States)

    Moore, Sarah A

    2016-01-01

    Disorders of the somatosensory system such as neuropathic pain are common in people with chronic neurologic and musculoskeletal diseases, yet these conditions remain an underappreciated morbidity in veterinary patients. This is likely because assessment of neuropathic pain in people relies heavily on self-reporting, something our veterinary patients are not able to do. The development of neuropathic pain is a complex phenomenon, and concepts related to it are frequently not addressed in the standard veterinary medical curriculum such that veterinarians may not recognize this as a potential problem in patients. The goals of this review are to discuss basic concepts in the pathophysiology of neuropathic pain, provide definitions for common clinical terms used in association with the condition, and discuss pharmacological treatment options for dogs with neuropathic pain. The development of neuropathic pain involves key mechanisms such as ectopic afferent nerve activity, peripheral sensitization, central sensitization, impaired inhibitory modulation, and pathologic activation of microglia. Treatments aimed at reducing neuropathic pain are targeted at one or more of these mechanisms. Several drugs are commonly used in the veterinary clinical setting to treat neuropathic pain. These include gabapentin, pregabalin, amantadine, and amitriptyline. Proposed mechanisms of action for each drug, and known pharmacokinetic profiles in dogs are discussed. Strong evidence exists in the human literature for the utility of most of these treatments, but clinical veterinary-specific literature is currently limited. Future studies should focus on objective methods to document neuropathic pain and monitor response to therapy in veterinary patients.

  16. Activation of Spinal α2-Adrenoceptors Using Diluted Bee Venom Stimulation Reduces Cold Allodynia in Neuropathic Pain Rats

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    Suk-Yun Kang

    2012-01-01

    Full Text Available Cold allodynia is an important distinctive feature of neuropathic pain. The present study examined whether single or repetitive treatment of diluted bee venom (DBV reduced cold allodynia in sciatic nerve chronic constriction injury (CCI rats and whether these effects were mediated by spinal adrenergic receptors. Single injection of DBV (0.25 or 2.5 mg/kg was performed into Zusanli acupoint 2 weeks post CCI, and repetitive DBV (0.25 mg/kg was injected for 2 weeks beginning on day 15 after CCI surgery. Single treatment of DBV at a low dose (0.25 mg/kg did not produce any anticold allodynic effect, while a high dose of DBV (2.5 mg/kg significantly reduced cold allodynia. Moreover, this effect of high-dose DBV was completely blocked by intrathecal pretreatment of idazoxan (α2-adrenoceptor antagonist, but not prazosin (α1-adrenoceptor antagonist or propranolol (nonselective β-adrenoceptor antagonist. In addition, coadministration of low-dose DBV (0.25 mg/kg and intrathecal clonidine (α2-adrenoceptor agonist synergically reduced cold allodynia. On the other hand, repetitive treatments of low-dose DBV showing no motor deficit remarkably suppressed cold allodynia from 7 days after DBV treatment. This effect was also reversed by intrathecal idazoxan injection. These findings demonstrated that single or repetitive stimulation of DBV could alleviate CCI-induced cold allodynia via activation of spinal α2-adrenoceptor.

  17. Intrathecal siRNA against Toll-like receptor 4 reduces nociception in a rat model of neuropathic pain

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    Fei-xiang Wu, Jin-jun Bian, Xue-rong Miao, Sheng-dong Huang, Xue-wu Xu, De-jun Gong, Yu-ming Sun, Zhi-jie Lu, Wei-feng Yu

    2010-01-01

    Full Text Available Background: Neuropathic pain is characterized by hyperalgesia, allodynia and spontaneous pain. It often occurs as a result of injury to peripheral nerves, dorsal root ganglions (DRG, spinal cord, or brain. Recent studies have suggested that Toll-like receptor 4 (TLR4 might play a role in neuropathic pain. Methodology/Principal Findings: In this study, we investigated the role of TLR4 in a rat chronic constriction injury (CCI model and explored the feasibility of treating neuropathic pain by inhibiting TLR4. Our results demonstrated that intrathecal siRNA-mediated suppression of TLR4 attenuated CCI-induced mechanical allodynia and thermal hyperalgesia through inhibiting the activation of NF-κB p65 and production of proinflammatory cytokines (e.g., TNF-α and IL-1β. Conclusions/Significance: These findings suggest that suppression of TLR4 mediated by intrathecally administered siRNA may be a new strategy for the treatment of neuropathic pain.

  18. Neuropathic pruritus.

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    Misery, Laurent; Brenaut, Emilie; Le Garrec, Raphaële; Abasq, Claire; Genestet, Steeve; Marcorelles, Pascale; Zagnoli, Fabien

    2014-07-01

    Pruritus, also known as itch, is a very common, unpleasant sensation that elicits an urge to scratch. Its origin is not always in the skin, and neuropathic itch that is caused by neuronal or glial damage is common, but poorly understood by both dermatologists and neurologists. Although pruritus has not been considered as serious a symptom as pain, it is difficult to treat and--if chronic--can severely impair quality of life. Neuropathic itch is often associated with other clinical symptoms, most commonly neuropathic pain, and hypersensitization to stimuli is present in both pruritus and pain of neuropathic origin. The shared aetiology can aid in finding suitable treatment for itch in some cases, but more detailed knowledge of the mechanisms of itch, along with standardized, well-controlled trials, is needed. Pruritus research is an emerging but currently very active field, and our understanding of this sensation is rapidly increasing. Here, we review new discoveries regarding the role of the nervous system and the contribution of different pathways in pruritus, discuss the different aetiologies of neuropathic itch, and outline currently available and potential strategies for managing neuropathic pruritus.

  19. Micronized Palmitoylethanolamide Reduces the Symptoms of Neuropathic Pain in Diabetic Patients

    OpenAIRE

    Chiara Schifilliti; Lelio Cucinotta; Viviana Fedele; Carmela Ingegnosi; Salvatore Luca; Carmelo Leotta

    2014-01-01

    The present study evaluated the effectiveness of micronized palmitoylethanolamide (PEA-m) treatment in reducing the painful symptoms experienced by diabetic patients with peripheral neuropathy. PEA-m, a fatty acid amide of the N-acylethanolamine family, was administered (300 mg twice daily) to 30 diabetic patients suffering from painful diabetic neuropathy. Before treatment start, after 30 and 60 days the following parameters were assessed: painful symptoms of diabetic peripheral neuropathy u...

  20. Neuropathic pain

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    Giuseppe Re

    2009-02-01

    Full Text Available Neuropathic pain is the expression of a dysfunction or primary lesion of a nerve in the peripheral or central nervous system, or both, rather than the biological signal transmitted by the nerve following peripheral nociceptor activation. It represents about 20% of all painful syndromes, with an estimated prevalence of 1.5%, however is actual incidence is hard to pinpoint due to the difficulties encountered in distinguishing it from chronic pain, of which it represents a significant percentage, on account of the not infrequent concurrence of conditions. It is crucial to recognise the variety of symptoms with which it can present: these can be negative and positive and, in turn, motor, sensitive and autonomic. In public health terms, it is important to emphasise that the diagnosis of neuropathic pain does not in most cases require sophisticated procedures and does not therefore weigh on health expenditure. In clinical practice, a validated scale (the LANSS is mentioned is useful for identifying patients presenting neuropathic pain symptoms. Therapy is based on three categories of medication: tricyclic antidepressants, anti-epileptics and opioids at high doses: neuropathic pain has a bad reputation for often resisting common therapeutic approaches and responding less well that nociceptor pain to monotherapy. Therapeutic strategies are all the more adequate the more they are based on symptoms and therefore on the pain generation mechanisms, although the recommendations are dictated more by expert opinions that double-blind randomised trials.

  1. A comparison of customised and prefabricated insoles to reduce risk factors for neuropathic diabetic foot ulceration: a participant-blinded randomised controlled trial

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    Paton Joanne S

    2012-12-01

    Full Text Available Abstract Background Neuropathic diabetic foot ulceration may be prevented if the mechanical stress transmitted to the plantar tissues is reduced. Insole therapy is one practical method commonly used to reduce plantar loads and ulceration risk. The type of insole best suited to achieve this is unknown. This trial compared custom-made functional insoles with prefabricated insoles to reduce risk factors for ulceration of neuropathic diabetic feet. Method A participant-blinded randomised controlled trial recruited 119 neuropathic participants with diabetes who were randomly allocated to custom-made functional or prefabricated insoles. Data were collected at issue and six month follow-up using the F-scan in-shoe pressure measurement system. Primary outcomes were: peak pressure, forefoot pressure time integral, total contact area, forefoot rate of load, duration of load as a percentage of stance. Secondary outcomes were patient perceived foot health (Bristol Foot Score, quality of life (Audit of Diabetes Dependent Quality of Life. We also assessed cost of supply and fitting. Analysis was by intention-to-treat. Results There were no differences between insoles in peak pressure, or three of the other four kinetic measures. The custom-made functional insole was slightly more effective than the prefabricated insole in reducing forefoot pressure time integral at issue (27% vs. 22%, remained more effective at six month follow-up (30% vs. 24%, p=0.001, but was more expensive (UK £656 vs. £554, p Conclusion The custom-made insoles are more expensive than prefabricated insoles evaluated in this trial and no better in reducing peak pressure. We recommend that where clinically appropriate, the more cost effective prefabricated insole should be considered for use by patients with diabetes and neuropathy. Trial registration Clinical trials.gov (NCT00999635. Note: this trial was registered on completion.

  2. Novel epigallocatechin-3-gallate (EGCG derivative as a new therapeutic strategy for reducing neuropathic pain after chronic constriction nerve injury in mice.

    Directory of Open Access Journals (Sweden)

    Xavier Xifró

    Full Text Available Neuropathic pain is common in peripheral nerve injury and often fails to respond to ordinary medication. Here, we investigated whether the two novel epigallocatechin-3-gallate (EGCG polyphenolic derivatives, compound 23 and 30, reduce the neuropathic pain in mice chronic constriction nerve injury (CCI. First, we performed a dose-response study to evaluate nociceptive sensation after administration of EGCG and its derivatives 23 and 30, using the Hargreaves test at 7 and 21 days after injury (dpi. We daily administered EGCG, 23 and 30 (10 to 100 mg/Kg; i.p. during the first week post-CCI. None of the doses of compound 23 caused significant pain diminution, whereas 50mg/kg was optimal for both EGCG and 30 to delay the latency of paw withdrawal. With 50 mg/Kg, we showed that EGCC prevented the thermal hyperalgesia from 7 to 21 dpi and compound 30 from 14 to 56 dpi. To evaluate the molecular mechanisms underpinning why EGCG and compound 30 differentially prevented the thermal hyperalgesia, we studied several biochemical parameters in the dorsal horn of the spinal cord at 14 and 56 dpi. We showed that the effect observed with EGCG and compound 30 was related to the inhibition of fatty acid synthase (FASN, a known target of these polyphenolic compounds. Additionally, we observed that EGCG and compound 30 reduced the expression of CCI-mediated inflammatory proteins and the nuclear localization of nuclear factor-kappa B at 14 dpi, but not at 56 dpi. We also strongly detected a decrease of synaptic plasma membrane levels of N-methyl-D-asparte receptor 2B in CCI-mice treated with compound 30 at 56 dpi. Altogether, compound 30 reduced the chronic thermal hyperalgesia induced by CCI better than the natural compound EGCG. Thus, our findings provide a rationale for the preclinical development of compound 30 as an agent to treat neuropathic pain.

  3. Tramadol reduces anxiety-related and depression-associated behaviors presumably induced by pain in the chronic constriction injury model of neuropathic pain in rats.

    Science.gov (United States)

    Caspani, Ombretta; Reitz, Marie-Céline; Ceci, Angelo; Kremer, Andreas; Treede, Rolf-Detlef

    2014-09-01

    Depression and anxiety are common comorbidities of neuropathic pain (NP). Pharmacological preclinical studies on NP have given abundant information on the effects of drugs on reflex measures of stimulus-evoked pain. However, few preclinical studies focus on relief of comorbidities evoked by NP. In this study, we investigated the effects of tramadol on nociceptive reflex, depression-associated and anxiety-related behaviors in a NP model in rats. We used chronic constriction injury (CCI) of the sciatic nerve as an animal model of neuropathic pain. We performed electronic von Frey tests (evF) to measure mechanical sensitivity, elevated plus maze tests (EPM) to record anxiety-related behaviors and forced swimming tests (FST) to evaluate depression-associated behaviors. In the evF, CCI rats showed a decrease of 82% of the paw withdrawal threshold (PWT) compared to sham (PTramadol increased the PWT by 336% in CCI rats (PTramadol increased the time spent on the open arms of CCI rats by 67% (PTramadol reduced the immobility time in CCI rats by 22% (PTramadol reversed the changes in mechanical sensitivity as well as anxiety-related and depression-associated behaviors that are caused by injury of the sciatic nerve with only minor effects in the absence of injury. These data suggest that tramadol relieves chronic pain and its indirect consequences and comorbidities, and that this study also is a model for pharmacological studies seeking to investigate the effect of drugs on the major disabling symptoms of NP.

  4. The endocannabinoid system and neuropathic pain.

    Science.gov (United States)

    Maldonado, Rafael; Baños, Josep Eladi; Cabañero, David

    2016-02-01

    The research of new therapeutic strategies for neuropathic pain represents a major current priority. Important drawbacks to advance in the development of these therapies are the limited translational value of the animal models now available and the elucidation of the complex neuronal and immune pathophysiological mechanisms underlying neuropathic pain. One of the neurotransmitter systems participating in neuropathic pain control that has recently raised a particular interest is the endocannabinoid system. This system is highly expressed in neurons and immune cells, and it plays a crucial role in the development of neuropathic pain. Preclinical studies have provided important findings, revealing the potential interest of the endocannabinoid system for the treatment of neuropathic pain. These studies have reported the analgesic effects of cannabinoid agonists in multiple neuropathic pain models, and they have identified specific targets within this system to develop more effective and safe analgesic compounds. However, further studies using more relevant neuropathic pain animal models are required to confirm these interesting results. Several clinical studies suggest that cannabinoids significantly reduced neuropathic pain, although most of these trials fail the required standards of quality. The different pain patient populations included in the systematic reviews also make it difficult to get adequate conclusions. Therefore, additional clinical trials that consider an adequate number of patients, the use active treatments as controls, and longer duration of administration are required to have an adequate profile of the effectiveness and safety of cannabinoids in neuropathic pain.

  5. Maraviroc reduces neuropathic pain through polarization of microglia and astroglia - Evidence from in vivo and in vitro studies.

    Science.gov (United States)

    Piotrowska, Anna; Kwiatkowski, Klaudia; Rojewska, Ewelina; Makuch, Wioletta; Mika, Joanna

    2016-09-01

    Recent studies suggest that CCR5 and its ligands are important regulators for the development of neuropathic pain and that their modulation can have some beneficial properties. Therefore, the aim of our study was to investigate the influence of maraviroc (MVC, a CCR5 antagonist) on glial polarization markers and intracellular signaling pathways in the spinal cord 7 days after chronic constriction injury (CCI) to the sciatic nerve and in primary glial cultures after LPS stimulation. Our results demonstrated that chronic intrathecal administration of MVC diminished neuropathic pain symptoms and nociceptive threshold ∼60 min after drug administration on days 3 and 7 post-CCI. MVC downregulated the levels of phosphorylated p38 MAPK, ERK1/2 and NF-κB proteins in the spinal cord and upregulated STAT3 in the dorsal root ganglia (DRG). Additionally, using Western blot analysis, we demonstrated that MVC effectively diminished "classical" activation markers: IL-1β, IL-18, IL-6 and NOS2 in the spinal cord. In contrast, MVC upregulated "alternative" antinociceptive activation markers: IL-1RA, IL-18BP and IL-10 in the spinal cord. In parallel, MVC downregulated the levels of phosphorylated p38 MAPK, ERK1/2 and NF-κB proteins and upregulated STAT3 in microglial and astroglial cell cultures. Similarly, MVC reduced pronociceptive (IL-1β, IL-18, IL-6, NOS2) and enhanced the antinociceptive (IL-1RA, IL-18BP, IL-10) factors after LPS stimulation. Our studies provide new evidence that MVC attenuates neuropathy symptoms, promotes spinal glial "alternative" polarization and restores the balance between pro- and antinociceptive factors. Our results suggest the modulation of CCR5 by MVC as a novel therapeutic approach for neuropathy.

  6. Ankle joint mobilization reduces axonotmesis-induced neuropathic pain and glial activation in the spinal cord and enhances nerve regeneration in rats.

    Science.gov (United States)

    Martins, Daniel F; Mazzardo-Martins, Leidiane; Gadotti, Vinícius M; Nascimento, Francisney P; Lima, Denise A N; Speckhann, Breno; Favretto, Gisela A; Bobinski, Franciane; Cargnin-Ferreira, Eduardo; Bressan, Elisângela; Dutra, Rafael C; Calixto, João B; Santos, Adair R S

    2011-11-01

    An important issue in physical rehabilitation is how to protect from or to reduce the effects of peripheral nerve injury. In the present study, we examined whether ankle joint mobilization (AJM) would reduce neuropathic pain and enhance motor functional recovery after nerve injury. In the axonotmesis model, AJM during 15 sessions every other day was conducted in rats. Mechanical and thermal hyperalgesia and motor performance deficit were measured for 5 weeks. After 5 weeks, we performed morphological analysis and quantified the immunoreactivity for CD11b/c and glial fibrillary acidic protein (GFAP), markers of glial activation, in the lumbar spinal cord. Mechanical and thermal hyperalgesia and motor performance deficit were found in the Crush+Anesthesia (Anes) group (P<0.001), which was significantly decreased after AJM (P<0.001). In the morphological analysis, the Crush+Anes group presented reduced myelin sheath thickness (P<0.05), but the AJM group presented enhanced myelin sheath thickness (P<0.05). Peripheral nerve injury increased the immunoreactivity for CD11b/c and GFAP in the spinal cord (P<0.05), and AJM markedly reduced CD11b/c and GFAP immunoreactivity (P<0.01). These results show that AJM in rats produces an antihyperalgesic effect and peripheral nerve regeneration through the inhibition of glial activation in the dorsal horn of the spinal cord. These findings suggest new approaches for physical rehabilitation to protect from or reduce the effects of nerve injury. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  7. Neuropathic Pain After Lung Surgery

    Science.gov (United States)

    2017-05-30

    Chronic Neuropathic Pain, Postoperative; Chronic Pain, Postoperative; Chronic Chemotherapy-induced Neuropathic Pain; Chronic Chemotherapy-induced Pain; Chronic Chemotherapy-induced Peripheral Neuropathy

  8. Neuropathic Pain After Breast Surgery

    Science.gov (United States)

    2017-07-31

    Chronic Neuropathic Pain, Postoperative; Chronic Pain, Postoperative; Chronic Chemotherapy-induced Neuropathic Pain; Chronic Chemotherapy-induced Pain; Chronic Chemotherapy-induced Peripheral Neuropathy

  9. Central Neuropathic Pain Syndromes.

    Science.gov (United States)

    Watson, James C; Sandroni, Paola

    2016-03-01

    Chronic pain is common in patients with neurologic complications of a central nervous system insult such as stroke. The pain is most commonly musculoskeletal or related to obligatory overuse of neurologically unaffected limbs. However, neuropathic pain can result directly from the central nervous system injury. Impaired sensory discrimination can make it challenging to differentiate central neuropathic pain from other pain types or spasticity. Central neuropathic pain may also begin months to years after the injury, further obscuring recognition of its association with a past neurologic injury. This review focuses on unique clinical features that help distinguish central neuropathic pain. The most common clinical central pain syndromes-central poststroke pain, multiple sclerosis-related pain, and spinal cord injury-related pain-are reviewed in detail. Recent progress in understanding of the pathogenesis of central neuropathic pain is reviewed, and pharmacological, surgical, and neuromodulatory treatments of this notoriously difficult to treat pain syndrome are discussed.

  10. Expression of tissue inhibitor of metalloprotease 3 is reduced in ischemic but not neuropathic ulcers from patients with type 2 diabetes mellitus.

    Science.gov (United States)

    Menghini, R; Uccioli, L; Vainieri, E; Pecchioli, C; Casagrande, V; Stoehr, R; Cardellini, M; Porzio, O; Rizza, S; Federici, M

    2013-12-01

    Diabetic foot ulceration remains one of the most common and most serious consequences of diabetes. Persistently high levels of matrix metalloproteases (MMPs) contribute to wound chronicity. Our aim was to assess the concentrations of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in neuropathic and ischemic diabetic foot ulcers by analyzing biopsy samples. In this study, biopsies were taken from 35 diabetic foot ulcers of type 2 diabetes mellitus patients and distinguished in neuropathic (n = 14) or ischemic (n = 21). Zymography assay was utilized for the analysis of MMP-2 and MMP-9 activity. TACE activity was evaluated by a specific fluorimetric assay. mRNA levels of MMPs as well as TIMPs were detected using quantitative real-time polymerase chain reaction. The activity of MMP9 and A Disintegrin and A MetalloProtease Domain 17/TNF-Alpha Converting Enzyme (ADAM17/TACE) was significantly increased in ischemic compared to neuropathic biopsies. No differences were detected between both groups for the mRNA levels of MMPs as well as of ADAMs. However, TIMP3 mRNA expression was decreased in ischemic samples. The combination of increased activity of MMP9 and ADAM17/TACE with decreased concentrations of TIMP-3 mRNA expression in ischemic diabetic foot ulcers compared to neuropathic samples suggests that the increased proteolytic environment may represent a causative factor in the ulcer progression. New treatment strategies for healing diabetic foot ulcers could be directed toward increasing levels of TIMP3.

  11. Orofacial neuropathic pain induced by oxaliplatin

    Science.gov (United States)

    Ling, Jennifer; Erol, Ferhat; Viatchenko-Karpinski, Viacheslav; Kanda, Hirosato

    2017-01-01

    Neuropathic pain induced by chemotherapy drugs such as oxaliplatin is a dose-limiting side effect in cancer treatment. The mechanisms underlying chemotherapy-induced neuropathic pain are not fully understood. KCNQ2 channels are low-threshold voltage-gated K+ channels that play a role in controlling neuronal excitability. Downregulation of KCNQ2 channels has been proposed to be an underlying mechanism of sensory hypersensitivity that leads to neuropathic pain. However, it is currently unknown whether KCNQ channels may be downregulated by chemotherapy drugs in trigeminal ganglion neurons to contribute to the pathogenesis of chemotherapy-induced orofacial neuropathic pain. In the present study, mechanical sensitivity in orofacial regions is measured using the operant behavioral test in rats treated with oxaliplatin. Operant behaviors in these animals show the gradual development of orofacial neuropathic pain that manifests with orofacial mechanical allodynia. Immunostaining shows strong KCNQ2 immunoreactivity in small-sized V2 trigeminal ganglion neurons in controls, and the numbers of KCNQ2 immunoreactivity positive V2 trigeminal ganglion neurons are significantly reduced in oxaliplatin-treated animals. Immunostaining is also performed in brainstem and shows strong KCNQ2 immunoreactivity at the trigeminal afferent central terminals innervating the caudal spinal trigeminal nucleus (Vc) in controls, but the KCNQ2 immunoreactivity intensity is significantly reduced in oxaliplatin-treated animals. We further show with the operant behavioral test that oxaliplatin-induced orofacial mechanical allodynia can be alleviated by the KCNQ2 potentiator retigabine. Taken together, these findings suggest that KCNQ2 downregulation may be a cause of oxaliplatin-induced orofacial neuropathic pain and KCNQ2 potentiators may be useful for alleviating the neuropathic pain. PMID:28741430

  12. Minocycline reduces the injury-induced expression of prodynorphin and pronociceptin in the dorsal root ganglion in a rat model of neuropathic pain.

    Science.gov (United States)

    Mika, J; Rojewska, E; Makuch, W; Przewlocka, B

    2010-02-17

    A role of neuropeptides in neuropathic pain development has been implicated; however, the neuroimmune interactions that are involved in the underlying mechanisms may be more important than previously thought. To examine a potential role of relations between glia cells and neuropeptides in neuropathic pain, we performed competitive reverse-transcription polymerase chain reaction (RT-PCR) from the dorsal lumbar spinal cord and the dorsal root ganglion (DRG) after chronic constriction injury (CCI) in the rat sciatic nerve. The RT-PCR results indicated that complement component 1, q subcomponent (C1q) mRNA expression was higher than glial fibrillary acidic protein (GFAP) in the spinal cord 3 and 7 days post-CCI, suggesting that spinal microglia and perivascular macrophages are more activated than astrocytes. In parallel, we observed a strong upregulation of prodynorphin mRNA in the spinal cord after CCI, with no changes in the expression of proenkephalin or pronociceptin. Conversely, the expression of GFAP mRNA in the DRG was higher than C1q, which suggests that the satellite cells are activated shortly after injury, followed by the macrophages and polymorphonuclear leukocytes infiltrating the DRG. In the DRG, we also observed a very strong upregulation of prodynorphin (1387%) as well as pronociceptin (122%) and a downregulation of proenkephalin (47%) mRNAs. Interestingly, preemptive and repeated i.p. injection of minocycline reversed the activation of microglia/macrophages in the spinal cord and the trafficking of peripheral immune cells into the DRG, and markedly diminished the upregulation of prodynorphin and pronociceptin in the DRG. We thus provide novel findings that inhibition of C1q-positive cells by minocycline can diminish injury-induced neuropeptide changes in the DRG. This suggests that immune cells-derived pronociceptive factors may influence opioid peptide expression. Therefore, the injury-induced activation of microglia and leukocytes and the subsequent

  13. Prevention of NKCC1 phosphorylation avoids downregulation of KCC2 in central sensory pathways and reduces neuropathic pain after peripheral nerve injury.

    Science.gov (United States)

    Mòdol, Laura; Cobianchi, Stefano; Navarro, Xavier

    2014-08-01

    Neuropathic pain after peripheral nerve injury is characterized by loss of inhibition in both peripheral and central pain pathways. In the adult nervous system, the Na(+)-K(+)-2Cl(-) (NKCC1) and neuron-specific K(+)-Cl(-) (KCC2) cotransporters are involved in setting the strength and polarity of GABAergic/glycinergic transmission. After nerve injury, the balance between these cotransporters changes, leading to a decrease in the inhibitory tone. However, the role that NKCC1 and KCC2 play in pain-processing brain areas is unknown. Our goal was to study the effects of peripheral nerve injury on NKCC1 and KCC2 expression in dorsal root ganglia (DRG), spinal cord, ventral posterolateral (VPL) nucleus of the thalamus, and primary somatosensory (S1) cortex. After sciatic nerve section and suture in adult rats, assessment of mechanical and thermal pain thresholds showed evidence of hyperalgesia during the following 2 months. We also found an increase in NKCC1 expression in the DRG and a downregulation of KCC2 in spinal cord after injury, accompanied by later decrease of KCC2 levels in higher projection areas (VPL and S1) from 2 weeks postinjury, correlating with neuropathic pain signs. Administration of bumetanide (30 mg/kg) during 2 weeks following sciatic nerve lesion prevented the previously observed changes in the spinothalamic tract projecting areas and the appearance of hyperalgesia. In conclusion, the present results indicate that changes in NKCC1 and KCC2 in DRG, spinal cord, and central pain areas may contribute to development of neuropathic pain.

  14. Duloxetine and 8-OH-DPAT, but not fluoxetine, reduce depression-like behaviour in an animal model of chronic neuropathic pain.

    Science.gov (United States)

    Hu, Bing; Doods, Henri; Treede, Rolf-Detlef; Ceci, Angelo

    2016-04-21

    The current study assessed whether antidepressant and/or antinociceptive drugs, duloxetine, fluoxetine as well as (±)-8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), are able to reverse depression-like behaviour in animals with chronic neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve in rats was selected as neuropathic pain model. Mechanical hypersensitivity and depression-like behaviour were evaluated 4 weeks after surgery by "electronic algometer" and forced swimming test (FST), which measured the time of immobility, and active behaviours climbing and swimming. The selective noradrenergic and serotonergic uptake blocker duloxetine (20mg/kg) and the selective 5-HT1A agonist 8-OH-DPAT (0.5mg/kg) significantly reversed both mechanical hypersensitivity and depression-like behaviour in CCI animals. Duloxetine significantly reversed depression-like behaviour in CCI rats by increasing the time of climbing and swimming, while 8-OH-DPAT attenuated depression-like behaviour mainly by increasing the time of swimming. However, the selective serotonergic uptake blocker fluoxetine (20mg/kg) failed to attenuate mechanical hypersensitivity and depression-like behaviour, possibly due to confounding pro-nociceptive actions at 5-HT3 receptors. These data suggest to target noradrenergic and 5-HT1A receptors for treatment of chronic pain and its comorbidity depression.

  15. Neuropathic orofacial pain.

    Science.gov (United States)

    Benoliel, R; Sharav, Y

    1998-11-01

    Neuropathic orofacial pain (NOP) is a challenging diagnostic problem. In some cases, symptomatology may be similar to that seen with dental pathology, resulting in unwarranted dental treatment. Rarely, NOP can herald serious disease or central tumors, and early diagnosis can be life-saving. The following review outlines the classification, clinical presentation, pathophysiology, and treatment of the more common NOP entities.

  16. Neuropathic pain in leprosy.

    Science.gov (United States)

    Raicher, Irina; Stump, Patrick Raymond Nicolas Andre Ghislain; Baccarelli, Rosemari; Marciano, Lucia H S C; Ura, Somei; Virmond, Marcos C L; Teixeira, Manoel Jacobsen; Ciampi de Andrade, Daniel

    2016-01-01

    Nerve impairment is a key clinical aspect of leprosy and may present the distribution of mononeuropathy or multiple nerve trunks, small cutaneous nerve fibers, and free nerve endings. The clinical range of leprosy is determined by individual cell-mediated immune response to infection that also may play a role in different types of pain syndromes in leprosy. Previous studies reported a high prevalence of neuropathic pain in leprosy. In an Ethiopian study with 48 patients, pure nociceptive pain was experienced by 43% of patients and pure neuropathic pain (NeP) by 11% of patients. In an Indian study, 21.8% of leprosy patients had pain with neuropathic characteristics. These rates underlie the need to develop tools for the early diagnosis and detection of infection and its complications, such as nerve damage and pain. In a larger sample with leprosy-associated NeP (n = 90), we have applied the Douleur Neuropathique en 4 questions (DN4) and found sensitivity = 97.1% and specificity = 57.9%. The high sensitivity of this tool in leprosy patients suggests that it could be a valuable tool to screen for neuropathic pain in this population and could be used as part of health care programs aimed at detecting, treating, and rehabilitating leprosy in endemic areas.

  17. Contemporary treatment neuropathic pain

    Directory of Open Access Journals (Sweden)

    Cvijanović Milan

    2011-01-01

    Full Text Available Introduction. Neuropathic pain, or pain associated with disease or injury to the peripheral or central nervous system, is a common symptom of a heterogeneous group of conditions, including diabetic neuropathy, trigeminal neuralgia, postherpetic neuralgia and spinal cord injury. Chronic neuropathic pain should not be thought of as a symptom. It should truly be thought of as a disease with a very complicated pathophysiology. Pathophysiology. The mechanisms involved in neuropathic pain are complex and involve both peripheral and central pathophysiologic phenomenon. The underlying dysfunction may involve deafferentation within the peripheral nervous system (e.g. neuropathy, deafferentation within the central nervous system (e.g. post-thalamic stroke or an imbalance between the two (e.g. phantom limb pain. Clinical characteristics. Neuropathic pain is non-nociceptive, in contrast to acute nociceptive pain, and it can be described as ”burning”, ”electric”, ”tingling”, and ”shooting” in nature. Treatment. Rational polypharmacy is often necessary and actually it is almost always the rule. It would be an exception if a patient was completely satisfied with his treatment. Treatment goals should include understanding that our patients may need to be titrated and managed with more than one agent and one type of treatment. There should be the balance of safety, efficacy, and tolerability. Conclusion. There are many new agents and new applications of the existing agents being currently studied which will most certainly lead to even more improved ways of managing this very complicated set of disorders.

  18. Neuronal mechanism for neuropathic pain

    OpenAIRE

    Zhuo Min

    2007-01-01

    Abstract Among different forms of persistent pain, neuropathic pain presents as a most difficult task for basic researchers and clinicians. Despite recent rapid development of neuroscience and modern techniques related to drug discovery, effective drugs based on clear basic mechanisms are still lacking. Here, I will review the basic neuronal mechanisms that maybe involved in neuropathic pain. I will present the problem of neuropathic pain as a rather difficult task for neuroscientists, and we...

  19. Managing Neuropathic Pain in Dogs

    OpenAIRE

    2016-01-01

    Disorders of the somatosensory system such as neuropathic pain are common in people with chronic neurologic and musculoskeletal diseases, yet these conditions remain an underappreciated morbidity in veterinary patients. This is likely because assessment of neuropathic pain in people relies heavily on self-reporting, something our veterinary patients are not able to do. The development of neuropathic pain is a complex phenomenon, and concepts related to it are frequently not addressed in the s...

  20. New therapy for neuropathic pain.

    Science.gov (United States)

    Mizoguchi, Hirokazu; Watanabe, Chizuko; Yonezawa, Akihiko; Sakurada, Shinobu

    2009-01-01

    Neuropathic pain is one of the worst painful symptoms in clinic. It contains nerve-injured neuropathy, diabetic neuropathy, chronic inflammatory pain, cancer pain, and postherpes pain, and is characterized by a tactile allodynia and hyperalgesia. Neuropathic pain, especially the nerve-injured neuropathy, the diabetic neuropathy, and the cancer pain, is opioid resistant pain. Since the downregulation of mu-opioid receptors is observed in dorsal spinal cord, morphine and fentanyl could not provide marked antihyperalgesic/antiallodynic effects in the course neuropathic pain states. The downregulation of mu-opioid receptors is suggested to be mediated through the activation of NMDA receptors. Moreover, at the neuropathic pain states, the increased expression of voltage-dependent Na+ channels and Ca2+ channels are observed. Based on the above information concerned with the pathophysiology of neural changes in neuropathic pain states, new drug treatments for neuropathic pain, using ketamine, methadone, and gabapentin, have been developed. These drugs show remarkable effectiveness against hyperalgesia and allodynia during neuropathic pain states. Oxycodone is a mu-opioid receptor agonist, which has different pharmacological profiles with morphine. The remarkable effectiveness of oxycodone for neuropathic pain provides the possibility that mu-opioid receptor agonists, which have different pharmacological profile with morphine, can be used for the management of neuropathic pain.

  1. Neuropathic pain and pharmacological treatment.

    Science.gov (United States)

    Jongen, Joost L M; Hans, Guy; Benzon, Honorio T; Huygen, Frank; Hartrick, Craig T

    2014-03-01

    Neuropathic pain is a serious chronic condition strongly affecting quality of life, which can be relieved but cannot be cured. Apart from symptomatic management, treatment should focus on the underlying disorder. The estimated prevalence is at least 1% to 5% of the general population. Neuropathic pain is characterized both by spontaneous and evoked pain. A diagnosis of neuropathic pain can usually be established based solely on history and neurological examination. Ancillary investigations may include EMG and computerized tomography/magnetic resonance imaging scans, depending on the localization of the suspected lesion. A limited number of agents, primarily directed at symptom control, are currently approved for use in neuropathic pain. A mechanism-based approach to pharmacological intervention supports the use of polypharmacy in neuropathic pain.

  2. The effect of Sativex in neuropathic pain and spasticity in spinal cord injury

    DEFF Research Database (Denmark)

    Andresen, Sven Robert; Hansen, Rikke Bod Middelhede; Johansen, Inger Lauge

    2014-01-01

    Introduction: Neuropathic pain and spasticity after spinal cord injury represent significant but still unresolved problems, which cause considerable suffering and reduced quality of life for patients with spinal cord injury. Treatment of neuropathic pain and spasticity is complicated and patients...... injury. Aims: To investigate the effect of Sativex (cannabinoid agonist given as an oral mucosal spray), on neuropathic pain and spasticity in patients with spinal cord injury. Methods: A randomized, double-blind, placebo-controlled crossover study. We will include 30 patients with neuropathic pain...

  3. Translational investigation and treatment of neuropathic pain

    OpenAIRE

    2012-01-01

    Abstract Neuropathic pain develops from a lesion or disease affecting the somatosensory system. Translational investigations of neuropathic pain by using different animal models reveal that peripheral sensitization, spinal and cortical plasticity may play critical roles in neuropathic pain. Furthermore, descending facilitatory or excitatory modulation may also act to enhance chronic pain. Current clinical therapy for neuropathic pain includes the use of pharmacological and nonpharmacological ...

  4. PUNICA GRANATUM ATTENUATES SCIATIC NERVE LIGATION INDUCED-NEUROPATHIC PAIN

    Directory of Open Access Journals (Sweden)

    Ramica Sharma et al.

    2012-02-01

    Full Text Available The study has been designed to investigate the effect of aqueous extract of rind of Punica granatum in sciatic nerve ligation induced-neuropathic pain in rats. Surgical procedure was performed with sciatic nerve ligation to develop neuropathic pain in rats. The development of neuropathic pain was assessed by employing behaviour parameters such as hyperalgesia and allodynia. Further, the functionality of sciatic nerve was assessed using the histopathological study of myelinated and unmyelinated fibers in sciatic nerve. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances (TBARS, catalase, glutathione and tissue TBARS and Superoxide dismutase (SOD. Rats exposed to sciatic nerve ligation produced marked increase in oxidative stress, which was assessed in terms of TBARS and SOD along with decrease in the level of catalase and glutathione. Moreover, it develops neuropathic pain by impairing the normal functions of myelinated and unmyelinated fibers in sciatic nerve. Treatment with aqueous extract of Punica granatum extract (100mg/kg, p.o markedly prevented sciatic nerve ligation-induced neuropathy and oxidative stress by increasing the pain threshold, by improving the functionality of sciatic nerve, by decreasing serum and tissue TBARS and tissue SOD, by increasing levels of serum glutathione and catalase. It may be concluded that Punica granatum extract reduced the oxidative stress via inhibiting p38MAPK and alleviates neuropathic symptoms and consequently improved the functionality of sciatic nerve and prevents sciatic nerve ligation–induced neuropathic pain.

  5. Topical phenytoin for the treatment of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Kopsky DJ

    2017-02-01

    Full Text Available David J Kopsky,1 Jan M Keppel Hesselink2 1Institute for Neuropathic Pain, Amsterdam, 2Institute for Neuropathic Pain, Bosch en Duin, the Netherlands Abstract: We developed and tested a new putative analgesic cream, based on the anticonvulsant phenytoin in patients suffering from treatment refractory neuropathic pain. The use of commercial topical analgesics is not widespread due to the facts that capsaicin creams or patches can give rise to side effects, such as burning, and analgesic patches (e.g., lidocaine 5% patches have complex handling, especially for geriatric patients. Only in a few countries, compounded creams based on tricyclic antidepressants or other (co-analgesics are available. Such topical analgesic creams, however, are easy to administer and have a low propensity for inducing side effects. We, therefore, developed a new topical cream based on 5% and 10% phenytoin and described three successfully treated patients suffering from neuropathic pain. All patients were refractory to a number of other analgesics. In all patients, phenytoin cream was effective in reducing pain completely, without any side effects, and the tolerability was excellent. The onset of action of the phenytoin creams was within 30 minutes. Phenytoin cream might become a new treatment modality of the treatment of neuropathic pain. Keywords: phenytoin, topical administration, neuropathic pain, diabetic neuropathy, chemotherapy-induced polyneuropathy, analgesia, drug repositioning

  6. The neuropathic diabetic foot.

    Science.gov (United States)

    Rathur, Haris M; Boulton, Andrew J M

    2007-01-01

    Diabetic foot problems are common throughout the world, and result in major medical, social and economic consequences for the patients, their families, and society. Foot ulcers are likely to be of neuropathic origin and, therefore, are eminently preventable. Individuals with the greatest risk of ulceration can easily be identified by careful clinical examination of their feet: education and frequent follow-up is indicated for these patients. When infection complicates a foot ulcer, the combination can be limb-threatening, or life-threatening. Infection is defined clinically, but wound cultures assist in identification of causative pathogens. Tissue specimens are strongly preferred to wound swabs for wound cultures. Antimicrobial therapy should be guided by culture results, and although such therapy may cure the infection, it does not heal the wound. Alleviation of the mechanical load on ulcers (offloading) should always be a part of treatment. Plantar neuropathic ulcers typically heal in 6 weeks with nonremovable casts, because pressure at the ulcer site is mitigated and compliance is enforced. The success of other approaches to offloading similarly depends on the patient's adherence to the strategy used for pressure relief.

  7. Neuropathic pain management in children.

    LENUS (Irish Health Repository)

    Hyde, Catherine

    2012-10-01

    There are difficulties in assessing, managing, and evaluating neuropathic pain in dying children, particularly those with neurological impairment. Neuropathic pain in children often presents differently to how it presents in the adult population. Comprehensive assessment as well as pharmacological and non-pharmacological interventions are crucial to its successful management and frequently require input from an interdisciplinary team. Notwithstanding the need for further research, this paper brings together research papers, reviews, and clinical guidelines to present an exploration of existing evidence regarding care for children with neuropathic pain and their families.

  8. Translational investigation and treatment of neuropathic pain

    Science.gov (United States)

    2012-01-01

    Neuropathic pain develops from a lesion or disease affecting the somatosensory system. Translational investigations of neuropathic pain by using different animal models reveal that peripheral sensitization, spinal and cortical plasticity may play critical roles in neuropathic pain. Furthermore, descending facilitatory or excitatory modulation may also act to enhance chronic pain. Current clinical therapy for neuropathic pain includes the use of pharmacological and nonpharmacological (psychological, physical, and surgical treatment) methods. However, there is substantial need to better medicine for treating neuropathic pain. Future translational researchers and clinicians will greatly facilitate the development of novel drugs for treating chronic pain including neuropathic pain. PMID:22400804

  9. Molecular mechanisms underlying the effects of acupuncture on neuropathic pain**

    Institute of Scientific and Technical Information of China (English)

    Ziyong Ju; Huashun Cui; Xiaohui Guo; Huayuan Yang; Jinsen He; Ke Wang

    2013-01-01

    Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity fol owing chronic constriction injury, es-pecial y electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function.

  10. Puerarin Alleviates Neuropathic Pain by Inhibiting Neuroinflammation in Spinal Cord

    Directory of Open Access Journals (Sweden)

    Ming Liu

    2014-01-01

    Full Text Available Neuropathic pain responds poorly to drug treatments, and partial relief is achieved in only about half of the patients. Puerarin, the main constituent of Puerariae Lobatae Radix, has been used extensively in China to treat hypertension and tumor. The current study examined the effects of puerarin on neuropathic pain using two most commonly used animal models: chronic constriction injury (CCI and diabetic neuropathy. We found that consecutive intrathecal administration of puerarin (4–100 nM for 7 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models puerarin inhibited the activation of microglia and astroglia in the spinal dorsal horn. Puerarin also reduced the upregulated levels of nuclear factor-κB (NF-κB and other proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. In summary, puerarin alleviated CCI- and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal cord. The anti-inflammation effect of puerarin might be related to the suppression of spinal NF-κB activation and/or cytokines upregulation. We conclude that puerarin has a significant effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.

  11. Neuropathic pain in children.

    Science.gov (United States)

    Howard, Richard F; Wiener, Suzanne; Walker, Suellen M

    2014-01-01

    Neuropathic pain (NP), due to a lesion or disease of the somatosensory nervous system, is not well documented or researched in children. NP is a clinical diagnosis that can be difficult, especially in younger children. Nevertheless, it is important to recognise NP, as pain mechanisms and consequently management and prognosis differ from other types of long-term pain. NP is common in adult pain clinics but many of the underlying disease states in which it occurs are infrequently or never encountered in paediatric practice. However, NP in childhood has been reported, even in the very young in certain clinical situations. Causes of NP include traumatic injury, complex regional pain syndrome type II, cancer and chemotherapy, chronic infection, neurological and metabolic disease, and inherited sensory nerve dysfunction. The clinical and laboratory study of traumatic peripheral nerve injury has revealed important age-related differences in clinical presentation and prognosis. It is clear that mechanisms operating during development can profoundly modify the consequences of nerve damage and NP. Clinically, diagnosis, assessment and treatment of NP are based on methods and evidence derived from data in adults. Improvements in the understanding and management of NP are likely to come from developmentally appropriate improvements in the clarity and consistency of diagnosis and systematic, well-researched approaches to treatment.

  12. Placebo, nocebo, and neuropathic pain.

    Science.gov (United States)

    Vase, Lene; Skyt, Ina; Hall, Kathryn T

    2016-02-01

    Over the last decade, the apparent increase in placebo responses in randomized controlled trials (RCTs) of neuropathic pain have complicated and potentially limited development and availability of new effective pain medication. Placebo analgesia and nocebo hyperalgesia effects are well described in nociceptive and idiopathic pain conditions, but less is known about the magnitude and mechanisms of placebo and nocebo effects in neuropathic pain. In neuropathic pain, placebo treatments have primarily been used as control conditions for active agents under investigation in RCTs and these placebo responses are typically not controlled for the natural history of pain and other confounding factors. Recently, mechanistic studies that control for the natural history of pain have investigated placebo and nocebo effects in neuropathic pain in their own right. Large placebo analgesia but no nocebo hyperalgesic effects have been found, and the underlying mechanisms are beginning to be elucidated. Here we review placebo and nocebo effects and the underlying mechanisms in neuropathic pain and compare them with those of nociceptive and idiopathic pain. This allows for a novel discussion on how knowledge of psychological, neurobiological, and genetic factors underlying well-controlled placebo effects may help improve the information that can be obtained from and potentially restore the utility of RCTs.

  13. Neuropathic pain: epidemiology, risk factors and prevention

    OpenAIRE

    Kamerman, Peter

    2016-01-01

    Neuropathic pain: epidemiology, risk factors and prevention. Presented in a teaching workshop at the 22nd World Congress of Neurology, Santiago, Chile, 2015 (Workshop title: Neuropathic pain - advice for clinical practice; chair: AL Oaklander, USA).The presentation covers the epidemiology of neuropathic pain.

  14. Electroacupuncture Reduces the Effects of Acute Noxious Stimulation on the Electrical Activity of Pain-Related Neurons in the Hippocampus of Control and Neuropathic Pain Rats

    Directory of Open Access Journals (Sweden)

    Jun-Ying Wang

    2016-01-01

    Full Text Available To study the effects of acupuncture analgesia on the hippocampus, we observed the effects of electroacupuncture (EA and mitogen-activated protein kinase (MEK inhibitor on pain-excited neurons (PENs and pain-inhibited neurons (PINs in the hippocampal area CA1 of sham or chronic constrictive injury (CCI rats. The animals were randomly divided into a control, a CCI, and a U0126 (MEK1/2 inhibitor group. In all experiments, we briefly (10-second duration stimulated the sciatic nerve electrically and recorded the firing rates of PENs and PINs. The results showed that in both sham and CCI rats brief sciatic nerve stimulation significantly increased the electrical activity of PENs and markedly decreased the electrical activity of PINs. These effects were significantly greater in CCI rats compared to sham rats. EA treatment reduced the effects of the noxious stimulus on PENs and PINs in both sham and CCI rats. The effects of EA treatment could be inhibited by U0126 in sham-operated rats. The results suggest that EA reduces effects of acute sciatic nerve stimulation on PENs and PINs in the CA1 region of the hippocampus of both sham and CCI rats and that the ERK (extracellular regulated kinase signaling pathway is involved in the modulation of EA analgesia.

  15. The effect of progesterone on expression and development of neuropathic pain in a rat model of peripheral neuropathy.

    Science.gov (United States)

    Verdi, Javad; Jafari-Sabet, Majid; Mokhtari, Rasool; Mesdaghinia, Azam; Banafshe, Hamid Reza

    2013-01-15

    Neuropathic pain results from lesions or diseases affecting the somatosensory system. The management of patients with chronic neuropathic pain remains a challenge. Several studies support the crucial role of neuroactive steroids in the modulation of pain. The present study was designed to investigate the effect of systemic administration of progesterone on expression and development of hyperalgesia and allodynia scores in chronic constriction injury model of neuropathic pain in rat. Progesterone at doses of 5, 10 and 15 mg/kg and its vehicle were injected intraperitoneally on days 1-13 after the surgery to study the effect of progesterone on development of neuropathic pain and only on 14th day post-surgery in order to assess its effect on expression of neuropathic pain.The chronic administration of progesterone significantly reduced the behavioral scores of cold- and mechano-allodynia and heat hyperalgesia but single dose of progesterone did not have any effect on behavioral scores of neuropathic pain. Our data indicate that the early chronic administration of progesterone prevents the development of neuropathic pain but its acute injection does not change the expression of neuropathic pain. These results suggest that progesterone could be considered as a new approach for management of neuropathic pain. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Nurse’s knowledge of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Ali Yavuz Karahan

    2014-08-01

    Full Text Available The aim of our study was to determine the levels of information and awareness of the nurses who work on neuropathic pain in the departments of physical medicine and rehabilitation, neurology and neurosurgery. A total of 60 nurses (20 per each department who work in the physical medicine and rehabilitation, neurology and neurosurgery departments of Beyhekim State Hospital of Konya in Turkey took part in the study. The level of information and awareness of the nurses on neuropathic pain were assessed via a questionnaire prepared by specialists in the light of recent literature. The questionnaire was composed of 30 questions including the definition, symptoms, treatment and management of neuropathic pain. None of 60 nurses participating in the study were given any previous in-service training on neuropathic pain. According to the assessments, 80% of nurses (48 were found not to have sufficient knowledge about definition of neuropathic pain; 83.3% (50 about diseases causing neuropathic pain; 83.3% (50 about symptoms of neuropathic pain; and 90% (54 about management of neuropathic pain. The findings obtained from the nurses of these three departments showed no statistically significant relation. Our findings indicated that the knowledge of participants’ about neuropathic pain who work in these three departments seriously lack of information. Informing nurses about neuropathic pain during in-service training will be an important step towards improving the quality of services provided.

  17. MicroRNA-93 alleviates neuropathic pain through targeting signal transducer and activator of transcription 3.

    Science.gov (United States)

    Yan, Xue-Tao; Ji, Li-Juan; Wang, Zhiyu; Wu, Xingjun; Wang, Quan; Sun, Shujie; Lu, Jing-Min; Zhang, Yang

    2017-05-01

    Emerging evidence suggests that microRNAs (miRNAs) play a critical role in the pathogenesis of neuropathic pain. However, the exact role of miRNAs in regulating neuropathic pain remains largely unknown. In this study, we aimed to investigate the potential role of miR-93 in a rat model of neuropathic pain induced by chronic constriction sciatic nerve injury (CCI). We found a significant decrease of miR-93 in the spinal cord of CCI rats compared with sham rats. Overexpression of miR-93 significantly alleviated neuropathic pain development and reduced inflammatory cytokine expression, including interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 in CCI rats. By bioinformatic analysis and dual-luciferase reporter assay, we found that miR-93 directly targeted the 3'-untranslated region (UTR) of signal transducer and activator of transcription 3 (STAT3), an important regulator of inflammation. Overexpression of miR-93 markedly suppressed the expression of STAT3 in vitro and in vivo. Furthermore, overexpression of STAT3 significantly reversed the miR-93 overexpression-induced suppressive effects on neuropathic pain development and neuroinflammation. Taken together, our study suggests that miR-93 inhibits neuropathic pain development of CCI rats possibly through inhibiting STAT3-mediated neuroinflammation. Our findings indicate that miR-93 may serve as a novel therapeutic target for neuropathic pain intervention. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. MiR-150 alleviates neuropathic pain via inhibiting toll-like receptor 5.

    Science.gov (United States)

    Ji, Li-Juan; Shi, Jing; Lu, Jing-Min; Huang, Qiang-Min

    2017-07-07

    MicroRNAs (miRNAs) are reported as vital participators in the pathophysiological course of neuropathic pain. However, the underlying mechanisms of the functional roles of miRNAs in neuropathic pain are largely unknown. This study was designed to explore the potential role of miR-150 in regulating the process of neuropathic pain in a rat model established by chronic sciatic nerve injury (CCI). Overexpression of miR-150 greatly alleviated neuropathic pain development and reduced inflammatory cytokine expression, including COX-2, interleukin IL-6, and tumor necrosis factor (TNF)-α in CCI rats. By bioinformatic analysis, 3'-untranslated region (UTR) of Toll-like receptor (TLR5) was predicted to be a target of miR-150. TLR5 commonly serves as an important regulator of inflammation. Overexpression of miR-150 significantly suppressed the expression of TLR5 in vitro and in vivo. Furthermore, upregulation of TLR5 decreased the miR-150 expression and downregulation of TLR5 increased miR-150, respectively. Overexpression of TLR5 significantly reversed the miR-150-induced suppressive effects on neuropathic pain. In conclusion, our current study indicates that miR-150 may inhibit neuropathic pain development of CCI rats through inhibiting TLR5-mediated neuroinflammation. Our findings suggest that miR-150 may provide a novel therapeutic target for neuropathic pain treatment. © 2017 Wiley Periodicals, Inc.

  19. Beyond neuropathic pain: gabapentin use in cancer pain and perioperative pain.

    Science.gov (United States)

    Yan, Peter Z; Butler, Paul M; Kurowski, Donna; Perloff, Michael D

    2014-07-01

    Gabapentin (GBP), originally an antiepileptic drug, is more commonly used in the treatment of neuropathic pain. In recent years, GBP has been used as an adjunct or primary therapy in non-neuropathic pain, most commonly for the treatment of perioperative and cancer pain. The aim of this study was to conduct a clinical evidence literature review of GBP's use in perioperative pain and cancer pain. Using PUBMED and OVID Medline databases, keyword searches for surgery and cancer in reference to GBP and pain were carried out. Nonblinded studies and case reports that did not present a unique finding were excluded. Studies that focused only on neuropathic pain were also excluded. An initial 142 references focusing on GBP's use in surgical pain and cancer pain were identified. Of these, 48 studies were quality of evidence at a level of II-2 or higher. Although efficacy varies, multiple well-designed clinical trials have demonstrated reduced pain and analgesic use with otolaryngology, orthopedic, mastectomy, and abdominal/pelvic surgical perioperative use of GBP, whereas there is limited or no efficacy for cardiothoracic surgery. Cancer pain studies have had greater design variability, often nonblinded, with pain benefit being mild to moderate, and more efficacious with partial neuropathic pain quality. Overall, GBP seems to have significant benefit in neuropathic and non-neuropathic pain associated with the perioperative period and cancer. Considering its favorable side effect profile, GBP represents a beneficial pain adjunctive therapy, beyond neuropathic symptoms.

  20. NOX4 is an early initiator of neuropathic pain.

    Science.gov (United States)

    Geis, Christian; Geuss, Eva; Sommer, Claudia; Schmidt, Harald H H W; Kleinschnitz, Christoph

    2017-02-01

    Treatment of neuropathic pain remains challenging as the etiology is heterogeneous and pathomechanisms are incompletely understood. One possible mechanism is oxidative stress due to unphysiological reactive oxygen species (ROS) formation. The only know dedicated enzymatic source of ROS are NADPH oxidases of which the type 4 isoform (NOX4) has been suggested to be involved in the subacute and chronic phase of neuropathic pain. Here, we aim to translate this finding into a treatment strategy by examining the efficacy of the NOX1/4-specific inhibitor GKT136901 using the chronic constriction injury (CCI) mouse model of neuropathic pain. Unexpectedly, post-nerve lesion treatment using GKT136901 was ineffective to reduce pain-related behavior after CCI. We therefore re-investigated the role of NOX4 using an independent KO mouse model. Early after CCI we found an increase in pro-inflammatory cytokines, ROS formation and the oxidative stress marker nitrotyrosine in the lesioned nerve together with an upregulated Nox4 gene expression. In NOX4 KO mice, mechanical allodynia was markedly reduced from day 4 after nerve injury as were all ROS related and acute biomarkers. In addition, we observed a reduction in the CCI-induced upregulation of pro-inflammatory cytokines in the sciatic nerve and dorsal root ganglia along with NOX4-deficiency. Thus, we conclude that NOX4 is involved in the development of neuropathic pain states by producing oxidative stress and subsequent cytokine dysregulation at the lesion site. This appears at very early stages immediately after nerve injury explaining ineffectiveness of post-acute pharmacological NOX inhibition. We suggest that future target validation of NOX4 should now focus on defining the possible therapeutic window in human neuropathic pain. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Neuropathic Pain in Elderly Patients with Chronic Low Back Painand Effects of Pregabalin: A Preliminary Study

    Science.gov (United States)

    Ito, Kenyu; Hida, Tetsuro; Ito, Sadayuki; Harada, Atsushi

    2015-01-01

    Study Design Preliminary study. Purpose To assess the association of neuropathic pain with chronic low back pain (LBP) and the effect of pregabalin on neuropathic pain in the elderly. Overview of Literature Of those with chronic LBP, 37% were predominantly presenting with neuropathic pain in young adults. Pregabalin is effective for pain in patients with diabetic neuropathy and peripheral neuralgia. No study has reported on the effects of pregabalin for chronic LBP in elderly patients yet. Methods Pregabalin was administered to 32 patients (age, ≥65 years) with chronic LBP for 4 weeks. Pain and activities of daily living were assessed using the Neuropathic Pain Screening Questionnaire (NePSQ), the pain DETECT questionnaire, visual analog scale, the Japanese Orthopedic Association score, the short form of the McGill Pain Questionnaire and the Roland Morris Disability Questionnaire. Modic change and spinal canal stenosis were investigated using magnetic resonance imaging. Results Altogether, 43.3% of patients had neuropathic pain according to the NePSQ and 15.6% patients had pain according to the pain DETECT. The efficacy rate of pregabalin was 73.3%. A significant effect was observed in patients with neuropathic pain after 4 weeks of administration. Conclusions Neuropathic pain was slightly less frequently associated with chronic LBP in the elderly. Pregabalin was effective in reducing pain in patients with chronic LBP accompanied with neuropathic pain. Lumbar spinal stenosis and lower limb symptoms were observed in patients with neuropathic pain. We recommend the use of pregabalin for patients after evaluating a screening score, clinical symptoms and magnetic resonance imaging studies. PMID:25901238

  2. Animal model of neuropathic tachycardia syndrome

    Science.gov (United States)

    Carson, R. P.; Appalsamy, M.; Diedrich, A.; Davis, T. L.; Robertson, D.

    2001-01-01

    Clinically relevant autonomic dysfunction can result from either complete or partial loss of sympathetic outflow to effector organs. Reported animal models of autonomic neuropathy have aimed to achieve complete lesions of sympathetic nerves, but incomplete lesions might be more relevant to certain clinical entities. We hypothesized that loss of sympathetic innervation would result in a predicted decrease in arterial pressure and a compensatory increase in heart rate. Increased heart rate due to loss of sympathetic innervation is seemingly paradoxical, but it provides a mechanistic explanation for clinical autonomic syndromes such as neuropathic postural tachycardia syndrome. Partially dysautonomic animals were generated by selectively lesioning postganglionic sympathetic neurons with 150 mg/kg 6-hydroxydopamine hydrobromide in male Sprague-Dawley rats. Blood pressure and heart rate were monitored using radiotelemetry. Systolic blood pressure decreased within hours postlesion (Delta>20 mm Hg). Within 4 days postlesion, heart rate rose and remained elevated above control levels. The severity of the lesion was determined functionally and pharmacologically by spectral analysis and responsiveness to tyramine. Low-frequency spectral power of systolic blood pressure was reduced postlesion and correlated with the diminished tyramine responsiveness (r=0.9572, P=0.0053). The tachycardia was abolished by treatment with the beta-antagonist propranolol, demonstrating that it was mediated by catecholamines acting on cardiac beta-receptors. Partial lesions of the autonomic nervous system have been hypothesized to underlie many disorders, including neuropathic postural tachycardia syndrome. This animal model may help us better understand the pathophysiology of autonomic dysfunction and lead to development of therapeutic interventions.

  3. Diagnostic tools for neuropathic pain

    Directory of Open Access Journals (Sweden)

    CHEN Xiang-jun

    2013-09-01

    Full Text Available Neuropathic pain (NP is a kind of chronic, severe and persistent pain syndrome. Due to the underlying mechanisms, the treatment for NP differs from that of nociceptive pain. An accurate diagnosis of NP is very important. However, the present diagnostic process which mainly depends on clinical and neurophysiological assessments is quite time-consuming and low efficient. In recent years, various screening tools and drug efficacy assessments for NP have been developed and validated. They become very useful in the diagnosis and treatment of NP, as well as in epidemiological study. These tools are also very useful in elucidating the underlying mechanism of NP.

  4. Interventional therapy for neuropathic pain

    Directory of Open Access Journals (Sweden)

    YANG Yang

    2013-10-01

    Full Text Available Neuropathic pain (NP is a common clinical refractory pain for which there are limited methods to treat. In this article, based on typical diseases, such as postherpetic neuralgia (PHN, trigeminal neuralgia, complex regional pain syndrome (CRPS, lower back pain with radiculopathy and failed back surgery syndrome (FBSS, phantom pain, the general treatment principle and method for NP are expatiated. Interventional methods for NP, including intraspinal block, radiofrequeney rhizotomy of trigeminal neuralgia, selective nerve root block, spinal cord stimulation (SCS and motor cortex stimulation (MCS are introduced, especially their indications, complications and matters needing attention.

  5. Electroacupuncture versus celecoxib for neuropathic pain in rat SNL model.

    Science.gov (United States)

    Lau, W K; Lau, Y M; Zhang, H Q; Wong, S C; Bian, Z X

    2010-10-13

    Though acupuncture has long been used to treat various kinds of pain, its mechanisms remain partly understood. Our recent study has shown that it may inhibit cyclooxygenase-2 (COX-2) in the spinal dorsal horn where COX-2 is upregulated after the development of neuropathic pain following spinal nerve ligation (SNL). The current study directly compared the effect of acupuncture with COX-2 inhibitor celecoxib in the spinal cord after SNL in rats. After L5 SNL, the rats were treated either with acupuncture applied to Zusanli (ST36) and Sanyinjiao (SP6) bilaterally with or without electrical stimulation (2 Hz, 0.5-1-2 mA) four times over 22 days, and/or celecoxib fed daily. Paw-withdrawal-threshold to mechanical stimulation and paw-withdrawal-latency to thermal test were tested for neuropathic pain at four intervals following the treatments in comparison with the pre-treatment and non-treatment controls. The results demonstrate that electroacupuncture (EA) had a long lasting and better analgesic effect than celecoxib in reducing neuropathic hypersensitivity. Though COX-2 expression in the spinal L4-L6 dorsal horn by immunostaining was significantly reduced by acupuncture just as well as by celecoxib, the superior analgesic mechanism of acupuncture appears well beyond COX-2 inhibition alone.

  6. The neurosurgical treatment of neuropathic facial pain.

    Science.gov (United States)

    Brown, Jeffrey A

    2014-04-01

    This article reviews the definition, etiology and evaluation, and medical and neurosurgical treatment of neuropathic facial pain. A neuropathic origin for facial pain should be considered when evaluating a patient for rhinologic surgery because of complaints of facial pain. Neuropathic facial pain is caused by vascular compression of the trigeminal nerve in the prepontine cistern and is characterized by an intermittent prickling or stabbing component or a constant burning, searing pain. Medical treatment consists of anticonvulsant medication. Neurosurgical treatment may require microvascular decompression of the trigeminal nerve. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Neuropathic Pain in Patients with Sickle Cell Disease

    Science.gov (United States)

    Brandow, Amanda M.; Farley, Rebecca A.; Panepinto, Julie A.

    2015-01-01

    Background Despite the suggestion of a neuropathic component to sickle cell disease (SCD) pain, there are minimal data on the systematic assessment of neuropathic pain in patients with SCD. Neuropathic pain is defined as pain primarily initiated by dysfunction of the peripheral or central nervous system. Procedure In a cross-sectional study, we used the painDETECT questionnaire, a one-page validated neuropathic pain screening tool, to determine the presence of neuropathic pain in patients with SCD and to evaluate the relationship between neuropathic pain, age, and gender. We hypothesized that 20% of patients with SCD will experience neuropathic pain and that neuropathic pain will be associated with older age and female gender. The completed painDETECT questionnaire yields a total score between 0–38 (≥19=definite neuropathic pain, 13–18=probable neuropathic pain, ≤12=no neuropathic pain). Scores ≥13 were designated as having evidence of neuropathic pain. Results A total of 56 patients participated. Median age was 20.3 years and 77% were female. We found 37% of patients had evidence of neuropathic pain. Age was positively correlated with total score [r=0.43; p=0.001] suggesting older patients experience more neuropathic pain. Females had higher mean total scores [13 vs 8.4; p=0.04]. Significantly more patients with neuropathic pain were taking hydroxyurea [90% vs 59%; p=0.015]. Despite 37% of patients experiencing neuropathic pain, only 5% were taking a neuropathic pain drug. Conclusions Neuropathic pain exists in SCD. Valid screening tools can identify patients that would benefit from existing and future neuropathic pain therapies and could determine the impact of these therapies. PMID:24167104

  8. Topical phenytoin for the treatment of neuropathic pain

    Science.gov (United States)

    Kopsky, David J; Keppel Hesselink, Jan M

    2017-01-01

    We developed and tested a new putative analgesic cream, based on the anticonvulsant phenytoin in patients suffering from treatment refractory neuropathic pain. The use of commercial topical analgesics is not widespread due to the facts that capsaicin creams or patches can give rise to side effects, such as burning, and analgesic patches (e.g., lidocaine 5% patches) have complex handling, especially for geriatric patients. Only in a few countries, compounded creams based on tricyclic antidepressants or other (co-)analgesics are available. Such topical analgesic creams, however, are easy to administer and have a low propensity for inducing side effects. We, therefore, developed a new topical cream based on 5% and 10% phenytoin and described three successfully treated patients suffering from neuropathic pain. All patients were refractory to a number of other analgesics. In all patients, phenytoin cream was effective in reducing pain completely, without any side effects, and the tolerability was excellent. The onset of action of the phenytoin creams was within 30 minutes. Phenytoin cream might become a new treatment modality of the treatment of neuropathic pain. PMID:28280381

  9. EZH2 regulates spinal neuroinflammation in rats with neuropathic pain.

    Science.gov (United States)

    Yadav, Ruchi; Weng, Han-Rong

    2017-02-28

    Alteration in gene expression along the pain signaling pathway is a key mechanism contributing to the genesis of neuropathic pain. Accumulating studies have shown that epigenetic regulation plays a crucial role in nociceptive process in the spinal dorsal horn. In this present study, we investigated the role of enhancer of zeste homolog-2 (EZH2), a subunit of the polycomb repressive complex 2, in the spinal dorsal horn in the genesis of neuropathic pain in rats induced by partial sciatic nerve ligation. EZH2 is a histone methyltransferase, which catalyzes the methylation of histone H3 on K27 (H3K27), resulting in gene silencing. We found that levels of EZH2 and tri-methylated H3K27 (H3K27TM) in the spinal dorsal horn were increased in rats with neuropathic pain on day 3 and day 10 post nerve injuries. EZH2 was predominantly expressed in neurons in the spinal dorsal horn under normal conditions. The number of neurons with EZH2 expression was increased after nerve injury. More strikingly, nerve injury drastically increased the number of microglia with EZH2 expression by more than sevenfold. Intrathecal injection of the EZH2 inhibitor attenuated the development and maintenance of mechanical and thermal hyperalgesia in rats with nerve injury. Such analgesic effects were concurrently associated with the reduced levels of EZH2, H3K27TM, Iba1, GFAP, TNF-α, IL-1β, and MCP-1 in the spinal dorsal horn in rats with nerve injury. Our results highly suggest that targeting the EZH2 signaling pathway could be an effective approach for the management of neuropathic pain.

  10. PHARMACOTHERAPY IN ELDERLY NEUROPATHIC PAIN

    Directory of Open Access Journals (Sweden)

    Thomas Eko P

    2013-10-01

    Full Text Available Normal 0 false false false IN X-NONE X-NONE MicrosoftInternetExplorer4 The incidence of pain increases with age. Neuropathic pain are common in elderly patients and pose challenges in both their diagnosis and treatment. The most common neuropathic pain in elderly are radiculopathy due to foraminal or spinal stenosis, diabetic neuropathy, and postherpetic neuralgia. Pain in the elderly is often unrecognized and undertreated. The main problem with pain in older adults relates to impaired quality of life secondary to pain which may be expressed by depression (including increased suicide risk, anxiety, sleep disruption, appetite disturbance, and weight loss, cognitive impairment, and limitations in the performance of daily activities. Pain management in elderly patients requires a different perspective from that of younger patients. Causes, comorbidities, and responses to both pain and its treatment differ between young healthy and older patients. Effective pain management in elderly patients should include both pharmacologic and nonpharmacologic strategies. Pharmacological approaches are the first line of pain management in older person for neuropathic pain. Pharmacologic strategies call for administration of nonopioid analgesics, opioid analgesics, and adjuvant medication. Polypharmacy, drug-drug and drug-disease interactions, age-associated changes in drug metabolism, and the high frequency of adverse drug reactions need to be carefully considered in using medications in this population /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso

  11. Neuroinflammation and the generation of neuropathic pain

    National Research Council Canada - National Science Library

    Ellis, A; Bennett, D L H

    2013-01-01

    .... Diverse causes of neuropathic pain are associated with excessive inflammation in both the peripheral and central nervous system which may contribute to the initiation and maintenance of persistent pain...

  12. Neuropathic pain: targeting the melatonin MT receptor

    African Journals Online (AJOL)

    (originating from injury to the brain or spinal cord) or peripheral. (originating from injury to the ... also diagnose neuropathic pain if a nerve lesion is found.9 The patient's sensory abilities ... Lancinating, shooting, electric-like, stabbing pain.

  13. [Neuromodulation in severe neuropathic pain].

    Science.gov (United States)

    van Dongen, Robert T M; Samwel, Han; Arnts, Inge J J; Steegers, Monique A H; Joosten, Elbert A; van Kleef, Maarten

    2015-01-01

    Pain relief in patients with chronic neuropathic pain can be difficult to accomplish. If pharmacological treatment combined with a form of physical therapy and psychological support does not lead to improvement, nerve blocks and rehabilitation can be considered. Appropriately screened patients with persistent incapacitating pain may respond to neuromodulation. A specific form of this technique - spinal cord stimulation - delivers electric pulses via an implanted electrode connected to a battery in the epidural space around the spinal cord. We describe three patients, two of whom had persistent leg pain after disc surgery. The third patient suffered from diabetic neuropathy. Despite thorough pre-procedural screening by an anaesthetist-pain specialist, psychologist, physical therapist and specialised nurse, spinal cord stimulation failed in one patient. Psycho-social factors, inadequate coping skills and depression may lead to inadequate improvement and failure of this therapy.

  14. Neuropathic pain due to fibromatosis: Does anticancer treatment help?

    Directory of Open Access Journals (Sweden)

    David Mathew

    2011-01-01

    Full Text Available Desmoid fibromatosis, although histologically benign, infiltrates local structures. The involvement of neural structures can lead to difficult neuropathic pain and the escalating use of analgesics. We report a patient with desmoid fibromatosis of the chest wall causing brachial plexus infiltration. As the tumor was locally invasive and unresectable, he was treated with radiation therapy and oral tamoxifen. On follow-up, there was significant pain relief, sustained reduction in the tumor size, and reduced analgesic requirement. Antineoplastic treatments like local radiation therapy and targeted systemic therapy with hormones or other agents can be considered in the management of selected unresectable desmoid fibromatosis to improve symptom control and reduce polypharmacy.

  15. Peripheral sensory neuron injury contributes to neuropathic pain in experimental autoimmune encephalomyelitis

    Science.gov (United States)

    Wang, I-Ching; Chung, Chen-Yen; Liao, Fang; Chen, Chih-Cheng; Lee, Cheng-Han

    2017-01-01

    Multiple sclerosis (MS)-induced neuropathic pain deteriorates quality of life in patients but is often refractory to treatment. In experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, animals develop neuropathy and inflammation-induced tissue acidosis, which suggests the involvement of acid-sensing ion channels (ASICs). Also, peripheral neuropathy is reported in MS patients. However, the involvement of the peripheral nervous system (PNS) in MS neuropathic pain remains elusive. This study investigated the contribution of ASICs and peripheral neuropathy in MS-induced neuropathic pain. Elicited pain levels were as high in Asic1a−/−, Asic2−/− and Asic3−/− mice as wild-type mice even though only Asic1a−/− mice showed reduced EAE disease severity, which indicates that pain in EAE was independent of disease severity. We thus adopted an EAE model without pertussis toxin (EAEnp) to restrain activated immunity in the periphery and evaluate the PNS contribution to pain. Both EAE and EAEnp mice showed similar pain behaviors and peripheral neuropathy in nerve fibers and DRG neurons. Moreover, pregabalin significantly reduced neuropathic pain in both EAE and EAEnp mice. Our findings highlight the essential role of the PNS in neuropathic pain in EAE and pave the way for future development of analgesics without side effects in the CNS. PMID:28181561

  16. Molecular hydrogen attenuates neuropathic pain in mice.

    Directory of Open Access Journals (Sweden)

    Masanori Kawaguchi

    Full Text Available Neuropathic pain remains intractable and the development of new therapeutic strategies are urgently required. Accumulating evidence indicates that overproduction of oxidative stress is a key event in the pathogenesis of neuropathic pain. However, repeated intra-peritoneal or intrathecal injections of antioxidants are unsuitable for continuous use in therapy. Here we show a novel therapeutic method against neuropathic pain: drinking water containing molecular hydrogen (H2 as antioxidant. The effect of hydrogen on neuropathic pain was investigated using a partial sciatic nerve ligation model in mice. As indicators of neuropathic pain, temporal aspects of mechanical allodynia and thermal hyperalgesia were analysed for 3 weeks after ligation. Mechanical allodynia and thermal hyperalgesia were measured using the von Frey test and the plantar test, respectively. When mice were allowed to drink water containing hydrogen at a saturated level ad libitum after ligation, both allodynia and hyperalgesia were alleviated. These symptoms were also alleviated when hydrogen was administered only for the induction phase (from day 0 to 4 after ligation. When hydrogen was administered only for the maintenance phase (from day 4 to 21 after ligation, hyperalgesia but not allodynia was alleviated. Immunohistochemical staining for the oxidative stress marker, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine, showed that hydrogen administration suppressed oxidative stress induced by ligation in the spinal cord and the dorsal root ganglion. In conclusion, oral administration of hydrogen water may be useful for alleviating neuropathic pain in a clinical setting.

  17. Molecular Hydrogen Attenuates Neuropathic Pain in Mice

    Science.gov (United States)

    Kawaguchi, Masanori; Satoh, Yasushi; Otsubo, Yukiko; Kazama, Tomiei

    2014-01-01

    Neuropathic pain remains intractable and the development of new therapeutic strategies are urgently required. Accumulating evidence indicates that overproduction of oxidative stress is a key event in the pathogenesis of neuropathic pain. However, repeated intra-peritoneal or intrathecal injections of antioxidants are unsuitable for continuous use in therapy. Here we show a novel therapeutic method against neuropathic pain: drinking water containing molecular hydrogen (H2) as antioxidant. The effect of hydrogen on neuropathic pain was investigated using a partial sciatic nerve ligation model in mice. As indicators of neuropathic pain, temporal aspects of mechanical allodynia and thermal hyperalgesia were analysed for 3 weeks after ligation. Mechanical allodynia and thermal hyperalgesia were measured using the von Frey test and the plantar test, respectively. When mice were allowed to drink water containing hydrogen at a saturated level ad libitum after ligation, both allodynia and hyperalgesia were alleviated. These symptoms were also alleviated when hydrogen was administered only for the induction phase (from day 0 to 4 after ligation). When hydrogen was administered only for the maintenance phase (from day 4 to 21 after ligation), hyperalgesia but not allodynia was alleviated. Immunohistochemical staining for the oxidative stress marker, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine, showed that hydrogen administration suppressed oxidative stress induced by ligation in the spinal cord and the dorsal root ganglion. In conclusion, oral administration of hydrogen water may be useful for alleviating neuropathic pain in a clinical setting. PMID:24941001

  18. Synergistic Interaction Between Dexmedetomidine and Ulinastatin Against Vincristine-Induced Neuropathic Pain in Rats.

    Science.gov (United States)

    Nie, Bilin; Zhang, Subo; Huang, Zhuxi; Huang, Jingxiu; Chen, Xiaodi; Zheng, Yaochao; Bai, Xiaohui; Zeng, Weian; Ouyang, Handong

    2017-07-08

    Antimicrotubulin chemotherapeutic agents such as vincristine (VCR), often induce peripheral neuropathic pain. It is usually permanent and seriously harmful to cancer patients' quality of life and can result in the hampering of clinical treatments. Currently, there is no definitive therapy, and many of the drugs approved for the treatment of other neuropathic pain have shown little or no analgesic effect. It is therefore vital to find new and novel therapeutic strategies for patients suffering from chemotherapeutic agent-induced neuropathic pain to improve patients' quality of life. This study shows that intrathecal injections of dexmedetomidine (DEX), or intraperitoneally administered ulinastatin (UTI) significantly reduces Sprague Dawley rats' mechanical allodynia induced by VCR via upregulation of interleukin-10 expression and activating the α2-adrenergic receptor in dorsal root ganglion (DRG). Moreover, when combined there is a synergistic interaction between DEX and UTI, which acts against VCR-induced neuropathic pain. This synergistic interaction between DEX and UTI may be partly attributed to a common analgesic pathway in which the upregulation of interleukin -10 plays an important role via activating α2-adrenergic receptor in rat dorsal root ganglion. The combined use of DEX and UTI does not affect the rat's blood pressure, heart rate, sedation, motor score, spatial learning, or memory function. All of these show that the combined use of DEX and UTI is an effective method in relieving VCR-induced neuropathic pain in rats. This article documents the synergistic interaction between 2 widely used drugs, DEX and UTI, against VCR-induced neuropathic pain. The results provide a potential target and novel drug administrated method for the clinical treatment of chemotherapy-induced peripheral neuropathic pain. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

  19. HIV Distal Neuropathic Pain Is Associated with Smaller Ventral Posterior Cingulate Cortex.

    Science.gov (United States)

    Keltner, John R; Connolly, Colm G; Vaida, Florin; Jenkinson, Mark; Fennema-Notestine, Christine; Archibald, Sarah; Akkari, Cherine; Schlein, Alexandra; Lee, Jisu; Wang, Dongzhe; Kim, Sung; Li, Han; Rennels, Austin; Miller, David J; Kesidis, George; Franklin, Donald R; Sanders, Chelsea; Corkran, Stephanie; Grant, Igor; Brown, Gregory G; Atkinson, J Hampton; Ellis, Ronald J

    2017-03-01

    . Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller. . HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images. . Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P  = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain. . The posterior cingulate is thought to be involved in inhibiting the perception of painful stimuli. Mechanistically a smaller posterior cingulate cortex structure may be related to reduced anti-nociception contributing to increased distal neuropathic pain.

  20. The effect of intrathecal gabapentin on mechanical and thermal hyperalgesia in neuropathic rats induced by spinal nerve ligation.

    OpenAIRE

    Cho, Hyun Sung; Kim, Myung Hee; Choi, Duck Hwan; LEE, JUNG IL; Gwak, Mi Sook; Hahm, Tae Soo

    2002-01-01

    Gabapentin decreases the level of glutamate and elevates that of alpha-amino-butyric acid in the central nervous system. Gabapentin was shown to have antinociceptive effects in several facilitated pain models. Intrathecal gabapentin was also known to be effective in reducing mechanical allodynia in animals with neuropathic pain. In this study, we investigated to see whether intrathecal gabapentin produces antihyperalgesic effects on thermal and mechanical hyperalgesia in neuropathic rats and ...

  1. AAPT Diagnostic Criteria for Central Neuropathic Pain.

    Science.gov (United States)

    Widerström-Noga, Eva; Loeser, John D; Jensen, Troels Staehelin; Finnerup, Nanna Brix

    2017-06-27

    Central neuropathic pain, which is pain caused by a lesion or disease of the central somatosensory nervous system, is a serious consequence of spinal cord injury, stroke, multiple sclerosis, and other conditions affecting the central nervous system. A collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership and the American Pain Society, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society Pain Taxonomy (AAPT) initiative, invited a working group to develop diagnostic criteria for central neuropathic pain. The criteria for central neuropathic pain that were developed expand upon existing criteria for neuropathic pain and the International Classification of Diseases 11th Revision draft criteria to ensure consistency. This article focuses on central neuropathic pain associated with spinal cord injury, stroke, and multiple sclerosis, but the AAPT framework can be extended to central pain due to other causes such as traumatic brain injury. The classification of central neuropathic pain is organized according to the AAPT multidimensional framework, specifically: 1) core diagnostic criteria, 2) common features, 3) common medical and psychiatric comorbidities, 4) neurobiological, psychosocial, and functional consequences, and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. The AAPT chronic central neuropathic pain taxonomy provides a classification for central pain associated with spinal cord injury, stroke, and multiple sclerosis. The diagnostic criteria are organized according to the AAPT multidimensional framework, specifically: 1) core diagnostic criteria, 2) common features, 3) common medical and psychiatric comorbidities, 4) neurobiological, psychosocial, and functional consequences, and 5) putative neurobiological and psychosocial

  2. [Case of acute exacerbation of neuropathic cancer pain rapidly relieved by simultaneous oral intake of immediate release oxycodone and pregabalin].

    Science.gov (United States)

    Baba, Mika; Gomwo, Ikuo

    2012-10-01

    Cancer pain consists of continuous pain lasting almost all day and transient exacerbation of pain called breakthrough pain. Breakthrough pain is classified as somatic pain and visceral pain, neuropathic pain according to the character of pain. Although the immediate release opioid is used as the first treatment of choice to breakthrough pain, the effect is not enough when it shows the character of neuropathic pain. Pregabalin has become the first medicine for the treatment of neuropathic pain, and it sometimes reveals prompt analgesic effect based on its pharmacological profile. It has also been reported that pregabalin used with oxycodine reveals analgesic effect with smaller dosage than pregabalin alone. We experienced a young patient with lung cancer suffering from sudden exacerbation of symptomatic sciatica, whose pain was markedly reduced within 30 minutes by taking immediate release oxycodone 5 mg and pregabalin 75 mg simultaneously. Conclusions : Pregabalin with immediate release oxycodone simultaneously may be able to improve acute exacerbation of neuropathic cancer pain rapidly.

  3. Statins alleviate experimental nerve injury-induced neuropathic pain.

    Science.gov (United States)

    Shi, Xiang Qun; Lim, Tony K Y; Lee, Seunghwan; Zhao, Yuan Qing; Zhang, Ji

    2011-05-01

    The statins are a well-established class of drugs that lower plasma cholesterol levels by inhibiting HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase. They are widely used for the treatment of hypercholesterolemia and for the prevention of coronary heart disease. Recent studies suggest that statins have anti-inflammatory effects beyond their lipid-lowering properties. We sought to investigate whether statins could affect neuropathic pain by mediating nerve injury-associated inflammatory responses. The effects of hydrophilic rosuvastatin and lipophilic simvastatin were examined in the mouse partial sciatic nerve ligation model. Systemic daily administration of either statin from days 0 to 14 completely prevented the development of mechanical allodynia and thermal hyperalgesia. When administered from days 8 to 14 after injury, both statins dose-dependently reduced established hypersensitivity. After treatment, the effects of the statins were washed out within 2 to 7 days, depending on dose. Effects of both statins in alleviating mechanical allodynia were further confirmed in a different injury-associated neuropathic pain model, mental nerve chronic constriction, in rats. Both statins were able to abolish interleukin-1β expression in sciatic nerve triggered by nerve ligation. Additionally, quantitative analysis with Iba-1 and glial fibrillary acid protein immunoreactivity demonstrated that rosuvastatin and simvastatin significantly reduced the spinal microglial and astrocyte activation produced by sciatic nerve injury. The increase of interleukin-1β mRNA in the ipsilateral side of spinal cords was also reduced by the treatment of either statin. We identified a potential new application of statins in the treatment of neuropathic pain. The pain-alleviating effects of statins are likely attributable to their immunomodulatory effects.

  4. Inhibition of Mammalian Target of Rapamycin (mTOR) Signaling in the Insular Cortex Alleviates Neuropathic Pain after Peripheral Nerve Injury.

    Science.gov (United States)

    Kwon, Minjee; Han, Jeongsoo; Kim, Un Jeng; Cha, Myeounghoon; Um, Sun Woo; Bai, Sun Joon; Hong, Seong-Karp; Lee, Bae Hwan

    2017-01-01

    Injury of peripheral nerves can trigger neuropathic pain, producing allodynia and hyperalgesia via peripheral and central sensitization. Recent studies have focused on the role of the insular cortex (IC) in neuropathic pain. Because the IC is thought to store pain-related memories, translational regulation in this structure may reveal novel targets for controlling chronic pain. Signaling via mammalian target of rapamycin (mTOR), which is known to control mRNA translation and influence synaptic plasticity, has been studied at the spinal level in neuropathic pain, but its role in the IC under these conditions remains elusive. Therefore, this study was conducted to determine the role of mTOR signaling in neuropathic pain and to assess the potential therapeutic effects of rapamycin, an inhibitor of mTORC1, in the IC of rats with neuropathic pain. Mechanical allodynia was assessed in adult male Sprague-Dawley rats after neuropathic surgery and following microinjections of rapamycin into the IC on postoperative days (PODs) 3 and 7. Optical recording was conducted to observe the neural responses of the IC to peripheral stimulation. Rapamycin reduced mechanical allodynia and downregulated the expression of postsynaptic density protein 95 (PSD95), decreased neural excitability in the IC, thereby inhibiting neuropathic pain-induced synaptic plasticity. These findings suggest that mTOR signaling in the IC may be a critical molecular mechanism modulating neuropathic pain.

  5. Cytokines in Neuropathic Pain and Associated Depression.

    Science.gov (United States)

    Lees, Justin G; Fivelman, Brett; Duffy, Samuel S; Makker, Preet G S; Perera, Chamini J; Moalem-Taylor, Gila

    2015-01-01

    Neuropathic pain occurs as a result of lesion or disease affecting the somatosensory nervous system and is present in a diverse set of peripheral and central pathologies such as nerve trauma, diabetic neuropathy, post-herpetic neuralgia, chemotherapy-induced peripheral neuropathy, spinal cord injury and multiple sclerosis. Debilitating symptoms including allodynia, hyperalgesia and spontaneous pain have a substantial negative impact on patients' quality of life. The currently available therapeutic treatments are generally ineffective and characterised by poor response rates. Accumulating evidence suggests that neuroinflammation and cytokine signalling play a critical role in neuropathic pain. Numerous experimental studies have demonstrated that certain pro-inflammatory cytokines are elevated in neuropathic pain conditions, and administration of these cytokines can elicit pain hypersensitivity in the absence of injury or disease. This phenomenon is also apparent in the 'sickness response', which encompasses a broad inflammatory response to disease and injury and involves a series of physiological and behavioural changes including pain hypersensitivity. Interestingly, the 'sickness response' is also similar in nature to some of the defining characteristics of the depressed state of affective disorder. In this review, we explore links that may relate the co-existence of depression in neuropathic pain patients with the activity of cytokines and discuss the role of several key pro-inflammatory and anti-inflammatory cytokines in neuropathic pain.

  6. Neurotrophins and Neuropathic Pain: Role in Pathobiology

    Directory of Open Access Journals (Sweden)

    Nemat Khan

    2015-06-01

    Full Text Available Neurotrophins (NTs belong to a family of trophic factors that regulate the survival, growth and programmed cell death of neurons. In mammals, there are four structurally and functionally related NT proteins, viz. nerve growth factor (NGF, brain-derived neurotrophic factor (BDNF, neurotrophin 3 and neurotrophin 4. Most research on NTs to date has focussed on the effects of NGF and BDNF signalling via their respective cognate high affinity neurotrophic tyrosine kinase viz TrkA and TrkB receptors. Apart from the key physiologic roles of NGF and BDNF in peripheral and central nervous system function, NGF and BDNF signalling via TrkA and TrkB receptors respectively have been implicated in mechanisms underpinning neuropathic pain. Additionally, NGF and BDNF signalling via the low-affinity pan neurotrophin receptor at 75 kDa (p75NTR may also contribute to the pathobiology of neuropathic pain. In this review, we critically assess the role of neurotrophins signalling via their cognate high affinity receptors as well as the low affinity p75NTR in the pathophysiology of peripheral neuropathic and central neuropathic pain. We also identify knowledge gaps to guide future research aimed at generating novel insight on how to optimally modulate NT signalling for discovery of novel therapeutics to improve neuropathic pain relief.

  7. A pharmacological treatment algorithm for localized neuropathic pain.

    Science.gov (United States)

    Allegri, Massimo; Baron, Ralf; Hans, Guy; Correa-Illanes, Gerardo; Mayoral Rojals, Victor; Mick, Gerard; Serpell, Michael

    2016-01-01

    Neuropathic pain is caused by a lesion or disease affecting the somatosensory system and is difficult to manage, often proving refractory to existing treatments. In more than half of cases, it is localized and affects a specific, clearly circumscribed area of the body (localized neuropathic pain, or LNP). A recently developed screening tool enables patients with probable neuropathic pain/LNP to be identified quickly and easily. In view of the conflicting current treatment recommendations, an advisory board of pain specialists met in June 2015 to develop a complementary treatment guidance algorithm, for use in the primary care setting and by non-pain specialists. The starting point of the algorithm is a diagnosis of LNP and there was consensus that first-line treatment should be a topical analgesic agent, because the benefit/risk ratios are far better than for systemic agents. Topical application offers site-specific delivery, a lower total systemic dose and avoidance of first-pass metabolism, reducing the risk of adverse events and drug/drug interactions. The 5% lidocaine medicated plaster has most evidence supporting its use in LNP, producing effective analgesia and reducing the associated area of allodynia, but other topical agents include capsaicin, clonidine and botulinum toxin type A. Treatment should be commenced with the topical agent of choice, and the patient re-assessed after an appropriate period. Where the response is good the topical agent is continued, with a re-evaluation after 3-6 months. A systemic agent (e.g. gabapentin, pregabalin, duloxetine, venlafaxine) is added if there is only a partial response, or substituted if there is no response, and the patient re-assessed after a month. If there is poor or no response to the systemic agent the patient should be switched to an alternative one and, if this also proves ineffective, referred to a pain specialist.

  8. AAPT Diagnostic Criteria for Central Neuropathic Pain

    DEFF Research Database (Denmark)

    Widerstrom-Noga, Eva; Loeser, John D.; Jensen, Troels Staehelin

    2017-01-01

    framework can be extended to central pain due to other causes such as traumatic brain injury. The classification of central neuropathic pain is organized according to the AAPT multidimensional framework, specifically (1) core diagnostic criteria; (2) common features; (3) common medical and psychiatric......Central neuropathic pain, which is pain caused by a lesion or disease of the central somatosensory nervous system, is a serious consequence of spinal cord injury, stroke, multiple sclerosis and other conditions affecting the central nervous system. A collaborative effort between the Analgesic......, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership and the American Pain Society (APS), the ACTTION-APS Pain Taxonomy (AAPT) initiative, invited a working group to develop diagnostic criteria for central neuropathic pain...

  9. Evidence for neuropathic processes in chronic cough.

    Science.gov (United States)

    Niimi, Akio; Chung, Kian Fan

    2015-12-01

    Chronic cough is a very common symptom for which patients seek medical attention but can often be difficult to manage, because associated causes may remain elusive and treatment of any associated causes does not always provide adequate relief. Current antitussives have limited efficacy and undesirable side-effects. Patients with chronic cough typically describe sensory symptoms suggestive of upper airway and laryngeal neural dysfunction. They often report cough triggered by low-level physical and chemical stimuli supporting the recently emerging concept of 'cough hypersensitivity syndrome'. Chronic cough is a neuropathic condition that could be secondary to sensory nerve damage caused by inflammatory, infective and allergic factors. Mechanisms underlying peripheral and central augmentation of the afferent cough pathways have been identified. Successful treatment of chronic cough with agents used for treating neuropathic pain, such as gabapentin and amitriptyline, would also support this concept. Further research of neuropathic cough may lead to the discovery of more effective antitussives in the future.

  10. Individualized pharmacological treatment of neuropathic pain.

    Science.gov (United States)

    Helfert, S M; Reimer, M; Höper, J; Baron, R

    2015-02-01

    Patients with the same disease may suffer from completely different pain symptoms yet receive the same drug treatment. Several studies elucidate neuropathic pain and treatment response in human surrogate pain models. They show promising results toward a patient stratification according to the mechanisms underlying the pain, as reflected in their symptoms. Several promising new drugs produced negative study results in clinical phase III trials. However, retrospective analysis of treatment response based on baseline pain phenotyping could demonstrate positive results for certain subgroups of patients. Thus, a prospective classification of patients according to pain phenotype may play an increasingly important role in personalized treatment of neuropathic pain states. A recent prospective study using stratification based on pain-related sensory abnormalities confirmed the concept of personalized pharmacological treatment of neuropathic pain.

  11. Somatosensory Profiles but Not Numbers of Somatosensory Abnormalities of Neuropathic Pain Patients Correspond with Neuropathic Pain Grading

    NARCIS (Netherlands)

    Konopka, Karl-Heinz; Harbers, Marten; Houghton, Andrea; Kortekaas, Rudie; van Vliet, Andre; Timmerman, Wia; den Boer, Johan A.; Struys, Michel M. R. F.; van Wijhe, Marten

    2012-01-01

    Due to the lack of a specific diagnostic tool for neuropathic pain, a grading system to categorize pain as 'definite', 'probable', 'possible' and 'unlikely' neuropathic was proposed. Somatosensory abnormalities are common in neuropathic pain and it has been suggested that a greater number of

  12. Advances in brain imaging of neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    CHEN Fu-yong; TAO Wei; LI Yong-jie

    2008-01-01

    Objective To review the literature on the use of brain imaging,including functional magnetic resonance imaging(fMRI), positron emission tomography(PET),magnetic resonance spectroscopy(MRS)and voxel-based morphometry(VBM)in investigation of the activity in diverse brain regions that creates and modulates chronic neuropathic pain. Data sources English literatures from January 1,2000 to July 31,2007 that examined human brain activity in chronic neuropathic pain were accessed through MEDLINE/CD ROM,using PET,fMRI,VBM,MRS and receptor binding. Study selection Published articles about the application of fMRI,PET,VBM,MRS and chronic neuropathic pain were selected. Data extraction Data were mainly extracted from 40 representative articles as the research basis. Results The PET studies suggested that spontaneous neuropathic pain is associated with changes in thalamic activity. Both PET and fMRI have been used to investigate the substrate of allodynia.The VBM demonstrated that brain structural changes are involved in chronic neuropathic pain,which is not seen in a matched control group.However,the results obtained had a large variety,which may be due to different pain etiology,pain distribution,lesion tomography,symptoms and stimulation procedures. Conclusions Application of the techniques of brain imaging plays a very important role in the study of structural and functional reorganization In patients with neuropathic pain.However,a unique"pain matrix" has not been defined.Future studies should be conducted using a prospective longitudinal research design,which would guarantee the control for many confounding factors.

  13. Maintaining efficacy in the treatment of diabetic peripheral neuropathic pain: role of duloxetine

    Directory of Open Access Journals (Sweden)

    Lindsay Zilliox

    2010-01-01

    Full Text Available Lindsay Zilliox1, James W Russell1,21Department of Neurology, Neuromuscular Division, The University of Maryland School of Medicine, 2VA Maryland Health Care System, Baltimore, MD, USAIntroduction: Neuropathy is one of the most frequent complications of diabetes. Of all the symptoms associated with diabetic neuropathy, pain has the largest impact on sleep and quality of life. In the past few years further medications have been added to the available therapies for neuropathic pain. One of these medications, duloxetine hydrochloride (duloxetine, is a balanced and potent selective serotonin and norepinephrine reuptake inhibitor.Methods: Medline was searched from January 2005 to September 2009 using the key words duloxetine and peripheral neuropathy for clinical trials limited to human research published in English and duloxetine and pharmacology in the nervous system.Results: Duloxetine has been shown to effectively reduce diabetic peripheral neuropathic pain compared to placebo at doses of 60 mg/day and 120 mg/day with minimal to moderate side effects. This effect is seen with minimal effects on glycemic control and without any clinically relevant effects on lipid control, or cardiovascular parameters. In addition, its efficacy and tolerability is comparable to other medications commonly used in the management of neuropathic pain. Furthermore, duloxetine performs favorably both in terms of quality of life and in cost utility analyses.Discussion and conclusion: This article reviewed the issues related to management of diabetic peripheral neuropathic pain, the pharmacology and rationale for use of duloxetine, efficacy studies, and the safety and tolerability of treatment with duloxetine. Duloxetine is an acceptable initial or alternative treatment for patients with diabetic neuropathic pain.Keywords: duloxetine, diabetic neuropathy, neuropathic pain

  14. Gene therapy for neuropathic pain by silencing of TNF-α expression with lentiviral vectors targeting the dorsal root ganglion in mice.

    Directory of Open Access Journals (Sweden)

    Nobuhiro Ogawa

    Full Text Available Neuropathic pain can be a debilitating condition. Many types of drugs that have been used to treat neuropathic pain have only limited efficacy. Recent studies indicate that pro-inflammatory mediators including tumor necrosis factor α (TNF-α are involved in the pathogenesis of neuropathic pain. In the present study, we engineered a gene therapy strategy to relieve neuropathic pain by silencing TNF-α expression in the dorsal root ganglion (DRG using lentiviral vectors expressing TNF short hairpin RNA1-4 (LV-TNF-shRNA1-4 in mice. First, based on its efficacy in silencing TNF-α in vitro, we selected shRNA3 to construct LV-TNF-shRNA3 for in vivo study. We used L5 spinal nerve transection (SNT mice as a neuropathic pain model. These animals were found to display up-regulated mRNA expression of activating transcription factor 3 (ATF3 and neuropeptide Y (NPY, injury markers, and interleukin (IL-6, an inflammatory cytokine in the ipsilateral L5 DRG. Injection of LV-TNF-shRNA3 onto the proximal transected site suppressed significantly the mRNA levels of ATF3, NPY and IL-6, reduced mechanical allodynia and neuronal cell death of DRG neurons. These results suggest that lentiviral-mediated silencing of TNF-α in DRG relieves neuropathic pain and reduces neuronal cell death, and may constitute a novel therapeutic option for neuropathic pain.

  15. The players involved in neuropathic pain pathophysiology

    Directory of Open Access Journals (Sweden)

    Francesco Amato

    2015-03-01

    Full Text Available The author presents a well documentated review on the receptorial mechanisms involved in the neuropathic pain physiopathology. In particular, the review focus on the role of TRPV1 receptors, on the processes subserving their sensitization and on the role of P2x4R microglial receptors.

  16. Importance of glial activation in neuropathic pain.

    Science.gov (United States)

    Mika, Joanna; Zychowska, Magdalena; Popiolek-Barczyk, Katarzyna; Rojewska, Ewelina; Przewlocka, Barbara

    2013-09-15

    Glia plays a crucial role in the maintenance of neuronal homeostasis in the central nervous system. The microglial production of immune factors is believed to play an important role in nociceptive transmission. Pain may now be considered a neuro-immune disorder, since it is known that the activation of immune and immune-like glial cells in the dorsal root ganglia and spinal cord results in the release of both pro- and anti-inflammatory cytokines, as well as algesic and analgesic mediators. In this review we presented an important role of cytokines (IL-1alfa, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-15, IL-18, TNFalpha, IFNgamma, TGF-beta 1, fractalkine and CCL2); complement components (C1q, C3, C5); metaloproteinases (MMP-2,-9) and many other factors, which become activated on spinal cord and DRG level under neuropathic pain. We discussed the role of the immune system in modulating chronic pain. At present, unsatisfactory treatment of neuropathic pain will seek alternative targets for new drugs and it is possible that anti-inflammatory factors like IL-10, IL-4, IL-1alpha, TGF-beta 1 would fulfill this role. Another novel approach for controlling neuropathic pain can be pharmacological attenuation of glial and immune cell activation. It has been found that propentofylline, pentoxifylline, minocycline and fluorocitrate suppress the development of neuropathic pain. The other way of pain control can be the decrease of pro-nociceptive agents like transcription factor synthesis (NF-kappaB, AP-1); kinase synthesis (MEK, p38MAPK, JNK) and protease activation (cathepsin S, MMP9, MMP2). Additionally, since it is known that the opioid-induced glial activation opposes opioid analgesia, some glial inhibitors, which are safe and clinically well tolerated, are proposed as potential useful ko-analgesic agents for opioid treatment of neuropathic pain. This review pointed to some important mechanisms underlying the development of neuropathic pain, which led to identify some possible

  17. Nav1.7 protein and mRNA expression in the dorsal root ganglia of rats with chronic neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    Chao Liu; Jing Cao; Xiuhua Ren; Weidong Zang

    2012-01-01

    Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in rats. Behavioral tests showed that the thresholds for thermal and mechanical hyperalgesia were significantly reduced in neuropathic pain rats 3-28 days following model induction. The results of immunohistochemistry,western blot assays and reverse transcription-PCR showed that Nav1.7 protein and mRNA expression was significantly increased in the injured dorsal root ganglia. These findings indicated that Nav1.7 might play an important role in the model of chronic neuropathic pain.

  18. Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse.

    Science.gov (United States)

    Yowtak, June; Wang, Jigong; Kim, Hee Young; Lu, Ying; Chung, Kyungsoon; Chung, Jin Mo

    2013-11-01

    One feature of neuropathic pain is a reduced spinal gamma-aminobutyric acid (GABA)-ergic inhibitory function. However, the mechanisms behind this attenuation remain to be elucidated. This study investigated the involvement of reactive oxygen species in the spinal GABA neuron loss and reduced GABA neuron excitability in spinal nerve ligation (SNL) model of neuropathic pain in mice. The importance of spinal GABAergic inhibition in neuropathic pain was tested by examining the effects of intrathecally administered GABA receptor agonists and antagonists in SNL and naïve mice, respectively. The effects of SNL and antioxidant treatment on GABA neuron loss and functional changes were examined in transgenic GAD67-enhanced green fluorescent protein positive (EGFP+) mice. GABA receptor agonists transiently reversed mechanical hypersensitivity of the hind paw in SNL mice. On the other hand, GABA receptor antagonists made naïve mice mechanically hypersensitive. Stereological analysis showed that the numbers of enhanced green fluorescent protein positive (EGFP+) GABA neurons were significantly decreased in the lateral superficial laminae (I-II) on the ipsilateral L5 spinal cord after SNL. Repeated antioxidant treatments significantly reduced the pain behaviors and prevented the reduction in EGFP+ GABA neurons. The response rate of the tonic firing GABA neurons recorded from SNL mice increased with antioxidant treatment, whereas no change was seen in those recorded from naïve mice, which suggested that oxidative stress impaired some spinal GABA neuron activity in the neuropathic pain condition. Together the data suggest that neuropathic pain, at least partially, is attributed to oxidative stress, which induces both a GABA neuron loss and dysfunction of surviving GABA neurons. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  19. Cerebral stimulation for the affective component of neuropathic pain.

    Science.gov (United States)

    Machado, Andre G; Baker, Kenneth B; Plow, Ela; Malone, Donald A

    2013-01-01

    To review the current state of cerebral stimulation for neuropathic pain and to propose that cerebral stimulation should aim also at the affective sphere of chronic pain rather than solely focusing on the primary sensory-discriminative sphere. The past and current goals of cerebral stimulation are reviewed as well as its limitations. A novel deep brain stimulation approach is proposed to evaluate this conceptual shift from somatosensory to affective sphere of pain targeting. Thalamic and other central pain syndromes are typically intractable to current treatment methods, including cerebral neuromodulation of somatosensory pathways, leading to long-term distress and disability. Our modern understanding of chronic pain pathophysiology is based largely on the neuromatrix theory, where cognitive, affective, and sensory-discriminative spheres contribute equally to the overall pain experience. During the last decade, the safety and feasibility of chronic stimulation of neural pathways related to mood and affect has been explored with promising results. Here, we propose a novel approach to modulate the affective sphere of chronic pain by targeting similar networks in patients with treatment-refractory central pain. Our primary goal is not to produce (or measure) analgesia, but rather to modulate the affective burden of chronic pain. Cerebral neuromodulation for neuropathic pain has had limited efficacy thus far. Shifting our aim to neural networks related to the affective sphere of pain may allow us to reduce pain conditioning and pain-related disability. Our ultimate goal is to promote rehabilitation from chronic pain-social and occupational. © 2012 International Neuromodulation Society.

  20. Neuropathic sensory symptoms: association with pain and psychological factors

    Science.gov (United States)

    Shaygan, Maryam; Böger, Andreas; Kröner-Herwig, Birgit

    2014-01-01

    Background A large number of population-based studies of chronic pain have considered neuropathic sensory symptoms to be associated with a high level of pain intensity and negative affectivity. The present study examines the question of whether this association previously found in non-selected samples of chronic pain patients can also be found in chronic pain patients with underlying pathology of neuropathic sensory symptoms. Methods Neuropathic sensory symptoms in 306 patients with chronic pain diagnosed as typical neuropathic pain, radiculopathy, fibromyalgia, or nociceptive back pain were assessed using the Pain DETECT Questionnaire. Two separate cluster analyses were performed to identify subgroups of patients with different levels of self-reported neuropathic sensory symptoms and, furthermore, to identify subgroups of patients with distinct patterns of neuropathic sensory symptoms (adjusted for individual response bias regarding specific symptoms). Results ANOVA (analysis of variance) results in typical neuropathic pain, radiculopathy, and fibromyalgia showed no significant differences between the three levels of neuropathic sensory symptoms regarding pain intensity, pain chronicity, pain catastrophizing, pain acceptance, and depressive symptoms. However, in nociceptive back pain patients, significant differences were found for all variables except pain chronicity. When controlling for the response bias of patients in ratings of symptoms, none of the patterns of neuropathic sensory symptoms were associated with pain and psychological factors. Conclusion Neuropathic sensory symptoms are not closely associated with higher levels of pain intensity and cognitive-emotional evaluations in chronic pain patients with underlying pathology of neuropathic sensory symptoms. The findings are discussed in term of differential response bias in patients with versus without verified neuropathic sensory symptoms by clinical examination, medical tests, or underlying pathology of

  1. Differential drug effects on spontaneous and evoked pain behavior in a model of trigeminal neuropathic pain

    Science.gov (United States)

    Deseure, K; Hans, GH

    2017-01-01

    Purpose Baclofen and morphine have shown efficacy against mechanical allodynia after infraorbital nerve chronic constriction injury (IoN-CCI). No drug effects have yet been reported on spontaneous trigeminal neuropathic pain. It has been proposed that the directed face grooming behavior that also develops following IoN-CCI offers a measure of spontaneous trigeminal neuropathic pain. Subjects and methods We examined the effects of a continuous 1-week infusion of 30 mg/day carbamazepine (the first-line drug treatment for trigeminal neuralgia), 1.06 mg/day baclofen, 4.18 mg/day clomipramine, and 5 mg/day morphine on spontaneous and mechanically evoked pain behavior (ie, directed face grooming and von Frey testing) in IoN-CCI rats. Results Isolated face grooming was significantly reduced in rats receiving carbamazepine and baclofen but not in clomipramine- or morphine-treated rats. All drugs showed significant antiallodynic effects; carbamazepine showed the strongest effects, whereas clomipramine had only minor efficacy. Conclusion The tested drugs have differential effects in the IoN-CCI model, and different neuropathological mechanisms may underlie the different somatosensory symptoms in this model. A mechanism-based approach may be needed to treat (trigeminal) neuropathic pain. The present data support IoN-CCI as a model of trigeminal neuralgia in which isolated face grooming is used as a measure of spontaneous neuropathic pain. PMID:28184169

  2. A central neuropathic pain model by DSP-4 induced lesion of noradrenergic neurons: preliminary report.

    Science.gov (United States)

    Kudo, Takashi; Kushikata, Tetsuya; Kudo, Mihoko; Kudo, Tsuyoshi; Hirota, Kazuyoshi

    2010-09-06

    Neuropathic pain models are classified as central and peripheral pain models. Although various peripheral neuropathic pain models are established, central pain models are based only on spinal cord injury. DSP-4 is a competitive inhibitor of norepinephrine uptake that selectively degenerates the locus coeruleus (LC)-noradrenergic neurons projection to the cerebral cortex and hippocampus. In the present study, we have tested whether lesion of LC-noradrenergic neurons by ip DSP-4 (0, 10, 30, 50 mg/kg, n=7 each) could provide a new central neuropathic pain model in rats using a hot-plate and tail-flick tests. DSP-4 significantly reduced the hot-plate latency and norepinephrine contents especially in the coerulean regions. However, DSP-4 did not change tail-flick latency. There are significant correlations of the latency in the hot-plate test with norepinephrine contents in the cerebral cortex (r=0.432, p=0.022), the hippocampus (r=0.465, p=0.013) and the pons (r=0.400, p=0.035) but not with those in the hypothalamus and the spinal cord. As response to hot-plate and tail-flick implies supra-spinal process and spinal reflex, respectively, central neuropathic pain may be facilitated by DSP-4 depleting LC-noradrenergic neurons although the present data are preliminary.

  3. Topical phenytoin for the treatment of neuropathic pain

    OpenAIRE

    Kopsky,David; Keppel Hesselink, Jan

    2017-01-01

    David J Kopsky,1 Jan M Keppel Hesselink2 1Institute for Neuropathic Pain, Amsterdam, 2Institute for Neuropathic Pain, Bosch en Duin, the Netherlands Abstract: We developed and tested a new putative analgesic cream, based on the anticonvulsant phenytoin in patients suffering from treatment refractory neuropathic pain. The use of commercial topical analgesics is not widespread due to the facts that capsaicin creams or patches can give rise to side effects, such as burning, and analgesic patches...

  4. Impact of chronobiology on neuropathic pain treatment.

    Science.gov (United States)

    Gilron, Ian

    2016-01-01

    Inflammatory pain exhibits circadian rhythmicity. Recently, a distinct diurnal pattern has been described for peripheral neuropathic conditions. This diurnal variation has several implications: advancing understanding of chronobiology may facilitate identification of new and improved treatments; developing pain-contingent strategies that maximize treatment at times of the day associated with highest pain intensity may provide optimal pain relief as well as minimize treatment-related adverse effects (e.g., daytime cognitive dysfunction); and consideration of the impact of chronobiology on pain measurement may lead to improvements in analgesic study design that will maximize assay sensitivity of clinical trials. Recent and ongoing chronobiology studies are thus expected to advance knowledge and treatment of neuropathic pain.

  5. Classification of neuropathic pain in cancer patients

    DEFF Research Database (Denmark)

    Brunelli, Cinzia; Bennett, Michael I; Kaasa, Stein

    2014-01-01

    Neuropathic pain (NP) in cancer patients lacks standards for diagnosis. This study is aimed at reaching consensus on the application of the International Association for the Study of Pain (IASP) special interest group for neuropathic pain (NeuPSIG) criteria to the diagnosis of NP in cancer patients...... was found on the statement "the pathophysiology of NP due to cancer can be different from non-cancer NP" (MED=9, IQR=2). Satisfactory consensus was reached for the first 3 NeuPSIG criteria (pain distribution, history, and sensory findings; MEDs⩾8, IQRs⩽3), but not for the fourth one (diagnostic test....../imaging; MED=6, IQR=3). Agreement was also reached on clinical examination by soft brush or pin stimulation (MEDs⩾7 and IQRs⩽3) and on the use of PRO descriptors for NP screening (MED=8, IQR=3). Based on the study results, a clinical algorithm for NP diagnostic criteria in cancer patients with pain...

  6. Neuropathic pain: A personal case reflection on a critical incident

    Directory of Open Access Journals (Sweden)

    Balaji P Duraisamy

    2011-01-01

    Full Text Available Neuropathic pain is a distressing symptom for the patient and a difficult symptom for the physician to treat. There is lack of evidence-based clinical guidelines for the management of malignant neuropathic pain. The case reflection is a personal account of what has been learnt from a critical incident in a particular patient in the management of neuropathic pain. Psychological issues are known to increase pain percetion and affect the quality of life. The case reflection explores problem areas, defines lacunae in knowledge, and demonstrates active learning of the management of neuropathic pain through reflective practice.

  7. Use of Methadone for Neuropathic Pain

    OpenAIRE

    Dwight Moulin

    2003-01-01

    Chronic neuropathic pain is often considered to be a common complication of injury to the central or peripheral nervous system and the pain itself is usually assumed to be intractable. Both of these assumptions are inaccurate. For example, numbness and tingling in glove and stocking distribution are common accompaniments of longstanding diabetes mellitus, but only about 10% of patients with diabetic neuropathy consider these sensory changes to be painful (1). Anticonvulsant and antide...

  8. Neuropathic pain and cytokines: current perspectives

    Directory of Open Access Journals (Sweden)

    Clark AK

    2013-11-01

    Full Text Available Anna K Clark, Elizabeth A Old, Marzia Malcangio Wolfson Centre for Age Related Diseases, King's College London, London, UK Abstract: Neuropathic pain represents a major problem in clinical medicine because it causes debilitating suffering and is largely resistant to currently available analgesics. A characteristic of neuropathic pain is abnormal response to somatic sensory stimulation. Thus, patients suffering peripheral neuropathies may experience pain caused by stimuli which are normally nonpainful, such as simple touching of the skin or by changes in temperature, as well as exaggerated responses to noxious stimuli. Convincing evidence suggests that this hypersensitivity is the result of pain remaining centralized. In particular, at the first pain synapse in the dorsal horn of the spinal cord, the gain of neurons is increased and neurons begin to be activated by innocuous inputs. In recent years, it has become appreciated that a remote damage in the peripheral nervous system results in neuronal plasticity and changes in microglial and astrocyte activity, as well as infiltration of macrophages and T cells, which all contribute to central sensitization. Specifically, the release of pronociceptive factors such as cytokines and chemokines from neurons and non-neuronal cells can sensitize neurons of the first pain synapse. In this article we review the current evidence for the role of cytokines in mediating spinal neuron–non-neuronal cell communication in neuropathic pain mechanisms following peripheral nerve injury. Specific and selective control of cytokine-mediated neuronal–glia interactions results in attenuation of the hypersensitivity to both noxious and innocuous stimuli observed in neuropathic pain models, and may represent an avenue for future therapeutic intervention. Keywords: anti-inflammatory cytokines, proinflammatory cytokines, microglia, astrocytes, first pain synapse

  9. Use of Methadone for Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Dwight Moulin

    2003-01-01

    Full Text Available Chronic neuropathic pain is often considered to be a common complication of injury to the central or peripheral nervous system and the pain itself is usually assumed to be intractable. Both of these assumptions are inaccurate. For example, numbness and tingling in glove and stocking distribution are common accompaniments of longstanding diabetes mellitus, but only about 10% of patients with diabetic neuropathy consider these sensory changes to be painful (1. Anticonvulsant and antidepressant treatments provide effective analgesia in up to 50% of patients with chronic neuropathic pain (2 and there is a growing body of high-quality evidence that controlled-release opioid analgesics provide substantial pain relief in a further subset of patients (3-6. Even with polypharmacy, this still leaves perhaps 20% to 30% of chronic neuropathic pain sufferers lacking adequate analgesia, and side effects can be problematic. In addition, central pain appears to be more refractory to opioid treatment than pain due to peripheral nerve injury (7.

  10. Diabetic neuropathic pain: Physiopathology and treatment

    Institute of Scientific and Technical Information of China (English)

    Anne K Schreiber; Carina FM Nones; Renata C Reis; Juliana G Chichorro; Joice M Cunha

    2015-01-01

    Diabetic neuropathy is a common complication of bothtype 1 and type 2 diabetes, which affects over 90% ofthe diabetic patients. Although pain is one of the mainsymptoms of diabetic neuropathy, its pathophysiologicalmechanisms are not yet fully known. It is widelyaccepted that the toxic effects of hyperglycemia play animportant role in the development of this complication,but several other hypotheses have been postulated.The management of diabetic neuropathic pain consistsbasically in excluding other causes of painful peripheral neuropathy, improving glycemic control as a prophylactic therapy and using medications to alleviate pain. First line drugs for pain relief include anticonvulsants, such as pregabalin and gabapentin and antidepressants, especially those that act to inhibit the reuptake of serotonin and noradrenaline. In addition, there is experimental and clinical evidence that opioids can be helpful in pain control, mainly if associated with first line drugs. Other agents, including for topical application, such as capsaicin cream and lidocaine patches, have also been proposed to be useful as adjuvants in the control of diabetic neuropathic pain, but the clinical evidence is insufficient to support their use. In conclusion, a better understanding of the mechanisms underlying diabetic neuropathic pain will contribute to the search of new therapies, but also to the improvement of the guidelines to optimize pain control with the drugs currently available.

  11. 5% Lidocaine-medicated plaster for the treatment of chronic peripheral neuropathic pain: complex regional pain syndrome and other neuropathic conditions.

    Science.gov (United States)

    Calderón, Enrique; Calderón-Seoane, María Eloísa; García-Hernández, Rafael; Torres, Luis Miguel

    2016-01-01

    Chronic neuropathic pain and chronic complex regional pain syndrome (CRPS), in particular, are debilitating and difficult-to-treat conditions that have a strong impact on patient's quality of life. The aim of this study was to evaluate the effectiveness of 5% lidocaine-medicated plaster as add-on therapy in patients with chronic peripheral neuropathic pain conditions, including CRPS. This was a single-center, prospective, observational study set in a specialized pain unit of a tertiary hospital in Spain. A total of 56 patients with long-standing peripheral neuropathic pain, ten of them with CRPS, received 5% lidocaine-medicated plaster as add-on analgesic therapy for 6 months. After 6 months of treatment, a ≥50% reduction in pain intensity was attained by 75% of patients, as measured by numeric rating scale (NRS) for pain. The average NRS score was reduced by 61% (4.7 points), from a baseline mean score of 7.8 to an end point mean score of 3.1. Marked improvements were also observed in the CRPS group: six out of ten patients achieved a ≥50% reduction in NRS score, and the average NRS score for patients with CRPS was reduced by 51% (4.0 points), from a baseline mean score of 7.9 to an end point mean score of 3.9. The improvements in pain intensity were partially translated into a decrease in disability index and in anxiety levels. 5% Lidocaine-medicated plaster may be useful as add-on therapy for a number of peripheral neuropathic pain conditions, including CRPS.

  12. Somatosensory Profiles but Not Numbers of Somatosensory Abnormalities of Neuropathic Pain Patients Correspond with Neuropathic Pain Grading

    Science.gov (United States)

    Konopka, Karl-Heinz; Harbers, Marten; Houghton, Andrea; Kortekaas, Rudie; van Vliet, Andre; Timmerman, Wia; den Boer, Johan A.; Struys, Michel M. R. F.; van Wijhe, Marten

    2012-01-01

    Due to the lack of a specific diagnostic tool for neuropathic pain, a grading system to categorize pain as ‘definite’, ‘probable’, ‘possible’ and ‘unlikely’ neuropathic was proposed. Somatosensory abnormalities are common in neuropathic pain and it has been suggested that a greater number of abnormalities would be present in patients with ‘probable’ and ‘definite’ grades. To test this hypothesis, we investigated the presence of somatosensory abnormalities by means of Quantitative Sensory Testing (QST) in patients with a clinical diagnosis of neuropathic pain and correlated the number of sensory abnormalities and sensory profiles to the different grades. Of patients who were clinically diagnosed with neuropathic pain, only 60% were graded as ‘definite’ or ‘probable’, while 40% were graded as ‘possible’ or ‘unlikely’ neuropathic pain. Apparently, there is a mismatch between a clinical neuropathic pain diagnosis and neuropathic pain grading. Contrary to the expectation, patients with ‘probable’ and ‘definite’ grades did not have a greater number of abnormalities. Instead, similar numbers of somatosensory abnormalities were identified for each grade. The profiles of sensory signs in ‘definite’ and ‘probable’ neuropathic pain were not significantly different, but different from the ‘unlikely’ grade. This latter difference could be attributed to differences in the prevalence of patients with a mixture of sensory gain and loss and with sensory loss only. The grading system allows a separation of neuropathic and non-neuropathic pain based on profiles but not on the total number of sensory abnormalities. Our findings indicate that patient selection based on grading of neuropathic pain may provide advantages in selecting homogenous groups for clinical research. PMID:22927981

  13. The Central Analgesic Mechanism of YM-58483 in Attenuating Neuropathic Pain in Rats.

    Science.gov (United States)

    Qi, Zeyou; Wang, Yaping; Zhou, Haocheng; Liang, Na; Yang, Lin; Liu, Lei; Zhang, Wei

    2016-10-01

    Calcium channel antagonists are commonly used to treat neuropathic pain. Their analgesic effects rely on inhibiting long-term potentiation, and neurotransmitters release in the spinal cord. Store-operated Ca(2+)channels (SOCCs) are highly Ca(2+)-selective cation channels broadly expressed in non-excitable cells and some excitable cells. Recent studies have shown that the potent inhibitor of SOCCs, YM-58483, has analgesic effects on neuropathic pain, but its mechanism is unclear. This experiment performed on spinal nerve ligation (SNL)-induced neuropathic pain model in rats tries to explore the mechanism, whereby YM-58483 attenuates neuropathic pain. The left L5 was ligated to produce the SNL neuropathic pain model in male Sprague-Dawley rats. The withdrawal threshold of rats was measured by the up-down method and Hargreaves' method before and after intrathecal administration of YM-58483 and vehicle. The SOCCs in the spinal dorsal horn were located by immunofluorescence. The expression of phosphorylated ERK and phosphorylated CREB, CD11b, and GFAP proteins in spinal level was tested by Western blot, while the release of proinflammatory cytokines (IL-1β, TNF-α, PGE2) was measured by enzyme-linked immunosorbent assay (ELISA). Intrathecal YM-58483 at the concentration of 300 μM (1.5 nmol) and 1000 μM (10 nmol) produced a significant central analgesic effect on the SNL rats, compared with control + vehicle (n = 7, P pain, compared with normal + saline (P  0.05). YM-58483 also inhibited the release of spinal cord IL-1β, TNF-α, and PGE2, compared with control + vehicle (n = 5, #P central ERK/CREB signaling in the neurons and decreasing central IL-1β, TNF-α, and PGE2 release to reduce neuronal excitability in the spinal dorsal horn of the SNL rats.

  14. 5% lidocaine medicated plaster double effect in a case of orofacial localized neuropathic pain

    Directory of Open Access Journals (Sweden)

    Casale R

    2014-11-01

    Full Text Available Roberto Casale,1,2 Yuriy Romanenko,2,3 Massimo Allegri4–6 1Department of Clinical Neurophysiology and Pain Rehabilitation Unit, Foundation "Salvatore Maugeri", Research and Care Institute, IRCCS, Pavia, Italy; 2EFIC Montescano Pain School, Montescano, Italy; 3Department of Neurology, Lugansk City Hospital 4, Lugansk, Ukraine; 4Department of Clinical, Surgical, Diagnostic and Pediatric Sciences University of Pavia, Pavia, Italy; 5Pain Therapy Service Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 6SIMPAR group, Pavia, Italy Abstract: Localized neuropathic pain (LNP is a type of neuropathic pain that is characterized by “consistent and limited area(s of maximum pain associated with negative or positive sensory signs and/or spontaneous symptoms characteristic of neuropathic pain”. This definition encompasses a huge number of neuropathic orofacial pain syndromes. We present a case report of a patient who was affected with sleep apnea syndrome treated with nocturnal oxygen mask delivery, in whom orofacial LNP hampered the wearing of a mask due to unbearable burning and throbbing pain. The application of 5% lidocaine medicated plaster during the night led to an impressive reduction of both the pain level and the size of the painful area due to the plaster's pharmacological mechanisms, which were associated with a secondary benefit due to its mechanical protective action. This case report shows how these two factors could be of clinical value and have to be considered more systematically in the treatment of LNP in reducing pain and the size of the painful area. Keywords: trigeminal pain, localized neuropathic pain, topical treatment, 5% lidocaine medicated plaster

  15. Treatment of Neuropathic Pain with Venlafaxine: A Systematic Review.

    Science.gov (United States)

    Aiyer, Rohit; Barkin, Robert L; Bhatia, Anurag

    2016-11-11

    OBJECTIVE : To investigate the efficacy of venlafaxine for neuropathic pain and review literature to determine if the medication provides adequate neuropathic pain relief. METHODS : Literature was reviewed on MEDLINE using various key words. These key words include: "venlafaxine and pain," "venlafaxine ER and pain," "venlafaxine XR and pain," "venlafaxine and neuropathic pain," "venlafaxine and neuropathy," "SSRI and neuropathic pain," "SSRI and neuropathy," "SNRI and neuropathic pain," "SNRI and neuropathy," "serotonin reuptake inhibitor and neuropathic pain," "serotonin reuptake inhibitor and neuropathy," "serotonin norepinephrine reuptake inhibitor and neuropathic pain" and "serotonin norepinephrine reuptake inhibitor and neuropathy." Using this guideline, 13 articles were reviewed. RESULTS : A total of 13 studies reviewed, which are organized by date and diagnosis. It is evident that in the majority of studies, when compared with a placebo, there was a clinical significant reduction in neuropathic pain relief when using venlafaxine. Additionally, one study showed even more significant pain relief when using higher doses of venlafaxine (at least 150 mg). However, when compared with alternative neuropathic medications, venlafaxine for the most part did not perform any better in terms of efficacy. CONCLUSION : In conclusion, venlafaxine is a safe and well-tolerated analgesic drug for the symptomatic treatment of neuropathic pain, and there is limited evidence that high-dose venlafaxine (150 mg/day) can be even more beneficial. While the present evidence is quite encouraging regarding venlafaxine's use for neuropathic pain, further research is needed to continue to expand on these findings, particularly when in consideration with other possible pharmacological agents. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Duloxetine in the management of diabetic peripheral neuropathic pain

    Directory of Open Access Journals (Sweden)

    Boomershine CS

    2011-07-01

    Full Text Available Michelle J Ormseth, Beth A Sholz, Chad S BoomershineDivision of Rheumatology and Immunology, Vanderbilt University, Nashville, TN, USAAbstract: Diabetic neuropathy affects up to 70% of diabetics, and diabetic peripheral neuropathic pain (DPNP is the most common and debilitating of the diabetic neuropathies. DPNP significantly reduces quality of life and increases management costs in affected patients. Despite the impact of DPNP, management is poor with one-quarter of patients receiving no treatment and many treated with medications having little or no efficacy in managing DPNP. Duloxetine is one of two drugs approved by the United States Food and Drug Administration for DPNP management. Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI proven safe, effective, and cost-saving in reducing DPNP symptoms at a dose of 60 mg/day. Duloxetine doses greater than 60 mg/day for DPNP management are not recommended since they are no more efficacious and associated with more side effects; addition of pregabalin or gabapentin for these patients may be beneficial. Side effects of duloxetine are generally mild and typical for the SNRI class including nausea, dizziness, somnolence, fatigue, sweating, dry mouth, constipation, and diarrhea. Given its other indications, duloxetine is a particularly good choice for DPNP treatment in patients with coexisting depression, anxiety, fibromyalgia, or chronic musculoskeletal pain. Duloxetine treatment had no clinically significant effect on glycemic control and did not increase the risk of cardiovascular events in diabetes patients. However, duloxetine use should be avoided in patients with hepatic disease or severe renal impairment. Given its safety, efficacy, and tolerability, duloxetine is an excellent choice for DPNP treatment in many patients.Keywords: duloxetine, diabetic peripheral neuropathic pain, review, treatment

  17. Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial.

    Science.gov (United States)

    Rigo, Flavia Karine; Trevisan, Gabriela; Godoy, Maria C; Rossato, Mateus Fortes; Dalmolin, Gerusa D; Silva, Mariane A; Menezes, Mirian S; Caumo, Wolnei; Ferreira, Juliano

    2017-03-01

    Methadone and ketamine are used in neuropathic pain management. However, the benefits of both drugs association are uncertain in the treatment of neuropathic pain. Our primary objective was test the hypothesis that oral methadone combined with oral ketamine is more effective than oral methadone or ketamine alone in reducing neuropathic pain. We conducted a randomized, double blind, active-controlled parallel-group clinical trial. Forty-two patients with neuropathic pain refractory to conventional therapy were randomly assigned to receive oral methadone (n = 14), ketamine (n = 14), or methadone plus ketamine (n = 14) over a 3-month period. During these 90 days, we observed pain scores using a visual analogical scale (VAS), allodynia, burning/shooting pain, and some side effects. All treatments were effective in reducing pain scores by at least 40%. However, a significant improvement in pain was observed only in the ketamine alone group compared with both the methadone or methadone/ketamine groups. No significant differences were observed among the treatment groups for the reduction of burning or shooting pain, while ketamine alone was more effective than methadone or methadone/ketamine for the reduction of allodynia. Formal assessment for awareness of the allocation was not performed, some co-intervention bias may have occurred, our results could be only relevant to the patient population investigated and the use of VAS as the primary outcome detect changes in pain intensity but not to assess neuropathic pain symptoms. This study indicates that ketamine was better than methadone or methadone/ketamine for treating neuropathic pain.Key words: Multimodal analgesia, refractory pain, NMDA receptor, opioid.

  18. Managing neuropathic pain in multiple sclerosis: Pharmacological interventions.

    Science.gov (United States)

    Duffy, Samuel S; Lees, Justin G; Perera, Chamini J; Moalem-Taylor, Gila

    2017-09-06

    Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Of the plethora of motor and sensory disturbances experienced by sufferers, neuropathic pain is a highly prevalent and debilitating symptom, and at present remains extremely difficult to treat. Common forms of neuropathic pain seen in MS patients include central neuropathic pain, Lhermitte's phenomenon and trigeminal neuralgia, which are all speculated to arise from specific patterns of lesion formation. Efficacious pharmacological interventions for the treatment of neuropathic pain associated with MS are lacking, and have been largely informed by drug trials in peripheral neuropathies and spinal cord injury. Neuropathic pain in MS is inadequately relieved by conventional analgesics, and first-line therapies are generally comprised of anti-depressive and anti-convulsive drugs. A range of alternatives have been proposed and tested with variable success, including cannabinoids and certain opioid analgesics. Animals with experimental autoimmune encephalomyelitis (EAE), an autoimmune model of MS, also exhibit neuropathic pain symptoms. Studies aimed at understanding the mechanisms underlying EAE-induced neuropathic pain and investigating the efficacy of novel pharmacological interventions at the animal level offer an exciting area of future research, and may inform future therapeutic options for MS-associated neuropathic pain. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Tramadol for neuropathic pain in adults.

    Science.gov (United States)

    Duehmke, Rudolf Martin; Derry, Sheena; Wiffen, Philip J; Bell, Rae F; Aldington, Dominic; Moore, R Andrew

    2017-06-15

    This review is an update of a review of tramadol for neuropathic pain, published in 2006; updating was to bring the review in line with current standards. Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Peripheral neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the peripheral nervous system. To assess the analgesic efficacy of tramadol compared with placebo or other active interventions for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials. We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from inception to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. We included randomised, double-blind trials of two weeks' duration or longer, comparing tramadol (any route of administration) with placebo or another active treatment for neuropathic pain, with subjective pain assessment by the participant. Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH), using standard methods. We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. We identified six randomised, double-blind studies involving 438 participants

  20. Morphine for chronic neuropathic pain in adults.

    Science.gov (United States)

    Cooper, Tess E; Chen, Junqiao; Wiffen, Philip J; Derry, Sheena; Carr, Daniel B; Aldington, Dominic; Cole, Peter; Moore, R Andrew

    2017-05-22

    Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews. To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. We included randomised, double-blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. We identified five randomised, double-blind, cross-over studies with treatment periods of four to

  1. Neuropathic sensory symptoms: association with pain and psychological factors

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    Shaygan M

    2014-05-01

    Full Text Available Maryam Shaygan,1 Andreas Böger,2 Birgit Kröner-Herwig11Department of Clinical Psychology and Psychotherapy, University of Göttingen, Germany; 2Pain Management Clinic at the Red Cross Hospital, Kassel, GermanyBackground: A large number of population-based studies of chronic pain have considered neuropathic sensory symptoms to be associated with a high level of pain intensity and negative affectivity. The present study examines the question of whether this association previously found in non-selected samples of chronic pain patients can also be found in chronic pain patients with underlying pathology of neuropathic sensory symptoms.Methods: Neuropathic sensory symptoms in 306 patients with chronic pain diagnosed as typical neuropathic pain, radiculopathy, fibromyalgia, or nociceptive back pain were assessed using the Pain DETECT Questionnaire. Two separate cluster analyses were performed to identify subgroups of patients with different levels of self-reported neuropathic sensory symptoms and, furthermore, to identify subgroups of patients with distinct patterns of neuropathic sensory symptoms (adjusted for individual response bias regarding specific symptoms.Results: ANOVA (analysis of variance results in typical neuropathic pain, radiculopathy, and fibromyalgia showed no significant differences between the three levels of neuropathic sensory symptoms regarding pain intensity, pain chronicity, pain catastrophizing, pain acceptance, and depressive symptoms. However, in nociceptive back pain patients, significant differences were found for all variables except pain chronicity. When controlling for the response bias of patients in ratings of symptoms, none of the patterns of neuropathic sensory symptoms were associated with pain and psychological factors.Conclusion: Neuropathic sensory symptoms are not closely associated with higher levels of pain intensity and cognitive-emotional evaluations in chronic pain patients with underlying pathology of

  2. Ultramicronized palmitoylethanolamide in spinal cord injury neuropathic pain: A randomized, double-blind, placebo-controlled trial

    DEFF Research Database (Denmark)

    Andresen, Sven R; Bing, Jette; Hansen, Rikke Bod Middelhede

    2016-01-01

    Neuropathic pain and spasticity after spinal cord injury (SCI) represent significant problems. Palmitoylethanolamide (PEA), a fatty acid amide that is produced in many cells in the body, is thought to potentiate the action of endocannabinoids and to reduce pain and inflammation. This randomized, ......, insomnia, or psychological functioning. PEA was not associated with more adverse effects than placebo....

  3. Thiamine and cyanocobalamin relieve neuropathic pain in rats: synergy with dexamethasone.

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    Caram-Salas, Nadia L; Reyes-García, Gerardo; Medina-Santillán, Roberto; Granados-Soto, Vinicio

    2006-01-01

    Treatment of neuropathic pain is an area of largely unmet medical need. Therefore, this pain may require the development of novel drug entities. In the search for alternatives, B vitamins have been found to be a clinically useful pharmacological tool for patients with neuropathic pain. However, preclinical studies supporting this use are lacking. In this study, we assessed the possible antiallodynic effects of thiamine, pyridoxine, and cyanocobalamin as well as dexamethasone and their combination on spinal nerve ligation induced allodynia. Sub cutaneous administration of thiamine (75-600 mg/kg), pyridoxine (75-600 mg/kg), cyanocobalamin(0.75-6 mg/kg), and dexamethasone (4-32 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with 600 mg/kg of thiamine (approximately 58%), 600 mg/kg of pyridoxine (approximately 22%), 6 mg/kg of cyanocobalamin (approximately 73%), and 32 mg/kg of dexamethasone (approximately 68%). Since a small antiallodynic effect was observed with pyridoxine, this drug was not further analyzed in the combinations. Coadministration of thiamine or cyanocobalamin and dexamethasone remarkably reduced spinal nerve ligation induced allodynia (approximately 90%), showing a synergistic interaction between either thiamine or cyanocobalamin and dexamethasone. Our data indicate that thiamine and pyridoxine as well as the combination of B vitamins and dexamethasone are able to reduce tactile allodynia in rats and suggest the possible clinical use of these drugs in the treatment of neuropathic pain in human beings. Copyright 2006 S. Karger AG, Basel.

  4. Neuropathic Pain Features in Patients with Bone Metastases.

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    Nakamura, N; Takahashi, O; Zenda, S; Kawamori, J; Ogita, M; Onozawa, M; Arahira, S; Toshima, M; Motegi, A; Hirano, Y; Hojo, H; Akimoto, T

    2016-03-01

    The results of previous randomised controlled trials suggest that radiation oncologists should consider the presence of neuropathic pain when they prescribe dose fractionations for painful bone metastases. Although validated screening tools for neuropathic pain features are currently available, the prevalence of such features among patients with painful bone metastases is still poorly understood. The purpose of this study was to estimate the prevalence of neuropathic pain features among patients who received palliative radiotherapy for painful bone metastases. We conducted a cohort survey of consecutive patients who received palliative radiotherapy for painful bone metastases at St Luke's International Hospital between 2013 and 2014. Patients were prospectively assessed before radiotherapy using the validated screening questionnaire to identify neuropathic pain components in Japanese patients. Pain with neuropathic features was prospectively defined using the total score of the seven-item questionnaire and a cut-off score ≥9. The pain response was assessed 2 months after the start of radiotherapy according to the criteria defined by the International Bone Metastases Consensus Working Party. Eighty-seven patients were assessed. Twenty-four per cent of patients (95% confidence interval: 16-35%) were diagnosed as having pain with neuropathic features. On multivariate analysis, no significant correlations were seen between neuropathic pain features and patient characteristics. Sixty-four patients (74%) were assessable 2 months after the start of radiotherapy. Overall response rates were 59% (95% confidence interval: 33-82%) in patients with neuropathic features and 55% (95% confidence interval: 40-70%) in those without such features. A considerable proportion of the patients were proven to have bone pain with neuropathic features. Further investigations are warranted to validate symptom assessment tools in cooperation with pain distribution and image findings, and to

  5. Multidimensional Neuropathic Pain Phenotypes after Spinal Cord Injury.

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    Widerström-Noga, Eva; Felix, Elizabeth R; Adcock, James P; Escalona, Maydelis; Tibbett, Jacqueline

    2016-03-01

    Identifying clinical neuropathic pain phenotypes is a first step to better understand the underlying pain mechanisms after spinal cord injury (SCI). The primary purpose of the present study was to characterize multidimensional neuropathic pain phenotypes based on quantitative sensory testing (QST), pain intensity, and utilization of catastrophizing coping strategies. Thermal perception, thermal pain, and vibratory perception thresholds were assessed above and below the level of injury (LOI) in 101 persons with SCI and neuropathic pain, 18 persons with SCI and no neuropathic pain, and 50 able-bodied, pain-free controls. Cluster analysis of QST z-scores below the LOI, pain intensity ratings, and the Coping Strategies Questionnaire (CSQ) catastrophizing subscale scores in subjects with neuropathic pain resulted in two phenotypes: severe neuropathic pain (SNP) with greater pain intensity (7.39 ± 1.57) and thermal and vibratory sensitivity compared with the moderate neuropathic pain (MNP; 5.40 ± 1.43). A factor analysis including all CSQ subscales, the Neuropathic Pain Symptom Inventory (NPSI) total score, and thermal pain sensitivity above and below the LOI resulted in three factors: (1) adaptive pain coping including increasing activities, diverting attention, and reinterpreting pain sensations; (2) catastrophizing, neuropathic pain, and thermal sensitivity including greater NPSI total score, thermal pain sensitivity below the LOI, and catastrophizing; and (3) general pain sensitivity including greater thermal pain sensitivity above the LOI and lower catastrophizing. Our results suggest that neuropathic pain symptom severity post-SCI is significantly associated with residual spinothalamic tract function below the LOI and catastrophizing pain coping.

  6. Neuropathic pain due to malignancy: Mechanisms, clinical manifestations and therapy

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    Pjević Miroslava

    2004-01-01

    Full Text Available Introduction Neuropathic pain in cancer patients requires a focused clinical evaluation based on knowledge of common neuropathic pain syndromes. Definition Neuropathic pain is a non-nociceptive pain or "differentiation" pain, which suggests abnormal production of impulses by neural tissue that is separated from afferent input. Impulses arise from the peripheral nervous system or central nervous system. Causes of neuropathic pain due to malignancy Neuropathic pain is caused directly by cancer-related pathology (compression/infiltration of nerve tissue, combination of compression/infiltration or by diagnostic and therapeutic procedures (surgical procedures, chemotherapy, radiotherapy. Mechanisms Pathophysiological mechanisms are very complex and still not clear enough. Neuropathic pain is generated by electrical hyperactivity of neurons along the pain pathways. Peripheral mechanisms (primary sensitization of nerve endings, ectopically generated action potentials within damaged nerves, abnormal electrogenesis within sensory ganglia and central mechanisms (loss of input from peripheral nociceptors into dorsal horn, aberrant sprouting within dorsal horn, central sensitization, loss of inhibitory interneurons, mechanisms at higher centers are involved. Diagnosis The quality of pain presents as spontaneous pain (continuous and paroxysmal, abnormal pain (allodynia, hyperalgesia, hyperpathia, paroxysmal pain. Clinical manifestations Clinically, neuropathic pain is described as the pain in the peripheral nerve (cranial nerves, other mononeuropathies, radiculopathy, plexopathy, paraneoplastic peripheral neuropathy and relatively infrequent, central pain syndrome. Therapy Treatment of neuropathic pain remains a challenge for clinicians, because there is no accepted algorithm for analgesic treatment of neuropathic pain. Pharmacotherapy is considered to be the first line therapy. Opioids combined with non-steroidal antiinflammatory drugs are warrented. If

  7. Capsaicin 8 % Patch: A Review in Peripheral Neuropathic Pain.

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    Burness, Celeste B; McCormack, Paul L

    2016-01-01

    The capsaicin 8 % patch (QUTENZA®) is an adhesive patch containing a high concentration (8 % w/w) of synthetic capsaicin, a selective agonist of transient receptor potential vanilloid 1 channel. It is approved for treatment of peripheral neuropathic pain in adults either alone or in combination with other medicinal products for pain in the EU; it is only approved to treat postherpetic neuralgia (PHN) in the USA. In patients with painful diabetic peripheral neuropathy (PDPN), a single 30-min application of the capsaicin 8 % patch significantly improved pain relief and sleep quality compared with placebo in a 12-week double-blind trial. In a 52-week, randomized trial, up to seven consecutive 30-min treatments with the capsaicin 8 % patch (≤7 treatments each at least 8 weeks apart) plus standard of care therapy was associated with sustained pain relief and no negative neurological safety consequences compared with standard of care. In two randomized trials, a single 60-min application of the capsaicin 8 % patch reduced pain scores significantly more than a low-concentration (0.04 %) capsaicin control patch in patients with PHN. Capsaicin 8 % patch treatment was noninferior to pregabalin (optimized dosage) in a randomized trial in patients with nondiabetic peripheral neuropathic pain. Results in two trials in patients with HIV-AN were equivocal, with a significant improvement in pain intensity observed in one trial, but not in the other. The capsaicin 8 % patch was associated with expected, transient, capsaicin-related application-site adverse events such as erythema and pain.

  8. The evidence for pharmacologic treatment of neuropathic cancer pain: beneficial and adverse effects

    NARCIS (Netherlands)

    Jongen, J.L.; Huijsman, M.L.; Jessurun, J.; Ogenio, K.; Schipper, D.; Verkouteren, D.R.; Moorman, P.W.; Rijt, C.C. van der; Vissers, K.C.P.

    2013-01-01

    CONTEXT: The prevalence of neuropathic pain in patients with cancer pain has been estimated to be around 40%. Neuropathic pain may be caused by tumor invasion and is considered as mixed nociceptive-neuropathic pain, or caused by an anticancer treatment and considered as purely neuropathic pain. The

  9. Promoted Interaction of C/EBPα with Demethylated Cxcr3 Gene Promoter Contributes to Neuropathic Pain in Mice.

    Science.gov (United States)

    Jiang, Bao-Chun; He, Li-Na; Wu, Xiao-Bo; Shi, Hui; Zhang, Wen-Wen; Zhang, Zhi-Jun; Cao, De-Li; Li, Chun-Hua; Gu, Jun; Gao, Yong-Jing

    2017-01-18

    DNA methylation has been implicated in the pathogenesis of chronic pain. However, the specific genes regulated by DNA methylation under neuropathic pain condition remain largely unknown. Here we investigated how chemokine receptor CXCR3 is regulated by DNA methylation and how it contributes to neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased Cxcr3 mRNA and protein expression in the neurons of the spinal cord. Meanwhile, the CpG (5'-cytosine-phosphate-guanine-3') island in the Cxcr3 gene promoter region was demethylated, and the expression of DNA methyltransferase 3b (DNMT3b) was decreased. SNL also increased the binding of CCAAT (cytidine-cytidine-adenosine-adenosine-thymidine)/enhancer binding protein α (C/EBPα) with Cxcr3 promoter and decreased the binding of DNMT3b with Cxcr3 promoter in the spinal cord. C/EBPα expression was increased in spinal neurons after SNL, and inhibition of C/EBPα by intrathecal small interfering RNA attenuated SNL-induced pain hypersensitivity and reduced Cxcr3 expression. Furthermore, SNL-induced mechanical allodynia and heat hyperalgesia were markedly reduced in Cxcr3(-/-) mice. Spinal inhibition of Cxcr3 by shRNA or CXCR3 antagonist also attenuated established neuropathic pain. Moreover, CXCL10, the ligand of CXCR3, was increased in spinal neurons and astrocytes after SNL. Superfusing spinal cord slices with CXCL10 enhanced spontaneous EPSCs and potentiated NMDA-induced and AMPA-induced currents of lamina II neurons. Finally, intrathecal injection of CXCL10 induced CXCR3-dependent pain hypersensitivity in naive mice. Collectively, our results demonstrated that CXCR3, increased by DNA demethylation and the enhanced interaction with C/EBPα, can be activated by CXCL10 to facilitate excitatory synaptic transmission and contribute to the maintenance of neuropathic pain. Peripheral nerve injury induces changes of gene expression in the spinal cord that may contribute to the pathogenesis of neuropathic

  10. Hyperbaric oxygenation alleviates chronic constriction injury (CCI)-induced neuropathic pain and inhibits GABAergic neuron apoptosis in the spinal cord.

    Science.gov (United States)

    Fu, Huiqun; Li, Fenghua; Thomas, Sebastian; Yang, Zhongjin

    2017-09-15

    Dysfunction of GABAergic inhibitory controls contributes to the development of neuropathic pain. We examined our hypotheses that (1) chronic constriction injury (CCI)-induced neuropathic pain is associated with increased spinal GABAergic neuron apoptosis, and (2) hyperbaric oxygen therapy (HBO) alleviates CCI-induced neuropathic pain by inhibiting GABAergic neuron apoptosis. Male rats were randomized into 3 groups: CCI, CCI+HBO and the control group (SHAM). Mechanical allodynia was tested daily following CCI procedure. HBO rats were treated at 2.4 atmospheres absolute (ATA) for 60min once per day. The rats were euthanized and the spinal cord harvested on day 8 and 14 post-CCI. Detection of GABAergic cells and apoptosis was performed. The percentages of double positive stained cells (NeuN/GABA), cleaved caspase-3 or Cytochrome C in total GABAergic cells or in total NeuN positive cells were calculated. HBO significantly alleviated mechanical allodynia. CCI-induced neuropathic pain was associated with significantly increased spinal apoptotic GABA-positive neurons. HBO considerably decreased these spinal apoptotic cells. Cytochrome-C-positive neurons and cleaved caspase-3-positive neurons were also significantly higher in CCI rats. HBO significantly decreased these positive cells. Caspase-3 mRNA was also significantly higher in CCI rats. HBO reduced mRNA expression of caspase-3. CCI-induced neuropathic pain was associated with increased apoptotic GABAergic neurons induced by activation of key proteins of mitochondrial apoptotic pathways in the dorsal horn of the spinal cord. HBO alleviated CCI-induced neuropathic pain and reduced GABAergic neuron apoptosis. The beneficial effect of HBO may be via its inhibitory role in CCI-induced GABAergic neuron apoptosis by suppressing mitochondrial apoptotic pathways in the spinal cord. Increased apoptotic GABAergic neurons induced by activation of key proteins of mitochondrial apoptotic pathways in the dorsal horn of the spinal

  11. Anti-nociceptive roles of the glia-specific metabolic inhibitor fluorocitrate in paclitaxel-evoked neuropathic pain.

    Science.gov (United States)

    Xu, Yongming; Cheng, Guangxia; Zhu, Yanrong; Zhang, Xin; Pu, Shaofeng; Wu, Junzhen; Lv, Yingying; Du, Dongping

    2016-10-01

    Paclitaxel (Taxol) is a powerful chemotherapy drug used in breast cancers, but it often causes neuropathic pain, leading to the early cessation of therapy and poor treatment outcomes. Approaches for the management of paclitaxel-induced neuropathic pain are urgently needed. The involvement of spinal astrocytes in the pathogenesis of paclitaxel-induced neuropathy has been reported, but little is known about the role of fluorocitrate (FC), a selective inhibitor of astrocyte activation, during neuropathic pain related to paclitaxel treatment. In this study, we investigated the effects of FC on paclitaxel-induced neuropathic pain. Glial fibrillary acidic protein (GFAP) expression was determined to assess astrocyte activation. To explore the mechanisms involved, the expression of glial glutamate transporter 1 (GLT-1) and the activation of mitogen-activated protein kinases in the spinal dorsal horn were analyzed. The results showed that paclitaxel decreased the mechanical nociceptive thresholds and increased GFAP expression, leading to spinal astrocyte activation. After paclitaxel treatment, GLT-1 was significantly down-regulated, and the phosphorylation of ERK1/2 and JNK were obviously up-regulated. However, paclitaxel treatment did not increase p38 phosphorylation. Additional studies showed that paclitaxel-evoked mechanical hypersensitivity was reduced by FC treatment. Moreover, FC treatment inhibited the activation of astrocytes and reversed the changes in GLT-1 expression and MAPK phosphorylation. Further study indicated that FC did not influence the antitumor effect of paclitaxel, suggesting that FC blocked paclitaxel-induced neuropathic pain without antagonizing its antitumor effect. Together, these results suggested that paclitaxel induced astrocyte-specific activation, which may contribute to mechanical allodynia and hyperalgesia, and that FC could be a potential therapeutic agent for paclitaxel-induced neuropathic pain. © The Author 2016. Published by Oxford

  12. The effects of music therapy on pain in patients with neuropathic pain.

    Science.gov (United States)

    Korhan, Esra Akın; Uyar, Meltem; Eyigör, Can; Hakverdioğlu Yönt, Gülendam; Çelik, Serkan; Khorshıd, Leyla

    2014-03-01

    The aim of this study was to investigate the effect of relaxing music on pain intensity in patients with neuropathic pain. A quasi-experimental study, repeated measures design was used. Thirty patients, aged 18-70 years, with neuropathic pain and hospitalized in an Algology clinic were identified as a convenience sample. Participants received 60 minutes of music therapy. Classical Turkish music was played to patients using a media player (MP3) and headphones. Participants had pain scores taken immediately before the intervention and at the 30th and 60th minutes of the intervention. Data were collected over a 6-month period in 2012. The patients' mean pain intensity scores were reduced by music, and that decrease was progressive over the 30th and 60th minutes of the intervention, indicating a cumulative dose effect. The results of this study implied that the inclusion of music therapy in the routine care of patients with neuropathic pain could provide nurses with an effective practice for reducing patients' pain intensity. Copyright © 2014 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

  13. Anti-allodynic Effect of Nefopam and Morphine in a Rat Model of Neuropathic Pain

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    Taraneh Moini Zanjani

    2013-05-01

    Full Text Available Please cite this article as: Moini Zanjani T, Saghaei E, Ameli H, Sabetkasaei M. Anti-allodynic Effect of Nefopam and Morphine in a Rat Model of Neuropathic Pain. Novel Biomed 2013;1:16-22.Background: Neuropathic pain is a chronic pain due to a disorder in the peripheral or central nervous system with different pathophysiological mechanisms. Current treatments are not effective. Here we compared the analgesic effect of nefopam, and morphine in chronic constriction injury (CCI model of neuropathic pain.Methods: Male wistar rat (150-200g, n=8 were divided into 3 different groups: 1- Saline-treated CCI group, 2- Saline-treated sham group, and 3- Drug-treated CCI groups. In CCI model of neuropathic pain, the left sciatic nerve was exposed and 4 loose chromic gut ligatures were placed around the nerve proximal to the trifurcation. Ketamine 60mg/kg and xylazine 10 mg/kg were used for anesthesia. Nefopam (10, 20, 30mg/kg, and morphine (1, 3, 5mg/kg were injected 30 minutes before surgery and continued daily to day 14 post-ligation. Von Frey filaments for mechanical allodynia and acetone test for cold allodynia were respectively used as pain behavioral tests. Experiments were performed on day 0 (before surgery and days 1, 3, 5,7,10 and 14 post injury. Behavioral studies were performed in a quiet room between 9:00 to 11:00 AM. All experiments followed the IASP guidelines on ethical standards for investigation of experimental pain in animals.Results: Nefopam (20 and 30mg/kg blocked mechanical and cold allodynia during the experimental period, but the analgesic effects of morphine (5mg/kg lasted for 7 days.Conclusions: It seems that nefopam could effectively reduce pain behavior compared to morphine with reduced adverse effects.

  14. A modified score to identify and discriminate neuropathic pain: a study on the German version of the neuropathic pain symptom inventory (NPSI)

    Science.gov (United States)

    2011-01-01

    Background Neuropathic pain must be correctly diagnosed for optimal treatment. The questionnaire named Neuropathic Pain Symptom Inventory (NPSI) was developed in its original French version to evaluate the different symptoms of neuropathic pain. We hypothesized that the NPSI might also be used to differentiate neuropathic from non-neuropathic pain. Methods We translated the NPSI into German using a standard forward-backward translation and administered it in a case-control design to patients with neuropathic (n = 68) and non-neuropathic pain (headache and osteoarthritis, n = 169) to validate it and to analyze its discriminant properties, its sensitivity to change, and to detect neuropathic pain subgroups with distinct profiles. Results Using a sum score (the NPSI-G score), we found sensitivity to change (r between 0.37 and 0.5 for pain items of the graded chronic pain scale) and could distinguish between neuropathic and other pain on a group basis, but not for individual patients. Post hoc development of a discriminant score with optimized diagnostic properties to distinguish neuropathic pain from non-neuropathic pain resulted in an instrument with high sensitivity (91%) and acceptable specificity (70%). We detected six different pain profiles in the patient group with neuropathic pain; three profiles were found to be distinct. Conclusions The NPSI-G potentially combines the properties of a diagnostic tool and an instrument to identify subtypes of neuropathic pain. PMID:21861889

  15. Neuropathic pain: is quantitative sensory testing helpful?

    Science.gov (United States)

    Krumova, Elena K; Geber, Christian; Westermann, Andrea; Maier, Christoph

    2012-08-01

    Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory system and is characterised by a combination of positive and negative sensory symptoms. Quantitative sensory testing (QST) examines the sensory perception after application of different mechanical and thermal stimuli of controlled intensity and the function of both large (A-beta) and small (A-delta and C) nerve fibres, including the corresponding central pathways. QST can be used to determine detection, pain thresholds and stimulus-response curves and can thus detect both negative and positive sensory signs, the second ones not being assessed by other methods. Similarly to all other psychophysical tests QST requires standardised examination, instructions and data evaluation to receive valid and reliable results. Since normative data are available, QST can contribute also to the individual diagnosis of neuropathy, especially in the case of isolated small-fibre neuropathy, in contrast to the conventional electrophysiology which assesses only large myelinated fibres. For example, detection of early stages of subclinical neuropathy in symptomatic or asymptomatic patients with diabetes mellitus can be helpful to optimise treatment and identify diabetic foot at risk of ulceration. QST assessed the individual's sensory profile and thus can be valuable to evaluate the underlying pain mechanisms which occur in different frequencies even in the same neuropathic pain syndromes. Furthermore, assessing the exact sensory phenotype by QST might be useful in the future to identify responders to certain treatments in accordance to the underlying pain mechanisms.

  16. Pharmacological treatment of diabetic neuropathic pain.

    Science.gov (United States)

    Smith, Howard S; Argoff, Charles E

    2011-03-26

    Neuropathic pain continues to be a difficult and challenging clinical issue to deal with effectively. Painful diabetic polyneuropathy is a complex pain condition that occurs with reasonable frequency in the population and it may be extremely difficult for clinicians to provide patients with effective analgesia. Chronic neuropathic pain may occur in approximately one of every four diabetic patients. The pain may be described as burning or a deep-seated ache with sporadic paroxysms of lancinating painful exacerbations. The pain is often constant, moderate to severe in intensity, usually primarily involves the feet and generally tends to worsen at night. Treatment may be multimodal but largely involves pharmacological approaches. Pharmacological therapeutic options include antidepressants (tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors), α2δ ligands and topical (5%) lidocaine patch. Other agents may be different antiepileptic drugs (carbamazepine, lamotrigine, topiramate), topical capsaicin, tramadol and other opioids. Progress continues with respect to understanding various mechanisms that may contribute to painful diabetic neuropathy. Agents that may hold some promise include neurotrophic factors, growth factors, immunomodulators, gene therapy and poly (adenosine diphosphate-ribose) polymerase inhibitors. It is hoped that in the future clinicians will be able to assess patient pathophysiology, which may help them to match optimal therapeutic agents to target individual patient aberrant mechanisms.

  17. Neuropathic Pain and Spinal Cord Injury: Phenotypes and Pharmacological Management.

    Science.gov (United States)

    Widerström-Noga, Eva

    2017-06-01

    Chronic neuropathic pain is a complicated condition after a spinal cord injury (SCI) that often has a lifelong and significant negative impact on life after the injury; therefore, improved pain management is considered a significant and unmet need. Neuropathic pain mechanisms are heterogeneous and the difficulty in determining their individual contribution to specific pain types may contribute to poor treatment outcomes in this population. Thus, identifying human neuropathic pain phenotypes based on pain symptoms, somatosensory changes, or cognitive and psychosocial factors that reflect specific spinal cord or brain mechanisms of neuropathic pain is an important goal. Once a pain phenotype can be reliably replicated, its relationship with biomarkers and clinical treatment outcomes can be analyzed, and thereby facilitate translational research and further the mechanistic understanding of individual differences in the pain experience and in clinical trial outcomes. The present article will discuss clinical aspects of SCI-related neuropathic pain, neuropathic pain phenotypes, pain mechanisms, potential biomarkers and pharmacological interventions, and progress regarding how defining neuropathic pain phenotypes may lead to more targeted treatments for these difficult pain conditions.

  18. Motor cortex electric stimulation for the treatment of neuropathic pain

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    Walter J. Fagundes-Pereyra

    2010-12-01

    Full Text Available OBJECTIVE: Motor cortex stimulation (MCS is considered to be an effective treatment for chronic neuropathic pain. The aim of the present study was to assess the efficacy of MCS for treating neuropathic pain. METHOD: 27 patients with chronic neuropathic pain were operated. Electrodes were implanted with the use of an stereotactic frame. Electrophysiological evaluations (motor stimulation and somatosensory evoked potentials were performed, with guidance by means of three-dimensional reconstruction of magnetic resonance images of the brain. 10 patients (37% presented central neuropathic pain (post-stroke pain and 17 others (63% presented peripheral neuropathic pain (brachial plexus avulsion, phantom limb pain or trigeminal pain. RESULTS: In 15 patients (57.7% the pain relief was 50% or more; while in ten patients (38.5%, more than 60% of the original pain was relieved. No differences were found in relation to central and peripheral neuropathic pain (p=0.90, pain location (p=0.81, presence of motor deficit (p=0.28 and pain duration (p=0.72. No major complications were observed. CONCLUSION: MCS was efficient for treating patients presenting chronic central or peripheral neuropathic pain.

  19. A preliminary report on stem cell therapy for neuropathic pain in humans

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    Vickers ER

    2014-05-01

    Full Text Available E Russell Vickers,1 Elisabeth Karsten,2 John Flood,3 Richard Lilischkis21Sydney Oral and Maxillofacial Surgery, NSW, Australia; 2Regeneus Ltd, Gordon, NSW, Australia; 3St Vincents Hospital, Sydney, NSW, AustraliaObjective: Mesenchymal stem cells (MSCs have been shown in animal models to attenuate chronic neuropathic pain. This preliminary study investigated if: i injections of autologous MSCs can reduce human neuropathic pain and ii evaluate the safety of the procedure.Methods: Ten subjects with symptoms of neuropathic trigeminal pain underwent liposuction. The lipoaspirate was digested with collagenase and washed with saline three times. Following centrifugation, the stromal vascular fraction was resuspended in saline, and then transferred to syringes for local injections into the pain fields. Outcome measures at 6 months assessed reduction in: i pain intensity measured by standard numerical rating scale from 0–10 and ii daily dosage requirements of antineuropathic pain medication.Results: Subjects were all female (mean age 55.3 years ± standard deviation [SD] 14.67; range 27–80 years with pain symptoms lasting from 4 months to 6 years and 5 months. Lipoaspirate collection ranged from 102–214 g with total cell numbers injected from 33 million to 162 million cells. Cell viability was 62%–91%. There were no systemic or local tissue side effects from the stem cell therapy (n=41 oral and facial injection sites. Clinical pain outcomes showed that at 6 months, 5/9 subjects had reduced both pain intensity scores and use of antineuropathic medication. The mean pain score pre-treatment was 7.5 (SD 1.58 and at 6 months had decreased to 4.3 (SD 3.28, P=0.018, Wilcoxon signed-rank test. Antineuropathic pain medication use showed 5/9 subjects reduced their need for medication (gabapentin, P=0.053, Student's t-test.Conclusion: This preliminary open-labeled study showed autologous administration of stem cells for neuropathic trigeminal pain

  20. (-)-Linalool attenuates allodynia in neuropathic pain induced by spinal nerve ligation in c57/bl6 mice.

    Science.gov (United States)

    Berliocchi, Laura; Russo, Rossella; Levato, Alessandra; Fratto, Vincenza; Bagetta, Giacinto; Sakurada, Shinobu; Sakurada, Tsukasa; Mercuri, Nicola Biagio; Corasaniti, Maria Tiziana

    2009-01-01

    (-)-Linalool is a natural compound with anti-inflammatory and antinociceptive properties. The antinociceptive action of linalool has been reported in several models of inflammatory pain. However, its effects in neuropathic pain have not been investigated. Here, we used the spinal nerve ligation (SNL) model of neuropathic pain and studied the effects of acute and chronic administration of an established antinociceptive dose of linalool on mechanical and thermal sensitivity induced by the nerve injury in mice. Linalool did not affect pain behavior triggered by mechanical or thermal stimuli when administered as a single dose before SNL. However, mechanical allodynia was reduced transiently in neuropathic animals when linalool was administered for 7 consecutive days, while no changes were seen in the sensitivity to noxious radiant heat. We investigated the possible involvement of the PI3K/Akt pathway in linalool antinociceptive effect by western blot analysis. Linalool did not induce significant changes in Akt expression and phopshorylation though a trend toward an increased ratio of phosphorylated versus total Akt was observed in SNL animals treated with linalool, in comparison to SNL alone or sham. We then wondered whether linalool could modulate inflammatory processes and investigated spinal glia activation and IL-1beta contents following linalool treatment in SNL animals. The data suggest that mechanisms other than an action on inflammatory processes may mediate linalool ability to reduce mechanical allodynia in this model of neuropathic pain.

  1. Neuropathic osteoarthropathy: iconographic essay; Osteoartropatia neurotrofica: ensaio iconografico

    Energy Technology Data Exchange (ETDEWEB)

    Fernandes, Joao Luiz; Rocha, Arthemizio Antonio Lopes [Hospital Santa Lucia, Brasilia, DF (Brazil); Viana, Sergio Lopes [Clinica Radiologica Vila Rica, Brasilia DF (Brazil)]. E-mail: radiolog@uol.com.br

    2005-04-15

    Neuropathic osteoarthropathy is characterized by chronic, destructive and non-infectious bone and joint disease developing in patients with some level of loss of proprioception or pain insensitivity. Currently, diabetes mellitus is the most frequent cause of neuropathic osteoarthropathy. The classic appearance on X-rays is bone fragmentation, osteophytosis, joint effusion and joint instability, with preserved bone density. Although conventional X-rays is the most frequently used imaging modality for the evaluation of neuropathic osteoarthropathy and the role of the imaging methods are reviewed as a pictorial essay. (author)

  2. Can We Distinguish between Inflammatory and Neuropathic Pain?

    Directory of Open Access Journals (Sweden)

    Gary J Bennett

    2006-01-01

    Full Text Available Inflammatory and neuropathic pain were once considered to be distinct entities. However, research over the past decade or so has brought to light many shared mechanisms, and the distinction between the two is no longer clear. Consideration of mechanisms, symptoms and the effects of analgesic drugs does not reveal any definitive or universally applicable differentiating factors. Given the present level of understanding, it may not be possible to distinguish between inflammatory and neuropathic pain in a large number of patients, and a satisfying definition of neuropathic pain may not be possible.

  3. Treatment of neuropathic pain: a new method, transdermic route

    Directory of Open Access Journals (Sweden)

    Vittorio Iorno

    2006-05-01

    Full Text Available The therapy of neuropathic pain is difficult due to the lack of reliable classification. This pain can be defined as peripheral, central, mixed or based on the underlying mechanisms. Following this last criterium, we selected 44 patients affected by peripheral neuropathic pain. The not invasive care consisted in giving a pharmacological cocktail by a transdermal hydroelectrophoretic technique. 34% of all patients showed a pain relief between 70 and 99% (good results, while 9% had a complete resolution of pain (very good results. We concluded suggesting the transdermic hydroelectrophoretic techniques as useful and efficient in drugs administration to patients with peripheral neuropathic pain.

  4. Can treatment success with 5% lidocaine medicated plaster be predicted in cancer pain with neuropathic components or trigeminal neuropathic pain?

    Science.gov (United States)

    Kern, Kai-Uwe; Nalamachu, Srinivas; Brasseur, Louis; Zakrzewska, Joanna M

    2013-01-01

    An expert group of 40 pain specialists from 16 countries performed a first assessment of the value of predictors for treatment success with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain. Results were based on the retrospective analysis of 68 case reports (sent in by participants in the 4 weeks prior to the conference) and the practical experience of the experts. Lidocaine plaster treatment was mostly successful for surgery or chemotherapy-related cancer pain with neuropathic components. A dose reduction of systemic pain treatment was observed in at least 50% of all cancer pain patients using the plaster as adjunct treatment; the presence of allodynia, hyperalgesia or pain quality provided a potential but not definitively clear indication of treatment success. In trigeminal neuropathic pain, continuous pain, severe allodynia, hyperalgesia, or postherpetic neuralgia or trauma as the cause of orofacial neuropathic pain were perceived as potential predictors of treatment success with lidocaine plaster. In conclusion, these findings provide a first assessment of the likelihood of treatment benefits with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain and support conducting large, well-designed multicenter studies.

  5. Can treatment success with 5% lidocaine medicated plaster be predicted in cancer pain with neuropathic components or trigeminal neuropathic pain?

    Science.gov (United States)

    Kern, Kai-Uwe; Nalamachu, Srinivas; Brasseur, Louis; Zakrzewska, Joanna M

    2013-01-01

    An expert group of 40 pain specialists from 16 countries performed a first assessment of the value of predictors for treatment success with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain. Results were based on the retrospective analysis of 68 case reports (sent in by participants in the 4 weeks prior to the conference) and the practical experience of the experts. Lidocaine plaster treatment was mostly successful for surgery or chemotherapy-related cancer pain with neuropathic components. A dose reduction of systemic pain treatment was observed in at least 50% of all cancer pain patients using the plaster as adjunct treatment; the presence of allodynia, hyperalgesia or pain quality provided a potential but not definitively clear indication of treatment success. In trigeminal neuropathic pain, continuous pain, severe allodynia, hyperalgesia, or postherpetic neuralgia or trauma as the cause of orofacial neuropathic pain were perceived as potential predictors of treatment success with lidocaine plaster. In conclusion, these findings provide a first assessment of the likelihood of treatment benefits with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain and support conducting large, well-designed multicenter studies. PMID:23630431

  6. Galectin-3 Inhibition Is Associated with Neuropathic Pain Attenuation after Peripheral Nerve Injury.

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    Zhicong Ma

    Full Text Available Neuropathic pain remains a prevalent and persistent clinical problem because it is often poorly responsive to the currently used analgesics. It is very urgent to develop novel drugs to alleviate neuropathic pain. Galectin-3 (gal3 is a multifunctional protein belonging to the carbohydrate-ligand lectin family, which is expressed by different cells. Emerging studies showed that gal3 elicits a pro-inflammatory response by recruiting and activating lymphocytes, macrophages and microglia. In the study we investigated whether gal3 inhibition could suppress neuroinflammation and alleviate neuropathic pain following peripheral nerve injury. We found that L5 spinal nerve ligation (SNL increases the expression of gal3 in dorsal root ganglions at the mRNA and protein level. Intrathecal administration of modified citrus pectin (MCP, a gal3 inhibitor, reduces gal3 expression in dorsal root ganglions. MCP treatment also inhibits SNL-induced gal3 expression in primary rat microglia. SNL results in an increased activation of autophagy that contributes to microglial activation and subsequent inflammatory response. Intrathecal administration of MCP significantly suppresses SNL-induced autophagy activation. MCP also inhibits lipopolysaccharide (LPS-induced autophagy in cultured microglia in vitro. MCP further decreases LPS-induced expression of proinflammatory mediators including IL-1β, TNF-α and IL-6 by regulating autophagy. Intrathecal administration of MCP results in adecreased mechanical and cold hypersensitivity following SNL. These results demonstrated that gal3 inhibition is associated with the suppression of SNL-induced inflammatory process andneurophathic pain attenuation.

  7. Recombinant neural progenitor transplants in the spinal dorsal horn alleviate chronic central neuropathic pain.

    Science.gov (United States)

    Jergova, Stanislava; Gajavelli, Shyam; Pathak, Nirmal; Sagen, Jacqueline

    2016-04-01

    Neuropathic pain induced by spinal cord injury (SCI) is clinically challenging with inadequate long-term treatment options. Partial pain relief offered by pharmacologic treatment is often counterbalanced by adverse effects after prolonged use in chronic pain patients. Cell-based therapy for neuropathic pain using GABAergic neuronal progenitor cells (NPCs) has the potential to overcome untoward effects of systemic pharmacotherapy while enhancing analgesic potency due to local activation of GABAergic signaling in the spinal cord. However, multifactorial anomalies underlying chronic pain will likely require simultaneous targeting of multiple mechanisms. Here, we explore the analgesic potential of genetically modified rat embryonic GABAergic NPCs releasing a peptidergic NMDA receptor antagonist, Serine-histogranin (SHG), thus targeting both spinal hyperexcitability and reduced inhibitory processes. Recombinant NPCs were designed using either lentiviral or adeno-associated viral vectors (AAV2/8) encoding single and multimeric (6 copies of SHG) cDNA. Intraspinal injection of recombinant cells elicited enhanced analgesic effects compared with nonrecombinant NPCs in SCI-induced pain in rats. Moreover, potent and sustained antinociception was achieved, even after a 5-week postinjury delay, using recombinant multimeric NPCs. Intrathecal injection of SHG antibody attenuated analgesic effects of the recombinant grafts suggesting active participation of SHG in these antinociceptive effects. Immunoblots and immunocytochemical assays indicated ongoing recombinant peptide production and secretion in the grafted host spinal cords. These results support the potential for engineered NPCs grafted into the spinal dorsal horn to alleviate chronic neuropathic pain.

  8. Treatment of localized neuropathic pain after disk herniation with 5% lidocaine medicated plaster

    Science.gov (United States)

    Likar, Rudolf; Kager, Ingo; Obmann, Michael; Pipam, Wolfgang; Sittl, Reinhard

    2012-01-01

    Objective To assess treatment with the 5% lidocaine medicated plaster for peripheral neuropathic pain after disk herniation. Study design Case series, single center, retrospective data. Patients and methods Data of 23 patients treated for neuropathic pain with the lidocaine plaster for up to 24 months after a protrusion or prolapse of the cervical, thoracic, or lumbar vertebral disks were retrospectively analyzed. Changes in overall pain intensity, in intensity of different pain qualities and of allodynia and hyperalgesia were evaluated. Results Patients (14 female/nine male, mean age 53.5 ± 10.4 years) presented with radiating pain into the abdomen, back, neck, shoulder, or legs and feet with a mean pain intensity of 8.3 ± 1.5 on the 11-point Likert scale. Mean treatment duration was 7.6 months; 52% of the patients received lidocaine plaster as monotherapy. At the end of the observation, mean overall pain intensity had been reduced to 3.1 ± 1.8. All other parameters also improved. The treatment was well tolerated. Conclusion These results point to a safe and effective treatment approach with 5% lidocaine medicated plaster for localized neuropathic pain related to disk herniation. However, owing to the small sample size, further investigation in a larger-scale controlled trial is warranted. PMID:22973116

  9. Treatment of localized neuropathic pain after disk herniation with 5% lidocaine medicated plaster.

    Science.gov (United States)

    Likar, Rudolf; Kager, Ingo; Obmann, Michael; Pipam, Wolfgang; Sittl, Reinhard

    2012-01-01

    To assess treatment with the 5% lidocaine medicated plaster for peripheral neuropathic pain after disk herniation. Case series, single center, retrospective data. Data of 23 patients treated for neuropathic pain with the lidocaine plaster for up to 24 months after a protrusion or prolapse of the cervical, thoracic, or lumbar vertebral disks were retrospectively analyzed. Changes in overall pain intensity, in intensity of different pain qualities and of allodynia and hyperalgesia were evaluated. Patients (14 female/nine male, mean age 53.5 ± 10.4 years) presented with radiating pain into the abdomen, back, neck, shoulder, or legs and feet with a mean pain intensity of 8.3 ± 1.5 on the 11-point Likert scale. Mean treatment duration was 7.6 months; 52% of the patients received lidocaine plaster as monotherapy. At the end of the observation, mean overall pain intensity had been reduced to 3.1 ± 1.8. All other parameters also improved. The treatment was well tolerated. These results point to a safe and effective treatment approach with 5% lidocaine medicated plaster for localized neuropathic pain related to disk herniation. However, owing to the small sample size, further investigation in a larger-scale controlled trial is warranted.

  10. Effectiveness of transcranial direct current stimulation and visual illusion on neuropathic pain in spinal cord injury.

    Science.gov (United States)

    Soler, Maria Dolors; Kumru, Hatice; Pelayo, Raul; Vidal, Joan; Tormos, Josep Maria; Fregni, Felipe; Navarro, Xavier; Pascual-Leone, Alvaro

    2010-09-01

    The aim of this study was to evaluate the analgesic effect of transcranial direct current stimulation of the motor cortex and techniques of visual illusion, applied isolated or combined, in patients with neuropathic pain following spinal cord injury. In a sham controlled, double-blind, parallel group design, 39 patients were randomized into four groups receiving transcranial direct current stimulation with walking visual illusion or with control illusion and sham stimulation with visual illusion or with control illusion. For transcranial direct current stimulation, the anode was placed over the primary motor cortex. Each patient received ten treatment sessions during two consecutive weeks. Clinical assessment was performed before, after the last day of treatment, after 2 and 4 weeks follow-up and after 12 weeks. Clinical assessment included overall pain intensity perception, Neuropathic Pain Symptom Inventory and Brief Pain Inventory. The combination of transcranial direct current stimulation and visual illusion reduced the intensity of neuropathic pain significantly more than any of the single interventions. Patients receiving transcranial direct current stimulation and visual illusion experienced a significant improvement in all pain subtypes, while patients in the transcranial direct current stimulation group showed improvement in continuous and paroxysmal pain, and those in the visual illusion group improved only in continuous pain and dysaesthesias. At 12 weeks after treatment, the combined treatment group still presented significant improvement on the overall pain intensity perception, whereas no improvements were reported in the other three groups. Our results demonstrate that transcranial direct current stimulation and visual illusion can be effective in the management of neuropathic pain following spinal cord injury, with minimal side effects and with good tolerability.

  11. EFNS guidelines on pharmacological treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Attal, Nadine; Cruccu, G; Haanpää, M

    2006-01-01

    Neuropathic pain treatment remains unsatisfactory despite a substantial increase in the number of trials. This EFNS Task Force aimed at evaluating the existing evidence about the pharmacological treatment of neuropathic pain. Studies were identified using first the Cochrane Database then Medline...... neuralgia, other peripheral neuropathic pain states and multiple-aetiology neuropathic pains. The main peripheral pain conditions respond similarly well to tricyclic antidepressants, gabapentin, and pregabalin, but some conditions, such as HIV-associated polyneuropathy, are more refractory. There are too...... evaluated. Effects on pain symptoms/signs, quality of life and comorbidities were particularly searched for. Most of the randomized controlled trials included patients with postherpetic neuralgia (PHN) and painful polyneuropathies (PPN) mainly caused by diabetes. These trials provide level A evidence...

  12. Minociclyne, microglia and neuropathic pain (Minociclina, microglia e dolore neuropatico

    Directory of Open Access Journals (Sweden)

    Maria Luisa Sotgiu

    2014-03-01

    Full Text Available An update on minocicline properties with particular focus on its effect on the microglia activation and on a possible therapeutic utilization as analgesic in neuropathic pain is presented.

  13. MRI in acute neuropathic Gaucher's disease

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Y.C. [Department of Paediatrics, Chang Gung Memorial Children' s Hospital in Kaohsiung, Taiwan (Taiwan); Huang, C.C. [National Cheng Kung University Hospital, Taiwan (Taiwan); Chen, C.Y. [Department of Diagnostic Radiology, Tri-Service General Hospital and National Defence Medical Centre, Taipei (Taiwan); Zimmerman, R.A. [Department of Radiology, Children' s Hospital of Philadelphia (United States)

    2000-01-01

    We present the cranial MRI findings in a 6-month-old girl with biopsy-proven acute neuropathic Gaucher's disease, which include unilateral cerebral atrophy and dural thickening with contrast enhancement. (orig.)

  14. Biochanin-A attenuates neuropathic pain in diabetic rats

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    Venkateswarlu Chundi

    2016-10-01

    Conclusion: Biochanin-A demonstrated better efficacy in reversing mechanical allodynia than mechanical hyperalgesia. Biochanin-A could be a good drug candidate for further studies to establish the mechanism of attenuation of neuropathic pain.

  15. Prevalence of Neuropathic Pain and the Need for Treatment

    Directory of Open Access Journals (Sweden)

    Pat Morley-Forster

    2006-01-01

    There is an unmet need for the treatment of neuropathic pain as evidenced by reports of pain despite the use of opioids and anticonvulsants, continuing psychological difficulties, lack of access to treatments and patients seeking access to complementary therapy.

  16. Neuropathic Pain Treatment: Still a Challenge

    Science.gov (United States)

    Nascimento, Osvaldo J.M.; Pessoa, Bruno L.; Orsini, Marco; Ribeiro, Pedro; Davidovich, Eduardo; Pupe, Camila; Filho, Pedro Moreira; Dornas, Ricardo Menezes; Masiero, Lucas; Bittencourt, Juliana; Bastos, Victor Hugo

    2016-01-01

    Neuropathic pain (NP) is the result of a series of conditions caused by diseases or lesions to the somatosensory system. Due to the better understanding of NP pathophysiology previously unexplored therapies have been used with encouraging results. In this group, acetyl-L-carnitine, alpha-lipoic-acid, cannabinoids, clonidine, EMA401, botulinum toxin type A and new voltage-gated sodium channel blockers, can be included. Besides, changing paradigms may occur with the advent of optogenetics and a better understanding of epigenetic regulation. We reviewed the published literature on the pharmacological treatment of NP. Despite the interesting results, randomized controlled trials are demanded the majority of the therapies previously mentioned. In spite of several studies for the relief of NP, pain control continues being a challenge. PMID:27441065

  17. Neuropathic pain treatment: still a challenge

    Directory of Open Access Journals (Sweden)

    Osvaldo J.M. Nascimento

    2016-06-01

    Full Text Available Neuropathic pain (NP is the result of a series of conditions caused by diseases or lesions to the somatosensory system. Due to the better understanding of NP pathophysiology previously unexplored therapies have been used with encouraging results. In this group, acetyl-L-carnitine, alpha-lipoic-acid, cannabinoids, clonidine, EMA401, botulinum toxin type A and new voltage-gated sodium channel blockers, can be included. Besides, changing paradigms may occur with the advent of optogenetics and a better understanding of epigenetic regulation. We reviewed the published literature on the pharmacological treatment of NP. Despite the interesting results, randomized controlled trials are demanded the majority of the therapies previously mentioned. In spite of several studies for the relief of NP, pain control continues being a challenge.

  18. Diabetic neuropathic cachexia: report of a recurrent case

    OpenAIRE

    Jackson, C; R. Barohn

    1998-01-01

    Diabetic neuropathic cachexia is an uncommon peripheral neuropathy associated with diabetes mellitus and characterised by profound weight loss and painful dysaesthesias over the limbs and trunk. The pathophysiological basis of this disorder remains unknown and there have been no published cases of recurrent episodes. A hispanic man who experienced two episodes of diabetic neuropathic cachexia over a seven year period is described.



  19. Prevalence of Neuropathic Pain and the Need for Treatment

    OpenAIRE

    Pat Morley-Forster

    2006-01-01

    Recent publications have suggested that more than two million adults in the United States suffer from neuropathic pain, but this number seems to be a significant underestimate. The prevalence of neuropathic pain from diabetes and postherpetic neuralgia alone, using the most conservative estimates of incidence, would equal two million Americans. Lesions of the nervous system responsible for pain genesis can occur either in the central or the peripheral nervous system. The most common causes of...

  20. mir-500-Mediated GAD67 Downregulation Contributes to Neuropathic Pain.

    Science.gov (United States)

    Huang, Zhen-Zhen; Wei, Jia-You; Ou-Yang, Han-Dong; Li, Dai; Xu, Ting; Wu, Shao-Ling; Zhang, Xiao-Long; Liu, Cui-Cui; Ma, Chao; Xin, Wen-Jun

    2016-06-08

    Neuropathic pain is a common neurobiological disease involving multifaceted maladaptations ranging from gene modulation to synaptic dysfunction, but the interactions between synaptic dysfunction and the genes that are involved in persistent pain remain elusive. In the present study, we found that neuropathic pain induced by the chemotherapeutic drug paclitaxel or L5 ventral root transection significantly impaired the function of GABAergic synapses of spinal dorsal horn neurons via the reduction of the GAD67 expression. We also found that mir-500 expression was significantly increased and involved in the modulation of GAD67 expression via targeting the specific site of Gad1 gene in the dorsal horn. In addition, knock-out of mir-500 or using mir-500 antagomir rescued the GABAergic synapses in the spinal dorsal horn neurons and attenuated the sensitized pain behavior in the rats with neuropathic pain. To our knowledge, this is the first study to investigate the function significance and the underlying molecular mechanisms of mir-500 in the process of neuropathic pain, which sheds light on the development of novel therapeutic options for neuropathic pain. Neuropathic pain is a common neurobiological disease involving multifaceted maladaptations ranging from gene modulation to synaptic dysfunction, but the underlying molecular mechanisms remain elusive. The present study illustrates for the first time a mir-500-mediated mechanism underlying spinal GABAergic dysfunction and sensitized pain behavior in neuropathic pain induced by the chemotherapeutic drug paclitaxel or L5 ventral root transection, which sheds light on the development of novel therapeutic options for neuropathic pain. Copyright © 2016 the authors 0270-6474/16/366321-11$15.00/0.

  1. Evidence-based pharmacological management of chronic neuropathic pain

    Directory of Open Access Journals (Sweden)

    Zarrin Ansari

    2013-06-01

    Full Text Available Neuropathic pain (NP is a chronic, debilitating symptomatology of lesions/injuries of the central and peripheral nervous system. As per pooled estimates, the prevalence is 7-8% in the general population; however, the prevalence varies with different neuropathic conditions. The aetiology can range from peripheral neuropathic conditions viz. peripheral diabetic neuropathic pain (PDNP, post-herpetic neuralgia (PHN, trigeminal neuralgia, HIV- associated polyneuropathy, cervical radiculopathy to central neuropathic conditions, viz. central post-stroke pain, spinal cord injury and the neuropathic pain associated with multiple sclerosis. Apart from the symptomatic perception of pain, neuropathic pain affects the cognitive and emotional aspects of the affected individual. The pain, being debilitating and resistant to over-the-counter analgesics, diminishes the quality of life, disrupts sleep and leads to psychiatric complications such as comorbid anxiety and depression. The management is palliative and involves drugs, psychological intervention, stimulations and nerve-blocking techniques. This review concentrates on the pharmacological therapeutic options available and focuses on the selection of the agent/s in accordance with the evidence. The first-line treatment includes the tricyclic antidepressants ([TCAs]; amitriptyline, nortriptyline, selective serotonin norepinephrine inhibitors ([SNRIs]; duloxetine, venlafaxine, calcium channel alpha 2 - delta ligands (pregabalin, gabapentin, carbamazepine and oxcarbazepine. Lidocaine plasters are first-line options for specific focal conditions such as post-herpetic neuralgia. The second-line therapy includes the opioid analgesics and tramadol. The choice of drug selection should complement the patient’s age, type of neuropathic condition, tolerability to an agent, comorbid condition and cost-effectiveness. Management must be individualized with a realistic and composite goal of making the pain tolerable and

  2. Human surrogate models of neuropathic pain: validity and limitations.

    Science.gov (United States)

    Binder, Andreas

    2016-02-01

    Human surrogate models of neuropathic pain in healthy subjects are used to study symptoms, signs, and the hypothesized underlying mechanisms. Although different models are available, different spontaneous and evoked symptoms and signs are inducible; 2 key questions need to be answered: are human surrogate models conceptually valid, ie, do they share the sensory phenotype of neuropathic pain states, and are they sufficiently reliable to allow consistent translational research?

  3. Inhibition of glycogen synthase kinase 3β activity with lithium prevents and attenuates paclitaxel-induced neuropathic pain.

    Science.gov (United States)

    Gao, M; Yan, X; Weng, H-R

    2013-12-19

    Paclitaxel (taxol) is a first-line chemotherapy-drug used to treat many types of cancers. Neuropathic pain and sensory dysfunction are the major toxicities, which are dose-limiting and significantly reduce the quality of life in patients. Two known critical spinal mechanisms underlying taxol-induced neuropathic pain are an increased production of pro-inflammatory cytokines including interleukin-1β (IL-1β) and suppressed glial glutamate transporter activities. In this study, we uncovered that increased activation of glycogen synthase kinase 3beta (GSK3β) in the spinal dorsal horn was concurrently associated with increased protein expressions of GFAP, IL-1β and a decreased protein expression of glial glutamate transporter 1 (GLT-1), as well as the development and maintenance of taxol-induced neuropathic pain. The enhanced GSK3β activities were supported by the concurrently decreased AKT and mTOR activities. The changes of all these biomarkers were basically prevented when animals received pre-emptive lithium (a GSK3β inhibitor) treatment, which also prevented the development of taxol-induced neuropathic pain. Further, chronic lithium treatment, which began on day 11 after the first taxol injection, reversed the existing mechanical and thermal allodynia induced by taxol. The taxol-induced increased GSK3β activities and decreased AKT and mTOR activities in the spinal dorsal horn were also reversed by lithium. Meanwhile, protein expressions of GLT-1, GFAP and IL-1β in the spinal dorsal horn were improved. Hence, suppression of spinal GSK3β activities is a key mechanism used by lithium to reduce taxol-induced neuropathic pain, and targeting spinal GSK3β is an effective approach to ameliorate GLT-1 expression and suppress the activation of astrocytes and IL-1β over-production in the spinal dorsal horn.

  4. Aloperine attenuated neuropathic pain induced by chronic constriction injury via anti-oxidation activity and suppression of the nuclear factor kappa B pathway

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    Xu, Ya-Qiong [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Jin, Shao-Ju [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Luohe Medical College, Luohe 462002, Henan Province (China); Liu, Ning [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Li, Yu-Xiang [College of Nursing, Ningxia Medical University, Yinchuan 750004 (China); Zheng, Jie [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Ma, Lin [Ningxia Key Lab of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan 750004 (China); Du, Juan; Zhou, Ru [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Zhao, Cheng-Jun [Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan 750000 (China); Niu, Yang [Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004 (China); Sun, Tao [Ningxia Key Lab of Craniocerebral Diseases of Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan 750004 (China); Yu, Jian-Qiang, E-mail: Yujq910315@163.com [Department of Pharmacology, Ningxia Medical university, Yinchuan 750000 (China); Luohe Medical College, Luohe 462002, Henan Province (China)

    2014-09-05

    Highlights: • Aloperine has anti-nociceptive effects on neuropathic pain induced CCI. • Aloperine reduces ROS in neuropathic pain mice. • Aloperine down-regulates the expression of NF-κB and its downstream pro-inflammatory cytokines in neuropathic pain mice. - Abstract: Objective: To investigate whether aloperine (ALO) has antinociceptive effects on neuropathic pain induced by chronic constriction injury, whether ALO reduces ROS against neuropathic pain, and what are the mechanisms involved in ALO attenuated neuropathic pain. Methods: Mechanical and cold allodynia, thermal and mechanical hyperalgesia and spinal thermal hyperalgesia were estimated by behavior methods such as Von Frey filaments, cold-plate, radiant heat, paw pressure and tail immersion on one day before surgery and days 7, 8, 10, 12 and 14 after surgery, respectively. In addition, T-AOC, GSH-PX, T-AOC and MDA in the spinal cord (L4/5) were measured to evaluate anti-oxidation activity of ALO on neuropathic pain. Expressions of NF-κB and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in the spinal cord (L4/5) were analyzed by using Western blot. Results: Administration of ALO (80 mg/kg and 40 mg/kg, i.p.) significantly increased paw withdrawal threshold, paw pressure, paw withdrawal latencies, tail-curling latencies, T-AOC, GSH-PX and T-SOD concentration, reduced the numbers of paw lifts and MDA concentration compared to CCI group. ALO attenuated CCI induced up-regulation of expressions of NF-κB, TNF-α, IL-6, IL-1β at the dose of 80 mg/kg (i.p.). Pregabalin produced similar effects serving as positive control at the dose of 10 mg/kg (i.p.). Conclusion: ALO has antinociceptive effects on neuropathic pain induced by CCI. The antinociceptive effects of ALO against neuropathic pain is related to reduction of ROS, via suppression of NF-κB pathway.

  5. [Pharmacological treatment strategy and mirror visual feedback treatment for neuropathic pain].

    Science.gov (United States)

    Sumitani, Masahiko; Miyauchi, Satoru; Yamada, Yoshitsugu

    2012-11-01

    Neuropathic pain is a debilitating condition, and pharmacotherapy is the most established treatment strategy. A variety of pharmacotherapies is used for neuropathic pain management: however, pharmacotherapies with evidence for analgesic potency are less common. Several pharmacotherapeutic treatment guidelines for neuropathic pain treatment recommend the first- to third-line drugs on the basis of evidence-based medicine; however, neuropathic pain is often resistant to pharmacotherapies. We have treated pharmacotherapy-resistant neuropathic pain with neurorehabilitation techniques such as mirror visual feedback (MVF) treatment. Further to our clinical experience using MVF, we discuss the cerebral mechanism associated with neuropathic pain in this study.

  6. Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons.

    Science.gov (United States)

    Zhang, Zhi-Jun; Cao, De-Li; Zhang, Xin; Ji, Ru-Rong; Gao, Yong-Jing

    2013-10-01

    Recent studies have indicated an important role of chemokines such as CCL2 in the development of chronic pain. However, the distinct roles of different chemokines in the development and maintenance of neuropathic pain and in their interactions with neurons have not been clearly elucidated. We found that spinal nerve ligation (SNL) not only induced persistent neuropathic pain symptoms, including mechanical allodynia and heat hyperalgesia, but also produced sustained CXCL1 upregulation in the spinal cord. Double staining of immunofluorescence and in situ hybridization revealed that CXCL1 was primarily induced in spinal astrocytes. In cultured astrocytes, tumor necrosis factor-α induced robust CXCL1 expression via the activation of the c-jun N-terminal kinase. Intrathecal administration of CXCL1 neutralizing antibody transiently reduced SNL-induced pain hypersensitivity, suggesting an essential role of CXCL1 in neuropathic pain sensitization. In particular, intraspinal delivery of CXCL1 shRNA lentiviral vectors, either before or after SNL, persistently attenuated SNL-induced pain hypersensitivity. Spinal application of CXCL1 not only elicited pain hypersensitivity but also induced rapid neuronal activation, as indicated by the expression of phosphorylated extracellular signal-regulated kinase and cAMP response element binding protein, and c-Fos in spinal cord neurons. Interestingly, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after SNL, and the CXCR2 antagonist SB225002 completely blocked the CXCL1-induced heat hyperalgesia. SB225002 also attenuated SNL-induced pain hypersensitivity. Collectively, our results have demonstrated a novel form of chemokine-mediated glial-neuronal interaction in the spinal cord that can drive neuropathic pain. Inhibition of the CXCL1-CXCR2 signaling may offer a new therapy for neuropathic pain management.

  7. Activation of Corticostriatal Circuitry Relieves Chronic Neuropathic Pain

    Science.gov (United States)

    Lee, Michelle; Manders, Toby R.; Eberle, Sarah E.; Su, Chen; D'amour, James; Yang, Runtao; Lin, Hau Yueh; Deisseroth, Karl; Froemke, Robert C.

    2015-01-01

    Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation. PMID:25834050

  8. A subset of μ-opioid receptor-expressing cells in the rostral ventromedial medulla contribute to thermal hyperalgesia in experimental neuropathic pain.

    Science.gov (United States)

    Mase, Hiroshi; Sakai, Atsushi; Sakamoto, Atsuhiro; Suzuki, Hidenori

    2011-05-01

    The rostral ventromedial medulla (RVM) is a major region for the descending modulation of pain at the spinal cord level, and neurons in the RVM have been implicated in the inhibition and facilitation of spinal nociceptive transmission. Although recent studies have established that the RVM facilitation of nociceptive transmission in the spinal cord contributes to neuropathic pain, the underlying mechanisms remain largely unknown. In the present study, we investigated the effects of kainic acid (KA)-induced RVM damage on neuropathic pain behavior and the expression of molecules implicated in pain modulation. KA was injected into the RVM midline region after neuropathic pain was established by chronic constrictive injury of the left sciatic nerve. Thermal hyperalgesia, but not mechanical allodynia, was persistently suppressed in the ipsilateral paw by a single KA injection into the RVM for at least the next 7 days in a rat neuropathic pain model. KA injection alone did not affect the nocifensive responses to mechanical and thermal stimuli on the intact side. Immunohistochemical analysis revealed that KA injection into the RVM significantly reduced the number of immunoreactive neurons for μ-opioid receptors, but not tryptophan hydroxylase, in association with the analgesic effect. These results suggest that a subset of RVM neurons expressing μ-opioid receptors contribute to the maintenance of thermal hyperalgesia in neuropathic pain.

  9. Mechanisms of disease: mechanism-based classification of neuropathic pain - a critical analysis

    DEFF Research Database (Denmark)

    Finnerup, Nanna Brix; Jensen, Troels Staehelin

    2006-01-01

    Classification of neuropathic pain according to etiology or localization has clear limitations. The discovery of specific molecular and cellular events following experimental nerve injury has raised the possibility of classifying neuropathic pain on the basis of the underlying neurobiological...

  10. Treatment of interstitial cystitis/painful bladder syndrome as a neuropathic pain condition

    Directory of Open Access Journals (Sweden)

    Lakshmi Vas

    2014-01-01

    Full Text Available A lady of 52 years with painful bladder syndrome/interstitial cystitis (PBS/IC presented with chronic pelvic pain, irritative voiding with sphincter dominance on urodynamics. 3 yrs of oral analgesics, antispasmodics and intravesical therapy was ineffective. We surmised her pain, and irritative voiding to be secondary to constant straining against a dysfunctional pelvic floor. We treated PBS/IC as a neuropathic phenomenon with a combination of neuromodulator medications and continuous caudal epidural analgesia to reduce the pain induced peripheral and central sensitisation. Botulinum toxin type A injection into pelvic floor muscles appeared to address their dysfuction. Clinical and urodynamics response was encouraging.

  11. Synergistic antiallodynic interaction between gabapentin or carbamazepine and either benfotiamine or cyanocobalamin in neuropathic rats.

    Science.gov (United States)

    Mixcoatl-Zecuatl, Teresa; Quinonez-Bastidas, Geovanna N; Caram-Salas, Nadia L; Ambriz-Tututi, Monica; Araiza-Saldana, Claudia I; Rocha-Gonzalez, Hector I; Medina-Santillan, Roberto; Reyes-Garcia, Gerardo; Granados-Soto, Vinicio

    2008-01-01

    Anticonvulsants, including gabapentin and carbamazepine, have shown activity against several types of neuropathic pain; however, they have limiting side effects that may minimize their use. In this study the possible synergistic interaction between anticonvulsants and benfotiamine or cyanocobalamin on spinal nerve ligation-induced tactile allodynia was assessed. Oral administration of gabapentin (15-300 mg/kg), carbamazepine (10-300 mg/kg), benfotiamine (30-600 mg/kg) or cyanocobalamin (0.3-6.0 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with gabapentin 300 mg/kg (approximately 70%), carbamazepine 300 mg/kg (approximately 66%), benfotiamine 600 mg/kg (approximately 51%) and cyanocobalamin 6 mg/kg (approximately 59%). At the highest tested doses, gabapentin, but not carbamazepine, benfotiamine or cyanocobalamin, significantly reduced motor coordination. Coadministration of gabapentin or carbamazepine with benfotiamine or cyanocobalamin in a fixed ratio markedly reduced spinal nerve ligation-induced tactile allodynia, showing a synergistic interaction between anticonvulsants and B vitamins. Data indicate that combinations of anticonvulsants with benfotiamine or cyanocobalamin are able to reduce tactile allodynia without affecting motor coordination in rats, and suggest the possible clinical use of these combinations in the treatment of neuropathic pain in humans.

  12. Classification issues related to neuropathic trigeminal pain.

    Science.gov (United States)

    Zakrzewska, Joanna M

    2004-01-01

    The goal of a classification system of medical conditions is to facilitate accurate communication, to ensure that each condition is described uniformly and universally and that all data banks for the storage and retrieval of research and clinical data related to the conditions are consistent. Classification entails deciding which kinds of diagnostic entities should be recognized and how to order them in a meaningful way. Currently there are 3 major pain classification systems of relevance to orofacial pain: The International Association for the Study of Pain classification system, the International Headache Society classification system, and the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). All use different methodologies, and only the RDC/TMD take into account social and psychologic factors in the classification of conditions. Classification systems need to be reliable, valid, comprehensive, generalizable, and flexible, and they need to be tested using consensus views of experts as well as the available literature. There is an urgent need for a robust classification system for neuropathic trigeminal pain.

  13. Carbamazepine Withdrawal-induced Hyperalgesia in Chronic Neuropathic Pain.

    Science.gov (United States)

    Ren, Zhenyu; Yang, Bing; Yang, Bin; Shi, Le; Sun, Qing-Li; Sun, A-Ping; Lu, Lin; Liu, Xiaoguang; Zhao, Rongsheng; Zhai, Suodi

    2015-11-01

    Combined pharmacological treatments are the most used approach for neuropathic pain. Carbamazepine, an antiepileptic agent, is generally used as a third-line treatment for neuropathic pain and can be considered an option only when patients have not responded to the first- and second-line medications. In the case presented herein, a patient with neuropathic pain was treated using a combined pharmacological regimen. The patient's pain deteriorated, despite increasing the doses of opioids, when carbamazepine was discontinued, potentially because carbamazepine withdrawal disrupted the balance that was achieved by the multifaceted pharmacological regimen, thus inducing hyperalgesia. Interestingly, when carbamazepine was prescribed again, the patient's pain was successfully managed. Animal research has reported that carbamazepine can potentiate the analgesic effectiveness of morphine in rodent models of neuropathic pain and postoperative pain. This clinical case demonstrates that carbamazepine may have a synergistic effect on the analgesic effectiveness of morphine and may inhibit or postpone opioid-induced hyperalgesia. We postulate that a probable mechanism of action of carbamazepine may involve -aminobutyric acid-ergic potentiation and the interruption of glutamatergic function via N-methyl-D-aspartate receptors. Further research is warranted to clarify the analgesic action of carbamazepine and its potential use for the prevention of opioid-induced hyperalgesia in chronic neuropathic pain patients.

  14. The evidence for pharmacological treatment of neuropathic pain.

    Science.gov (United States)

    Finnerup, Nanna Brix; Sindrup, Søren Hein; Jensen, Troels Staehelin

    2010-09-01

    Randomized, double-blind, placebo-controlled trials on neuropathic pain treatment are accumulating, so an updated review of the available evidence is needed. Studies were identified using MEDLINE and EMBASE searches. Numbers needed to treat (NNT) and numbers needed to harm (NNH) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions. One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients.

  15. Cortical disinhibition in diabetic patients with neuropathic pain.

    Science.gov (United States)

    Turgut, N; Altun, B U

    2009-12-01

    Motor cortex disinhibition has a role in the mechanism of neuropathic pain. The duration of the cortical silent period (CSP) is used as a measure of excitability in cortical inhibitory circuits. We investigated cortical disinhibition in diabetic patients with and without neuropathic pain. We studied diabetic patients with (n = 20) and without (n = 50) neuropathic pain, and control subjects (n = 30). Transcranial magnetic stimulation (TMS) was performed on the right hemisphere at rest, and surface electromyography was recorded from the left first dorsal interosseous muscle for evaluation of motor evoked potential (MEP) latency and amplitude. CSP was recorded from the left FDI, and TMS was then delivered while the subject was performing a voluntary contraction. We showed a low resting motor threshold, a short CSP duration, and a low CSP duration/MEP amplitude ratio in patients with neuropathic pain (P < 0.0001, P < 0.0001, P < 0.0001). Our findings demonstrate that diabetic patients with neuropathic pain have a cortical disinhibition.

  16. Neuropathic pain. Redefinition and a grading system for clinical and research purposes

    DEFF Research Database (Denmark)

    Treede, R.-D.; Jensen, Troels Staehelin; Campbell, J.N.

    2008-01-01

    diagnostic tool for neuropathic pain, a grading system of definite, probable, and possible neuropathic pain is proposed. The grade possible can only be regarded as a working hypothesis, which does not exclude but does not diagnose neuropathic pain. The grades probable and definite require confirmatory...... evidence from a neurologic examination. This grading system is proposed for clinical and research purposes....

  17. Effect of a polyherbal formulation cream on diabetic neuropathic pain among patients with type 2 diabetes - A pilot study

    OpenAIRE

    Vijay Viswanathan; Seena Rajsekar; Bamila Selvaraj; Satyavani Kumpatla

    2016-01-01

    Background & objectives: Painful diabetic neuropathy is a common complication of diabetes and can severely limit patients′ daily functions. The aim of this pilot study was to evaluate the safety and effect of using a polyherbal formulation in reducing the symptoms of diabetic neuropathic pain in comparison with placebo among patients with type 2 diabetes. Methods: A total of 50 (M:F = 33:17) consecutive type 2 diabetes patients with painful diabetic neuropathy were enrolled in this study....

  18. Sustained-release pregabalin with methylcobalamin in neuropathic pain: an Indian real-life experience

    Directory of Open Access Journals (Sweden)

    Dongre YU

    2013-05-01

    Full Text Available Yasmin U Dongre, Onkar C Swami Unichem Laboratories Ltd, Unichem Bhavan, Mumbai, India Introduction: Neuropathic pain is intense in nature and difficult to manage. Thus, the primary goal is maximum relief from pain. The aim of this study was to assess the efficacy and safety of a fixed-dose combination of sustained-release pregabalin and methylcobalamin in reducing neuropathic pain in Indian patients, in the real-life situation. Methods: This was a multicenter, prospective, open-labeled, single-arm, observational, 14-day study. Patients received fixed dose combination of 75 or 150 mg sustained-release pregabalin combined with 1500 mcg immediate release methylcobalamin, depending on the clinical requirement. Data was collected for pain reduction and other positive and negative symptoms associated with neuropathy, including hyperesthesia, paresthesia, numbness/tingling, burning sensation, muscle weakness, sleep disturbances, and impairment of movement. Pain intensity was measured on a ten-point visual analog scale (VAS (0 represented "no pain," and 10 represented "worst pain ever". The safety of the drug was also evaluated throughout the study duration. Data was analyzed using appropriate statistical methods. Results: The overall reduction in mean VAS score over 14 days was 72.3%. The reduction in mean VAS score was significant as early as the first week. Both positive and negative symptoms of peripheral neuropathy were significantly improved in >50% patients within the 2 weeks. Giddiness (4.7%, followed by sedation (3.6%, dizziness (2.9%, drowsiness (2.3%, and nausea (2.3% were the most commonly observed adverse effects. The overall efficacy and tolerability was rated as good to excellent by >95% of the investigators and patients. Conclusion: Fixed dose combination of sustained-release pregabalin and methylcobalamin significantly reduced neuropathic pain, with significant improvement in both the positive and negative symptoms associated with

  19. Minocycline prevents dynorphin-induced neurotoxicity during neuropathic pain in rats.

    Science.gov (United States)

    Rojewska, Ewelina; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2014-11-01

    Despite many advances, our understanding of the involvement of prodynorphin systems in the development of neuropathic pain is not fully understood. Recent studies suggest an important role of neuro-glial interactions in the dynorphin effects associated with neuropathic pain conditions. Our studies show that minocycline reduced prodynorphin mRNA levels that were previously elevated in the spinal and/or dorsal root ganglia (DRG) following sciatic nerve injury. The repeated intrathecal administration of minocycline enhanced the analgesic effects of low-dose dynorphin (0.15 nmol) and U50,488H (25-100 nmol) and prevented the development of flaccid paralysis following high-dose dynorphin administration (15 nmol), suggesting a neuroprotective effect. Minocycline reverts the expression of IL-1β and IL-6 mRNA within the spinal cord and IL-1β mRNA in DRG, which was elevated following intrathecal administration of dynorphin (15 nmol). These results suggest an important role of these proinflammatory cytokines in the development of the neurotoxic effects of dynorphin. Similar to minocycline, a selective inhibitor of MMP-9 (MMP-9 levels are reduced by minocycline) exerts an analgesic effect in behavioral studies, and its administration prevents the occurrence of flaccid paralysis caused by high-dose dynorphin administration (15 nmol). In conclusion, our results underline the importance of neuro-glial interactions as evidenced by the involvement of IL-1β and IL-6 and the minocycline effect in dynorphin-induced toxicity, which suggests that drugs that alter the prodynorphin system could be used to better control neuropathic pain.

  20. The contribution of TRPM8 and TRPA1 channels to cold allodynia and neuropathic pain.

    Directory of Open Access Journals (Sweden)

    Ombretta Caspani

    Full Text Available Cold allodynia is a common feature of neuropathic pain however the underlying mechanisms of this enhanced sensitivity to cold are not known. Recently the transient receptor potential (TRP channels TRPM8 and TRPA1 have been identified and proposed to be molecular sensors for cold. Here we have investigated the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG and examined the cold sensitivity of peripheral sensory neurons in the chronic construction injury (CCI model of neuropathic pain in mice.In behavioral experiments, chronic constriction injury (CCI of the sciatic nerve induced a hypersensitivity to both cold and the TRPM8 agonist menthol that developed 2 days post injury and remained stable for at least 2 weeks. Using quantitative RT-PCR and in situ hybridization we examined the expression of TRPM8 and TRPA1 in DRG. Both channels displayed significantly reduced expression levels after injury with no change in their distribution pattern in identified neuronal subpopulations. Furthermore, in calcium imaging experiments, we detected no alterations in the number of cold or menthol responsive neurons in the DRG, or in the functional properties of cold transduction following injury. Intriguingly however, responses to the TRPA1 agonist mustard oil were strongly reduced.Our results indicate that injured sensory neurons do not develop abnormal cold sensitivity after chronic constriction injury and that alterations in the expression of TRPM8 and TRPA1 are unlikely to contribute directly to the pathogenesis of cold allodynia in this neuropathic pain model.

  1. Antihyperalgesic and antiallodynic effects of mianserin on diabetic neuropathic pain: a study on mechanism of action.

    Science.gov (United States)

    Üçel, Umut İrfan; Can, Özgür Devrim; Demir Özkay, Ümide; Öztürk, Yusuf

    2015-06-05

    This study used various experimental pain methods to investigate the effects of subacute mianserin administration on diabetes-induced neuropathic pain in rats. The effect of mianserin on hyperalgesia occurring in connection with peripheral diabetic neuropathy was examined using the Randall-Selitto (mechanical nociceptive stimulus), Hargreaves (thermal nociceptive stimulus), and cold-plate (4°C, thermal nociceptive stimulus) tests. The dynamic plantar aesthesiometer, which measures the threshold values for mechanical stimuli, was used for allodynia studies. Thermal allodynia was evaluated with the warm-plate (38°C) test. At 30 and 45 mg/kg, mianserin effectively improved mechanical and thermal hyperalgesia occurring in connection with diabetic neuropathy. Subacute administration of mianserin also reduced diabetes-associated mechanical and thermal allodynia. The ability of mianserin to reduce diabetic neuropathic pain was comparable to that of pregabalin (10mg/kg). The antihyperalgesic and antiallodynic effects of mianserin were reversed with α-methyl-para-tyrosine methyl ester (AMPT, an inhibitor of catecholamine synthesis), phentolamine (a non-selective α-adrenoceptor antagonist), propranolol (a non-selective β-adrenoceptor antagonist), and naloxone (a non-selective opioid receptor antagonist) administrations. The same effects were not reversed, however, by para-chlorophenylalanine methyl ester (PCPA; an inhibitor of serotonin synthesis). These results suggest that the beneficial effect of mianserin on diabetic neuropathic pain is mediated through an increase in catecholamine levels in the synaptic cleft as well as through interactions with both subtypes of adrenoceptors and opioid receptors. Considering that mianserin exhibits simultaneous antidepressant and antinociceptive effects, this drug could provide a good alternative for treating the pain associated with diabetic neuropathy and the mood disorders caused directly by diabetes.

  2. Active Nerve Regeneration with Failed Target Reinnervation Drives Persistent Neuropathic Pain

    Science.gov (United States)

    Xie, Wenrui

    2017-01-01

    Abstract Peripheral nerves can regenerate and, when injured, may cause neuropathic pain. We propose that the active regeneration process plays a pivotal role in the maintenance of neuropathic pain. In one commonly used rodent neuropathic pain model, pronounced pain behaviors follow ligation and cutting of the L5 spinal nerve. We found that the injured nerve regenerates into the sciatic nerve and functionally reinnervates target tissues: the regenerated nerve conducts electrical signals, mechanical responses, and tracers between the leg/hindpaw and axotomized sensory ganglion. The regenerating nerve is the primary source of abnormal spontaneous activity detected in vivo. Disrupting the regeneration inhibited pain. First, semaphorin 3A, an inhibitory axonal guidance molecule, reduced functional regeneration, spontaneous activity, and pain behaviors when applied to the injury site in vivo. Second, knockdown of the upregulated growth-associated protein 43 (GAP43) with siRNA injected into the axotomized sensory ganglion reduced pain behaviors. We next examined the spared nerve injury model, in which pain behaviors are essentially permanent. The regeneration resulted in tangled GAP43-positive neuromas at the nerve injury site without target reinnervation. Perfusing the nerve stump with semaphorin 3A, but not removing the tangled fibers, prevented or reversed pain behaviors. This effect far outlasted the semaphorin 3A perfusion. Hence, in this model the long-lasting chronic pain may reflect the anatomical inability of regenerating nerves to successfully reinnervate target tissues, resulting in an ongoing futile regeneration process. We propose that specifically targeting the regeneration process may provide effective long-lasting pain relief in patients when functional reinnervation becomes impossible. PMID:28197545

  3. The pharmacogenomics of escitalopram in the treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Andersen, Charlotte Brasch; Møller, Malik U; Sindrup, Søren Hein

      Painful polyneuropathy is a common neuropathic pain condition with painful diabetic neuropathy being a prominent example. Numerous pathophysiological mechanisms are involved in the generation and maintenance of neuropathic pain. In spite of increasing knowledge about the mechanisms, the treatment...... of neuropathic pain is still unsatisfactory. The effects of a selective serotonin reuptake inhibitor (SSRI), escitalopram, on pain in polyneuropathy was tested in an earlier randomized, placebo-controlled, double- blinded cross-over trial including  41 patients who were treated with 20 mg escitalopram...... and placebo. The clinical study showed a moderate, good or complete pain relief for escitalopram in 11 patients ("responders") but at only a slight or no relief  in 30 patients ("non-responders"). The difference in response to escitalopram may be caused by genetic differences between the responders...

  4. A role for uninjured afferents in neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    Richard A. Meyer; Matthias Ringkamp

    2008-01-01

    Diseases and injuries to the nervous system can lead to a devastating chronic pain condition called neuropathic pain. We review changes that occur in the peripheral nervous system that may play a role in this disease. Common animal models for neuropathic pain involve an injury to one or more peripheral nerves. Following such an injury, the nerve fibers that have been injured exhibit many abnormal properties including the development of spontaneous neural activity as well as a change in the expression of certain genes in their cell body. Recent data indicate that adjacent, uninjured nerve fibers also exhibit significant changes. These changes are thought to be driven by injury-induced alterations in the milieu surrounding the uninjured nerve and nerve terminals. Thus, alteration in neural signaling in both injured and uninjured neurons play a role in the development of neuropathic pain after peripheral nerve injury.

  5. Pharmacological treatment of neuropathic pain in older persons

    Directory of Open Access Journals (Sweden)

    Clair Haslam

    2008-03-01

    Full Text Available Clair Haslam1, Turo Nurmikko21The Walton Centre for Neurology and Neurosurgery, Liverpool, England, UK; 2The Pain Research Institute, Division of Neurological Science, University of Liverpool, Liverpool, England, UKAbstract: Interest and research into the mechanisms and treatment of neuropathic pain have increased during recent years, but current treatment is still far from satisfactory (Dworkin et al 2003; Attal et al 2006. The European Federation of Neurological Societies (EFNS Task Force recently published guidelines for the pharmacological treatment of neuropathic pain (Attal et al 2006. However, no particular consideration is given as to how the recommendations are applicable to the elderly population. This paper will review the guidelines in relation to this population and evaluate the existing evidence relating to the use of these drugs in older persons.Keywords: neuropathic pain, elderly, anticonvulsants, antidepressants, opioids, tramadol, lidocaine patch/plaster, capsaicin

  6. Electroacupuncture attenuates neuropathic pain after brachial plexus injury

    Institute of Scientific and Technical Information of China (English)

    Shenyu Zhang; Hailiang Tang; Junming Zhou; Yudong Gu

    2014-01-01

    Electroacupuncture has traditionally been used to treat pain, but its effect on pain following brachial plexus injury is still unknown. In this study, rat models of an avulsion injury to the left brachial plexus root (associated with upper-limb chronic neuropathic pain) were given electroacu-puncture stimulation at bilateralQuchi(LI11),Hegu(LI04),Zusanli(ST36) andYanglingquan (GB34). After electroacupuncture therapy, chronic neuropathic pain in the rats’ upper limbs was signiifcantly attenuated. Immunolfuorescence staining showed that the expression of β-endorphins in the arcuate nucleus was signiifcantly increased after therapy. Thus, experimental ifndings indi-cate that electroacupuncture can attenuate neuropathic pain after brachial plexus injury through upregulatingβ-endorphin expression.

  7. Acute and neuropathic orofacial antinociceptive effect of eucalyptol.

    Science.gov (United States)

    Melo Júnior, José de Maria de Albuquerque de; Damasceno, Marina de Barros Mamede Vidal; Santos, Sacha Aubrey Alves Rodrigues; Barbosa, Talita Matias; Araújo, João Ronielly Campêlo; Vieira-Neto, Antonio Eufrásio; Wong, Deysi Viviana Tenazoa; Lima-Júnior, Roberto César Pereira; Campos, Adriana Rolim

    2017-02-16

    Terpenes have a wide range of pharmacological properties, including antinociceptive action. The anti-inflammatory and antinociceptive effects of eucalyptol are well established. The purpose of this study was to evaluate the antinociceptive effect of eucalyptol on acute and neuropathic orofacial pain in rodent models. Acute orofacial and corneal nociception was induced with formalin, capsaicin, glutamate and hypertonic saline in mice. In another series, animals were pretreated with capsazepine or ruthenium red to evaluate the involvement of TRPV1 receptors in the effect of eucalyptol. In a separate experiment, perinasal tissue levels of IL-1β, TNF-α and IFN-γ were measured. Rats were pretreated with eucalyptol before induction of temporomandibular joint pain with formalin or mustard oil. In another experiment, rats were submitted to infraorbital nerve transection (IONX) to induce chronic pain, followed by induction of mechanical hypersensitivity using Von Frey hairs. Locomotor performance was evaluated with the open-field test, and molecular docking was conducted on the TRPV1 channel. Pretreatment with eucalyptol significantly reduced formalin-induced nociceptive behaviors in all mouse strains, but response was more homogenous in the Swiss strain. Eucalyptol produced antinociceptive effects in all tests. The effect was sensitive to capsazepine but not to ruthenium red. Moreover, eucalyptol significantly reduced IFN-γ levels. Matching the results of the experiment in vivo, the docking study indicated an interaction between eucalyptol and TRPV1. No locomotor activity changes were observed. Our study shows that eucalyptol may be a clinically relevant aid in the treatment of orofacial pain, possibly by acting as a TRPV1 channel antagonist.

  8. Anti-neuropathic effects of Rosmarinus officinalis L. terpenoid fraction: relevance of nicotinic receptors

    Science.gov (United States)

    Mannelli, Lorenzo Di Cesare; Micheli, Laura; Maresca, Mario; Cravotto, Giancarlo; Bellumori, Maria; Innocenti, Marzia; Mulinacci, Nadia; Ghelardini, Carla

    2016-01-01

    Traditional uses and current results highlight the neuroprotective properties of Rosmarinus officinalis L. The compelling need for novel strategies able to relieve neuropathic pain encouraged us to analyze different rosemary leaf extracts in rats following chronic constriction injury (CCI) of sciatic nerve. Ethanol, acetone, and the innovative ultrasound-hexane extractive methods were used to obtain: EE, AE, and for hexane extracts UREprel and URE. Extracts were characterized in terms of typical constituents and repeatedly administered to CCI-rats (13-days treatment, from the day of surgery). URE showed the best efficacy and potency in reducing hypersensitivity to noxious- and non-noxious stimuli and spontaneous pain. URE contained the higher quantity of the terpenoid carnosic acid (CA) and its efficacy was compared to pure CA. Histological analysis of the sciatic nerve revealed that URE prevented axon and myelin derangement, edema and inflammatory infiltrate. In the dorsal horn of the spinal cord, URE did not reduce astrocyte activation. Both the pain reliever and the neuroconservative effects of URE were significantly prevented by the nicotinic receptor (nAChR) antagonist mecamylamine. In conclusion, the hexane-ultrasound rosemary extract is able to reduce neuropathic hypersensitivity and protect nervous tissues. Effectiveness is mainly related to the terpenoid fraction by mechanisms involving nAChRs. PMID:27713514

  9. Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights.

    Science.gov (United States)

    Kremer, Mélanie; Salvat, Eric; Muller, André; Yalcin, Ipek; Barrot, Michel

    2016-12-03

    Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory system. It is generally chronic and challenging to treat. The recommended pharmacotherapy for neuropathic pain includes the use of some antidepressants, such as tricyclic antidepressants (TCAs) (amitriptyline…) or serotonin and noradrenaline re-uptake inhibitors (duloxetine…), and/or anticonvulsants such as the gabapentinoids gabapentin or pregabalin. Antidepressant drugs are not acute analgesics but require a chronic treatment to relieve neuropathic pain, which suggests the recruitment of secondary downstream mechanisms as well as long-term molecular and neuronal plasticity. Noradrenaline is a major actor for the action of antidepressant drugs in a neuropathic pain context. Mechanistic hypotheses have implied the recruitment of noradrenergic descending pathways as well as the peripheral recruitment of noradrenaline from sympathetic fibers sprouting into dorsal root ganglia; and importance of both α2 and β2 adrenoceptors have been reported. These monoamine re-uptake inhibitors may also indirectly act as anti-proinflammatory cytokine drugs; and their therapeutic action requires the opioid system, particularly the mu (MOP) and/or delta (DOP) opioid receptors. Gabapentinoids, which target the voltage-dependent calcium channels α2δ-1 subunit, inhibit calcium currents, thus decreasing the excitatory transmitter release and spinal sensitization. Gabapentinoids also activate the descending noradrenergic pain inhibitory system coupled to spinal α2 adrenoceptors. Gabapentinoid treatment may also indirectly impact on neuroimmune actors, like proinflammatory cytokines. These drugs are effective against neuropathic pain both with acute administration at high dose and with repeated administration. This review focuses on mechanistic knowledge concerning chronic antidepressant treatment and gabapentinoid treatment in a neuropathic pain context. Copyright © 2016 IBRO. Published by

  10. Peripheral nerve stimulation for the treatment of neuropathic craniofacial pain.

    Science.gov (United States)

    Slavin, K V

    2007-01-01

    Treatment of neuropathic pain in the region of head and face presents a challenging problem for pain specialists. In particular, those patients who do not respond to conventional treatment modalities usually continue to suffer from pain due to lack of reliable medical and surgical approaches. Peripheral nerve stimulation (PNS) has been used for treatment of neuropathic pain for many decades, but only recently it has been systematically applied to the craniofacial region. Here we summarize published experience with PNS in treatment of craniofacial pain and discuss some technical details of the craniofacial PNS procedure.

  11. Potential mechanisms of neuropathic pain in diabetes.

    Science.gov (United States)

    Calcutt, Nigel A

    2002-01-01

    Abnormal sensations and pain are features of approximately 10% of all cases of diabvetic neuropathy and can cause marked diminution in the quality of life for these patients. The quality and distribution of pain are variable, although descriptions of burning pain in the hands and feet are commonly reported. Like other neuropathic pain states, painful diabetic neuropathy has an unknown pathogenesis and, in many cases, is not alleviated by nonsteriodal anti-inflammatory drugs or opiates. In the last decase, a number of behavioral and physiologic studies have revealed indices of sensory dysfunction in animal models of diabetes. These include hyperalgesia to mechanical and noxious chemical stimuli and allodynia to light touch. Animal models of painful diabetic neuropathy have been used to investigate the therapeutic potential of a range of experimental agents and also to explore potential etiologic mechanisms. There is relatively little evidence to suggest that the peripheral sensory nerves of diabetic rodents exhibit spontaneous activity or increased responsiveness to peripheral stimuli. Indeed, the weight of eveidence suggests that sensory input to the spinal cord is decreased rather than increased in diabetic rodents. Aberrant spinal or supraspinal modulation of sensory processing may therefore be involved in generating allodynia and hyperalgesia in these models. Studies have supported a role for spinally mediated hyeralgesia in diabetic rats that may reflect either a response to diminished peripheral input or a consequence of hyperglycemia on local or descending modulatory systems. Elucidating the affects of diabetes on spinal sensory processing may assist development of novel therapeutic strategies for preventing and alleviating painful diabetic neuropathy.

  12. Botulinum Toxin Type A for the Treatment of Neuropathic Pain in Neuro-Rehabilitation

    Directory of Open Access Journals (Sweden)

    Domenico Intiso

    2015-06-01

    Full Text Available Pain is a natural protective mechanism and has a warning function signaling imminent or actual tissue damage. Neuropathic pain (NP results from a dysfunction and derangement in the transmission and signal processing along the nervous system and it is a recognized disease in itself. The prevalence of NP is estimated to be between 6.9% and 10% in the general population. This condition can complicate the recovery from stroke, multiple sclerosis, spinal cord lesions, and several neuropathies promoting persistent disability and poor quality of life. Subjects suffering from NP describe it as burning, itching, lancing, and numbness, but hyperalgesia and allodynia represent the most bothersome symptoms. The management of NP is a clinical challenge and several non-pharmacological and pharmacological interventions have been proposed with variable benefits. Botulinum toxin (BTX as an adjunct to other interventions can be a useful therapeutic tool for the treatment of disabled people. Although BTX-A is predominantly used to reduce spasticity in a neuro-rehabilitation setting, it has been used in several painful conditions including disorders characterized by NP. The underlying pharmacological mechanisms that operate in reducing pain are still unclear and include blocking nociceptor transduction, the reduction of neurogenic inflammation by inhibiting neural substances and neurotransmitters, and the prevention of peripheral and central sensitization. Some neurological disorders requiring rehabilitative intervention can show neuropathic pain resistant to common analgesic treatment. This paper addresses the effect of BTX-A in treating NP that complicates frequent disorders of the central and peripheral nervous system such as spinal cord injury, post-stroke shoulder pain, and painful diabetic neuropathy, which are commonly managed in a rehabilitation setting. Furthermore, BTX-A has an effect in relief pain that may characterize less common neurological disorders

  13. Discovery of a 1-isopropyltetrahydroisoquinoline derivative as an orally active N-type calcium channel blocker for neuropathic pain.

    Science.gov (United States)

    Ogiyama, Takashi; Yonezawa, Koichi; Inoue, Makoto; Watanabe, Toshihiro; Sugano, Yukihito; Gotoh, Takayasu; Kiso, Tetsuo; Koakutsu, Akiko; Kakimoto, Shuichiro; Shishikura, Jun-Ichi

    2015-08-01

    N-type calcium channel blockade is a promising therapeutic approach for the treatment of neuropathic pain. Starting from lead compound (S)-1, we focused our optimization efforts on potency for N-type calcium channel inhibition and improvement of CYP inhibition profile. 2-{[(1-Hydroxycyclohexyl)methyl]amino}-(1R)-(1-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethanone oxalate ((R)-5r) was identified as a novel orally active small-molecule N-type calcium channel inhibitor with reduced CYP inhibition liability. Oral administration of (R)-5r improved mechanical allodynia in a spinal nerve ligation model of neuropathic pain in rats with an ED50 value of 2.5 mg/kg. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Elphick Maurice R

    2009-07-01

    Full Text Available Abstract Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG, and the related compound N-palmitoylethanolamine (PEA, in neuropathic spinal cord. Selective spinal nerve ligation (SNL in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P P P P P

  15. Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain.

    Science.gov (United States)

    Guasti, Leonardo; Richardson, Denise; Jhaveri, Maulik; Eldeeb, Khalil; Barrett, David; Elphick, Maurice R; Alexander, Stephen P H; Kendall, David; Michael, Gregory J; Chapman, Victoria

    2009-07-01

    Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord. Selective spinal nerve ligation (SNL) in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days) significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P pain states.

  16. Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice.

    Science.gov (United States)

    Mika, Joanna; Wawrzczak-Bargiela, Agnieszka; Osikowicz, Maria; Makuch, Wioletta; Przewlocka, Barbara

    2009-01-01

    We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. Injections of morphine were combined with minocycline (30 mg/kg, i.p.) or pentoxifylline (20 mg/kg, i.p.) administered as two preemptive doses before first morphine administration in naive or pre-injury in CCI-exposed mice, and repeated twice daily 30 min before each morphine administration. With treatment, development of morphine tolerance was delayed by 5 days (from 6 to 11 days), as measured by the tail-flick test in naive and by tail-flick, von Frey, and cold plate tests in CCI-exposed mice. Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain.

  17. Nociceptor-expressed ephrin-B2 regulates inflammatory and neuropathic pain

    Directory of Open Access Journals (Sweden)

    Kullander Klas

    2010-11-01

    Full Text Available Abstract Background EphB receptors and their ephrin-B ligands play an important role in nervous system development, as well as synapse formation and plasticity in the adult brain. Recent studies show that intrathecal treatment with EphB-receptor activator ephrinB2-Fc induced thermal hyperalgesia and mechanical allodynia in rat, indicating that ephrin-B2 in small dorsal root ganglia (DRG neurons and EphB receptors in the spinal cord modulate pain processing. To examine the role of ephrin-B2 in peripheral pain pathways, we deleted ephrin-B2 in Nav1.8+ nociceptive sensory neurons with the Cre-loxP system. Sensory neuron numbers and terminals were examined using neuronal makers. Pain behavior in acute, inflammatory and neuropathic pain models was assessed in the ephrin-B2 conditional knockout (CKO mice. We also investigated the c-Fos expression and NMDA receptor NR2B phosphorylation in ephrin-B2 CKO mice and littermate controls. Results The ephrin-B2 CKO mice were healthy with no sensory neuron loss. However, pain-related behavior was substantially altered. Although acute pain behavior and motor co-ordination were normal, inflammatory pain was attenuated in ephrin-B2 mutant mice. Complete Freund's adjuvant (CFA-induced mechanical hyperalgesia was halved. Formalin-induced pain behavior was attenuated in the second phase, and this correlated with diminished tyrosine phosphorylation of N-methyl-D-aspartic acid (NMDA receptor subunit NR2B in the dorsal horn. Thermal hyperalgesia and mechanical allodynia were significantly reduced in the Seltzer model of neuropathic pain. Conclusions Presynaptic ephrin-B2 expression thus plays an important role in regulating inflammatory pain through the regulation of synaptic plasticity in the dorsal horn and is also involved in the pathogenesis of some types of neuropathic pain.

  18. Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats.

    Science.gov (United States)

    Simón-Arceo, Karina; González-Trujano, Ma Eva; Coffeen, Ulises; Fernández-Mas, Rodrigo; Mercado, Francisco; Almanza, Angélica; Contreras, Bernardo; Jaimes, Orlando; Pellicer, Francisco

    2017-07-12

    Salvia divinorum is a medicinal plant traditionally used in hallucinogenic ethnopharmacological practices and for its analgesic and antinflammatory properties. Its active compounds include diterpenes known as salvinorins which act as potent κ opioid receptor agonists. Given its effects in acute animal models of pain, as well as its antinflammatory attributes, we decided to investigate the analgesic effects of an SD extract in neuropathic (sciatic loose nerve ligature) and inflammatory (intra plantar carrageenan) pain models in rats. We also determined in this study the electrocorticographic changes to correlate similar hallucinogenic state and behavior as those produced in humans. Mechanical and thermonociceptive responses, plantar test and von Frey assay, respectively, were measured in adult Wistar rats 30min, 3h and 24h after the intraperitoneal administration of saline or an hydroponic SD extract. We also evaluated carbamazepine and celecoxib, as gold reference drugs, to compare its antinociceptive effects. Our results showed that administration of SD extract induced antialgesic effects in both neuropathic and inflammatory pain models. All those effects were blocked by nor-binaltorphimine (a Kappa opioid receptor antagonist). Moreover, it was observed an increase of the anterior power spectral density and a decrease in the posterior region as electrocorticographic changes. The present investigation give evidence that SD is capable to reduce algesic response associated to neuropathic and inflammatory nociception. This study support therapeutic alternatives for a disabling health problem due to the long term pain with high impact on population and personal and social implications. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  19. The effects of transcranial direct current stimulation in patients with neuropathic pain from spinal cord injury.

    Science.gov (United States)

    Ngernyam, Niran; Jensen, Mark P; Arayawichanon, Preeda; Auvichayapat, Narong; Tiamkao, Somsak; Janjarasjitt, Suparerk; Punjaruk, Wiyada; Amatachaya, Anuwat; Aree-uea, Benchaporn; Auvichayapat, Paradee

    2015-02-01

    Transcranial direct current stimulation (tDCS) has demonstrated efficacy for reducing neuropathic pain, but the respective mechanisms remain largely unknown. The current study tested the hypothesis that pain reduction with tDCS is associated with an increase in the peak frequency spectrum density in the theta-alpha range. Twenty patients with spinal cord injury and bilateral neuropathic pain received single sessions of both sham and anodal tDCS (2 mA) over the left primary motor area (M1) for 20 min. Treatment order was randomly assigned. Pre- to post-procedure changes in pain intensity and peak frequency of electroencephalogram spectral analysis were compared between treatment conditions. The active treatment condition (anodal tDCS over M1) but not sham treatment resulted in significant decreases in pain intensity. In addition, consistent with the study hypothesis, peak theta-alpha frequency (PTAF) assessed from an electrode placed over the site of stimulation increased more from pre- to post-session among participants in the active tDCS condition, relative to those in the sham tDCS condition. Moreover, we found a significant association between a decrease in pain intensity and an increase in PTAF at the stimulation site. The findings are consistent with the possibility that anodal tDCS over the left M1 may be effective, at least in part, because it results in an increase in M1 cortical excitability, perhaps due to a pain inhibitory effect of motor cortex stimulation that may influence the descending pain modulation system. Future research is needed to determine if there is a causal association between increased left anterior activity and pain reduction. The results provide new findings regarding the effects of tDCS on neuropathic pain and brain oscillation changes. Copyright © 2014 International Federation of Clinical Neurophysiology. All rights reserved.

  20. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial.

    Science.gov (United States)

    Ellis, Ronald J; Toperoff, Will; Vaida, Florin; van den Brande, Geoffrey; Gonzales, James; Gouaux, Ben; Bentley, Heather; Atkinson, J Hampton

    2009-02-01

    Despite management with opioids and other pain modifying therapies, neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals. Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception. We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV. This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes; they continued on their prestudy analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Treatments were placebo and active cannabis ranging in potency between 1 and 8% Delta-9-tetrahydrocannabinol, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout. The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale (DDS) from a pretreatment baseline to the end of each treatment week. Secondary measures included assessments of mood and daily functioning. Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among the completers, pain relief was greater with cannabis than placebo (median difference in DDS pain intensity change, 3.3 points, effect size=0.60; p=0.016). The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 0.18 (0.03, 0.32). Mood and daily functioning improved to a similar extent during both treatment periods. Although most side effects were mild and self-limited, two subjects experienced treatment-limiting toxicities. Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic

  1. [Evaluation of a neuropathic ulcers prevention program for patients with diabetes].

    Science.gov (United States)

    Cisneros, Lígia L

    2010-01-01

    Neuropathic foot ulcers are among the major health problems faced by patients with diabetes mellitus. To evaluate the preventive efficacy of a therapeutic education and protective footwear program in the incidence and recurrence of neuropathic ulcers due to diabetes. Fifty-three patients with diabetes and neuropathy from a public healthcare unit in Porto Alegre, Rio Grande do Sul, took part in a clinical trial for two years. The participants were randomly allocated to an intervention group (n=30) or a control group (n=23). Therapeutic education was provided in group sessions, and protective footwear was supplied in accordance with individual prescriptions. The nonparametric Mann-Whitney test was used to determine differences in incidence and recurrence of ulceration between the groups. Life-table analysis and the Kaplan-Meier method were used to measure the duration of ulcer-free survival. In the intervention group, the ulcer incidence rate was 38.1% compared to 51.1% in the control group. Among the participants who presented ulcers, 83% were in the control group and 16.7% in the intervention group. After one year, the participants in the intervention group had a 75% chance of being ulcer-free, compared with 61% in the control group, and these percentages reduced to 60% and 52% respectively after two years. There was a tendency toward shorter survival among the control group participants. Although the proposed program lowered recurrence rates and increased the duration of ulcer-free survival, it was unable to prevent occurrence and recurrence of neuropathic ulcers due to diabetes.

  2. Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA, mediates the induction of nerve-injured neuropathic pain

    Directory of Open Access Journals (Sweden)

    Chun Jerold

    2008-02-01

    Full Text Available Abstract Recently, we reported that lysophosphatidic acid (LPA induces long-lasting mechanical allodynia and thermal hyperalgesia as well as demyelination and upregulation of pain-related proteins through one of its cognate receptors, LPA1. In addition, mice lacking the LPA1 receptor gene (lpa1-/- mice lost these nerve injury-induced neuropathic pain behaviors and phenomena. However, since lpa1-/- mice did not exhibit any effects on the basal nociceptive threshold, it is possible that nerve injury-induced neuropathic pain and its machineries are initiated by LPA via defined biosynthetic pathways that involve multiple enzymes. Here, we attempted to clarify the involvement of a single synthetic enzyme of LPA known as autotaxin (ATX in nerve injury-induced neuropathic pain. Wild-type mice with partial sciatic nerve injury showed robust mechanical allodynia starting from day 3 after the nerve injury and persisting for at least 14 days, along with thermal hyperalgesia. On the other hand, heterozygous mutant mice for the autotaxin gene (atx+/-, which have 50% ATX protein and 50% lysophospholipase D activity compared with wild-type mice, showed approximately 50% recovery of nerve injury-induced neuropathic pain. In addition, hypersensitization of myelinated Aβ˜ MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi=xH8viVGI8Gi=hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY=rqGqVepae9pg0db9vqaiVgFr0xfr=xfr=xc9adbaqaaeGacaGaaiaabeqaaeqabiWaaaGcbaGafqOSdiMbaGaaaaa@2D83@- or Aδ-fiber function following nerve injury was observed in electrical stimuli-induced paw withdrawal tests using a Neurometer®. The hyperalgesia was completely abolished in lpa1-/- mice, and reduced by 50% in atx+/- mice. Taken together, these findings suggest that LPA biosynthesis through ATX is the source of LPA for LPA1 receptor-mediated neuropathic pain. Therefore, targeted inhibition of ATX-mediated LPA biosynthesis as well as

  3. Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice

    Science.gov (United States)

    Chen, Gang; Park, Chul-Kyu; Xie, Rou-Gang; Berta, Temugin; Nedergaard, Maiken

    2014-01-01

    Accumulating evidence suggests that spinal cord astrocytes play an important role in neuropathic pain sensitization by releasing astrocytic mediators (e.g. cytokines, chemokines and growth factors). However, it remains unclear how astrocytes control the release of astrocytic mediators and sustain late-phase neuropathic pain. Astrocytic connexin-43 (now known as GJ1) has been implicated in gap junction and hemichannel communication of cytosolic contents through the glial syncytia and to the extracellular space, respectively. Connexin-43 also plays an essential role in facilitating the development of neuropathic pain, yet the mechanism for this contribution remains unknown. In this study, we investigated whether nerve injury could upregulate connexin-43 to sustain late-phase neuropathic pain by releasing chemokine from spinal astrocytes. Chronic constriction injury elicited a persistent upregulation of connexin-43 in spinal astrocytes for >3 weeks. Spinal (intrathecal) injection of carbenoxolone (a non-selective hemichannel blocker) and selective connexin-43 blockers (connexin-43 mimetic peptides 43Gap26 and 37,43Gap27), as well as astroglial toxin but not microglial inhibitors, given 3 weeks after nerve injury, effectively reduced mechanical allodynia, a cardinal feature of late-phase neuropathic pain. In cultured astrocytes, TNF-α elicited marked release of the chemokine CXCL1, and the release was blocked by carbenoxolone, Gap26/Gap27, and connexin-43 small interfering RNA. TNF-α also increased connexin-43 expression and hemichannel activity, but not gap junction communication in astrocyte cultures prepared from cortices and spinal cords. Spinal injection of TNF-α-activated astrocytes was sufficient to induce persistent mechanical allodynia, and this allodynia was suppressed by CXCL1 neutralization, CXCL1 receptor (CXCR2) antagonist, and pretreatment of astrocytes with connexin-43 small interfering RNA. Furthermore, nerve injury persistently increased excitatory

  4. Minocycline enhances the effectiveness of nociceptin/orphanin FQ during neuropathic pain.

    Science.gov (United States)

    Popiolek-Barczyk, Katarzyna; Rojewska, Ewelina; Jurga, Agnieszka M; Makuch, Wioletta; Zador, Ferenz; Borsodi, Anna; Piotrowska, Anna; Przewlocka, Barbara; Mika, Joanna

    2014-01-01

    Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5-5 μg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Our in vitro study showed that minocycline reduced NOP mRNA, but not protein, level in rat primary microglial cell cultures. In [(35)S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain.

  5. Minocycline Enhances the Effectiveness of Nociceptin/Orphanin FQ during Neuropathic Pain

    Science.gov (United States)

    Popiolek-Barczyk, Katarzyna; Rojewska, Ewelina; Jurga, Agnieszka M.; Makuch, Wioletta; Zador, Ferenz; Piotrowska, Anna; Przewlocka, Barbara

    2014-01-01

    Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5–5 μg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Our in vitro study showed that minocycline reduced NOP mRNA, but not protein, level in rat primary microglial cell cultures. In [35S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain. PMID:25276817

  6. NGX-4010, a high-concentration capsaicin dermal patch for lasting relief of peripheral neuropathic pain.

    Science.gov (United States)

    Noto, Christopher; Pappagallo, Marco; Szallasi, Arpad

    2009-07-01

    NeurogesX Inc is developing NGX-4010, a rapid-delivery dermal patch application system that contains high-concentration trans-capsaicin, for the treatment of peripheral neuropathic pain. Capsaicin evokes a lasting and reversible refractory state in primary sensory neurons involved in the generation and maintenance of neuropathic pain. NGX-4010 can be applied to the painful skin area up to a total surface area of 1120 cm2. In phase I clinical trials, NGX-4010 increased the threshold for warmth detection, reduced epidermal sensory nerve fiber density and was well tolerated. In phase II trials, NGX-4010 was effective in reducing pain in patients with post-herpetic neuralgia (PHN), HIV-associated distal sensory neuropathy (HIV-DSP) and painful diabetic neuropathy (PDN). Data from phase III trials in patients with PHN demonstrated that significantly more pain relief was achieved by NGX-4010 (30 to 32% reduction from baseline) compared with a low-concentration capsaicin active control (20 to 24% reduction); however, only one of two studies involving patients with HIV-DSP met the primary endpoint. NGX-4010 appears to have the potential to be an effective adjunctive or a stand-alone therapy for PHN, as well as potentially for HIV-DSP and PDN. NGX-4010 has been granted approval by the European Commission and an NDA has been accepted for filing by the FDA.

  7. Minocycline Enhances the Effectiveness of Nociceptin/Orphanin FQ during Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Katarzyna Popiolek-Barczyk

    2014-01-01

    Full Text Available Nociceptin/orphanin FQ (N/OFQ antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP, was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p., a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5–5 μg i.t.. Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Our in vitro study showed that minocycline reduced NOP mRNA, but not protein, level in rat primary microglial cell cultures. In [35S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain.

  8. Rapid and Delayed Effects of Pulsed Radiofrequency on Neuropathic Pain: Electrophysiological, Molecular, and Behavioral Evidence Supporting Long-Term Depression.

    Science.gov (United States)

    Huang, Ren-Yu; Liao, Chia-Chi; Tsai, Shih-Ying; Yen, Chen-Tung; Lin, Chii-Wann; Chen, Tsung-Chi; Lin, Wei-Tso; Chang, Chi-Heng; Wen, Yeong-Ray

    2017-02-01

    Pulsed radiofrequency (PRF) has been widely employed for ameliorating clinical neuropathic pain. How PRF alters electrophysiological transmission and modulates biomolecular functions in neural tissues has yet to be clarified. We previously demonstrated that an early application of low-voltage bipolar PRF adjacent to the dorsal root ganglion (DRG) reduced acute neuropathic pain in animals. By contrast, the present study investigated how PRF alters postsynaptic sensitization to produce early and delayed effects on neuropathic pain. Our objective was to test the hypothesis that a 5-minute session of PRF could rapidly produce selective long-term depression (LTD) on C-fiber-mediated spinal sensitization and sustain the effect through the long-lasting inhibition of injury-induced ERK-MAPK activation. This may explain the prolonged analgesic effect of PRF on chronic neuropathic pain. Experiments were conducted on both normal rats and neuropathic pain rats that received spinal nerve ligation (SNL) 8 days prior. An animal laboratory in a medical center of a university in Taiwan. We first compared changes in field potentials in the L5 superficial spinal dorsal horn (SDH) that were evoked by conditioning electrical stimuli in the sciatic nerve in male adult rats before (as the baseline) and after PRF stimulation for at least 2 hours. Bipolar PRF was applied adjacent to the L5 DRG at an intensity of 5 V for 5 minutes, whereas the control rats were treated with sham applications. The electrophysiological findings were tested for any correlation with induction of spinal phospho-ERK (p-ERK) in normal and neuropathic pain rats. We then investigated the delayed effect of PRF on SNL-maintained pain behaviors for 2 weeks as well as p-ERK in SDH among the control, SNL, and PRF groups. Finally, potential injury in the DRGs after PRF stimulation was evaluated through behavioral observations and ATF-3, a neuronal stress marker. In the evoked field-potential study, the recordings mediated

  9. A neurotropic virus (chikungunya) and a neuropathic aminoacid

    National Research Council Canada - National Science Library

    Wadia, R

    2007-01-01

    ... virus (Chikungunya) and a neuropathic aminoacid (Homocysteine)." This implies two topics in one oration; however, in the previous year, nearly half a dozen different topics that were related only by sex were included. They both cause encephalopathy, myelopathy and neuropathy and may affect the muscles and eyes and show teratogenicity. Moreover, there ...

  10. Neuropathic pain and spasticity: intricate consequences of spinal cord injury

    DEFF Research Database (Denmark)

    Finnerup, Nanna Brix

    2017-01-01

    of SCI, and a careful examination and characterization of the symptoms and signs, are a prerequisite for understanding the relationship between neuropathic pain and spasticity and the intricate underlying mechanisms.Spinal Cord advance online publication, 11 July 2017; doi:10.1038/sc.2017.70....

  11. EFNS guidelines on neurostimulation therapy for neuropathic pain

    DEFF Research Database (Denmark)

    EFNS Panel on Neuropathic Pain, Vienna; Cruccu, Giorgio; Aziz, T. Z.

    2007-01-01

    and to produce relevant recommendations. We searched the literature from 1968 to 2006, looking for neurostimulation in neuropathic pain conditions, and classified the trials according to the EFNS scheme of evidence for therapeutic interventions. Spinal cord stimulation (SCS) is efficacious in failed back surgery...

  12. Spinal cord stimulation and modulation of neuropathic pain

    NARCIS (Netherlands)

    Vos, de C.C.

    2013-01-01

    This thesis reports on the opportunities of several new applications of spinal cord stimulation (SCS) for the treatment of neuropathic pain. Our pilot study and consecutively performed international randomised controlled trial on effects of SCS in patients with painful diabetic neuropathy showed tha

  13. Abstract Central neuropathic mechanisms in post-stroke shoulder pain

    NARCIS (Netherlands)

    Roosink, M.; Renzenbrink, G.J.; Buitenweg, Jan R.; Van Dongen, R.T.M.; Geurts, A.C.H.; IJzerman, Maarten Joost

    2009-01-01

    Central neuropathic pain mechanisms may play a larger role in chronic PSSP than is traditionally assumed. With the DN4, it is possible to select a subgroup of PSSP patients with more severe pain complaints and sensory abnormalities. Subgroup identification based on the DN4 might be used in future

  14. ARA290 : a novel treatment for neuropathic pain in sarcoidosis

    NARCIS (Netherlands)

    Heij, L.

    2016-01-01

    The general aim of this thesis is to investigate small fiber neuropathy in sarcoidosis and to asses whether ARA290 is a possible new agent to treat the neuropathic complaints in sarcoidosis population. The results of the various ARA290 trials in painful sarcoidosis are discussed. Painful neuropathy

  15. Recent advances in pharmacological treatment of neuropathic pain

    OpenAIRE

    2010-01-01

    Recent studies investigating the pharmacological management of neuropathic pain support the efficacy of certain antidepressants, anticonvulsants, and opioids. Novel directions in drug applications include topical applications of patches with either lidocaine or capsaicin and intradermal injections of botulinum toxin. In cases of partial pain relief, drug combinations may be considered.

  16. Evaluation of anticonvulsants for possible use in neuropathic pain.

    Science.gov (United States)

    Waszkielewicz, A M; Gunia, A; Słoczyńska, K; Marona, H

    2011-01-01

    Neuropathic pain is a kind of pain related with functional abnormality of neurons. Despite large progress in pharmacotherapy, neuropathic pain is still considered an unmet need. Nowadays, there are few drugs registered for this condition, such as pregabalin, gabapentin, duloxetine, carbamazepine, and lidocaine. Among them, pregabalin, gabapentin and carbamazepine are well known antiepileptic drugs. Among the group of new antiepileptic drugs, which are addressed to 1% of human world population suffering from seizures, it turned out that 30% of the seizures resistant to pharmacotherapy has not enough market to justify the costs of drug development. Therefore, it is already a phenomenon that researchers turn their projects toward a larger market, related with possible similar mechanism. Anticonvulsant mechanism of action is in the first place among primary indications for drugs revealing potential analgesic activity. Therefore, many drug candidates for epilepsy, still in preclinical stage, are being evaluated for activity in neuropathic pain. This review is focusing on antiepileptic drugs, which are evaluated for their analgesic activity in major tests related with neuropathic pain. Relation between structure, mechanism of action and result in tests such as the Chung model (spinal nerve ligation SNL), the Bennett model (chronic constriction injury of sciatic nerve CCI) and other tests are considered. The first examples are carbamazepine, gabapentin, and lacosamide as drugs well established in epilepsy market as well as drug candidates such as valnoctamide, and other valproic acid derivatives, novel biphenyl pyrazole derivatives, etc. Moreover, clinical efficacy related with listed animal models has been discussed.

  17. Chronic neuropathic pain: mechanisms, drug targets and measurement

    DEFF Research Database (Denmark)

    Finnerup, Nanna B; Sindrup, Søren H; Jensen, Troels S

    2007-01-01

    Neuropathic pain is common in many diseases or injuries of the peripheral or central nervous system, and has a substantial impact on quality of life and mood. Lesions of the nervous system may lead to potentially irreversible changes and imbalance between excitatory and inhibitory systems. Precli...

  18. 17beta-estradiol counteracts neuropathic pain: a behavioural, immunohistochemical, and proteomic investigation on sex-related differences in mice

    Science.gov (United States)

    Vacca, Valentina; Marinelli, Sara; Pieroni, Luisa; Urbani, Andrea; Luvisetto, Siro; Pavone, Flaminia

    2016-01-01

    Sex differences play a role in pain sensitivity, efficacy of analgesic drugs and prevalence of neuropathic pain, even if the underlying mechanisms are far from being understood. We demonstrate that male and female mice react differently to structural and functional changes induced by sciatic nerve ligature, used as model of neuropathic pain. Male mice show a gradual decrease of allodynia and a complete recovery while, in females, allodynia and gliosis are still present four months after neuropathy induction. Administration of 17β-estradiol is able to significantly attenuate this difference, reducing allodynia and inducing a complete recovery also in female mice. Parallel to pain attenuation, 17β-estradiol treated-mice show a functional improvement of the injured limb, a faster regenerative process of the peripheral nerve and a decreased neuropathy-induced gliosis. These results indicate beneficial effects of 17β-estradiol on neuropathic pain and neuronal regeneration and focuses on the importance of considering gonadal hormones also in clinical studies. PMID:26742647

  19. Altered rate-dependent depression of the spinal H-reflex as an indicator of spinal disinhibition in models of neuropathic pain.

    Science.gov (United States)

    Lee-Kubli, Corinne A G; Calcutt, Nigel A

    2014-02-01

    The unpredictable efficacy of current therapies for neuropathic pain may reflect diverse etiological mechanisms operating between, and within, diseases. As descriptions of pain rarely establish specific mechanisms, a tool that can identify underlying causes of neuropathic pain would be useful in developing patient-specific treatments. Rate-dependent depression (RDD), a measure of the change in amplitude of the Hoffman reflex over consecutive stimulations, is attenuated in diabetic rats that also exhibit impaired spinal γ-aminobutyric acid (GABA)A receptor function, reduced spinal potassium chloride co-transporter (KCC2) expression, and indices of painful neuropathy. To investigate whether loss of RDD is a reliable indicator of the contribution of spinal GABAergic dysfunction to neuropathic pain, we assessed RDD, tactile allodynia, and formalin-evoked hyperalgesia in 3 models: rats treated acutely with brain-derived neurotrophic factor (BDNF), diabetic rats treated with the BDNF-sequestering molecule tyrosine receptor kinase B/Fc (TrkB/Fc), and rats with paclitaxel-induced neuropathy. Delivery of BDNF to the spinal cord of normal rats produced RDD deficits and features of painful neuropathy associated with disrupted GABAA receptor-mediated inhibitory function and reduced dorsal spinal KCC2 expression. Treating diabetic rats with TrkB/Fc restored RDD and alleviated indices of painful neuropathy. In paclitaxel-treated rats, RDD was not impaired and behavioral indices of neuropathic pain were not associated with spinal GABAergic dysfunction or reduced dorsal spinal KCC2 expression. Our data reveal BDNF as part of the mechanism underlying spinal cord disinhibition caused by altered GABAA receptor function in diabetic rats and suggest that RDD deficits may be a useful indicator of neuropathic pain states associated with spinal disinhibition, thereby revealing specific therapeutic targets. Copyright © 2013 International Association for the Study of Pain. Published by

  20. Minocycline Effects on IL-6 Concentration in Macrophage and Microglial Cells in a Rat Model of Neuropathic Pain

    Science.gov (United States)

    Moini-Zanjani, Taraneh; Ostad, Seyed-Nasser; Labibi, Farzaneh; Ameli, Haleh; Mosaffa, Nariman; Sabetkasaei, Masoumeh

    2016-01-01

    Background: Evidence indicates that neuropathic pain pathogenesis is not confined to changes in the activity of neuronal systems but involves interactions between neurons, inflammatory immune and immune-like glial cells. Substances released from immune cells during inflammation play an important role in development and maintenance of neuropathic pain. It has been found that minocycline suppresses the development of neuropathic pain. Here, we evaluated the analgesic effect of minocycline in a chronic constriction injury (CCI) model of neuropathic pain in rat and assessed IL-6 concentration from cultured macrophage and microglia cells. Methods: Male Wistar rat (n=6, 150-200 g) were divided into three different groups: 1) CCI+vehicle, 2) sham+vehicle, and 3) CCI+drug. Minocycline (10, 20, and 40 mg/kg) was injected one hour before surgery and continued daily to day 14 post ligation. Von Frey filaments and acetone, as pain behavioral tests, were used for mechanical allodynia and cold allodynia, respectively. Experiments were performed on day 0 (before surgery) and days 1, 3, 5, 7, 10, and 14 post -injury. At day 14, rats were killed and monocyte-derived macrophage from right ventricle and microglia from lumbar part of the spinal cord were isolated and cultured in RPMI and Leibovitz’s media, respectively. IL-6 concentration was evaluated in cell culture supernatant after 24 h. Results: Minocycline (10, 20, and 40 mg/kg) attenuated pain behavior, and a decrease in IL-6 concentration was observed in immune cells compared to CCI vehicle-treated animals. Conclusion: Minocycline reduced pain behavior and decreased IL-6 concentration in macrophage and microglial cells. PMID:27221523

  1. Botulinum neurotoxin type A counteracts neuropathic pain and facilitates functional recovery after peripheral nerve injury in animal models.

    Science.gov (United States)

    Marinelli, S; Luvisetto, S; Cobianchi, S; Makuch, W; Obara, I; Mezzaroma, E; Caruso, M; Straface, E; Przewlocka, B; Pavone, F

    2010-11-24

    A growing interest was recently focused on the use of Botulinum neurotoxin serotype A (BoNT/A) for fighting pain. The aim of this study was to investigate the effects of BoNT/A on neuropathic pain. It was observed that BoNT/A is able to counteract neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve both in mice and in rats. This effect is already present after a single intraplantar (i.pl.) or intrathecal (i.t.) neurotoxin administration that significantly reduces the sciatic nerve ligation-induced mechanical allodynia in mice and rats and thermal hyperalgesia in rats. This effect was evident starting 24 h after the administration of BoNT/A and it was long-lasting, being present 81 or 25 days after i.pl. injection of the higher dose in mice (15 pg/paw) and rats (75 pg/paw), respectively, and 35 days after i.t. injection in rats (75 pg/rat). Moreover, BoNT/A-injected mice showed a quicker recovery of the walking pattern and weight bearing compared to control groups. The behavioral improvement was accompanied by structural modifications, as revealed by the expression of cell division cycle 2 (Cdc2) and growth associated protein 43 (GAP-43) regeneration associated proteins, investigated by immunofluorescence and Western blotting in the sciatic nerve, and by the immunofluorescence expression of S100β and glial fibrillary acidic protein (GFAP) Schwann cells proteins. In conclusion, the present research demonstrate long-lasting anti-allodynic and anti-hyperalgesic effects of BoNT/A in animal models of neuropathic pain together with an acceleration of regenerative processes in the injured nerve, as evidenced by both behavioral and immunohistochemistry/blotting analysis. These results may have important implications in the therapy of neuropathic pain.

  2. Guideline for the management of wounds in patients with lower-extremity neuropathic disease: an executive summary.

    Science.gov (United States)

    Crawford, Penny Ellen; Fields-Varnado, Myra

    2013-01-01

    This article summarizes the WOCN Evidence-Based Clinical Practice Guideline for Management of Wounds in Patients with Lower Extremity Neuropathic Disease. It is intended for use by physicians, nurses, therapists, and other health care professionals who work with adults who have or are at risk for, lower-extremity neuropathic disease (LEND), and includes updated scientific literature available from January 2003 through February 2012. The full guideline contains definitions of lower extremity neuropathic disorders and disease, prevalence of the problem, relevance and significance of the disorders, as well as comprehensive information about etiology, the nervous system, pathogenesis, and the overall management goals for patients at risk for developing neuropathic foot ulcers. A detailed assessment section describes how to conduct a full clinical history and physical examination. The guideline also provides two approaches to interventions. The first focuses on prevention strategies to reduce the risk of developing LEND wounds or recurrence, including life-long foot offloading, routine dermal temperature surveillance, use of adjunctive therapies, medication management, and implementing lower extremity amputation prevention measures and patient self-care education. The second approach summarized LEND wound management strategies including wound cleansing, debridement, infection management, maintenance of intact peri-wound skin, nutrition considerations, pain and paresthesia management, edema management, offloading and management of gait and foot deformity, medication management, surgical options, adjunctive therapies, patient education, and health care provider follow-up. A comprehensive reference list, glossary of terms, and several appendices regarding an algorithm to determine wound etiology, pharmacology, Lower Extremity Amputation (LEAP) Program, diabetes foot screening and other information is available at the end of the guideline.

  3. Inflammatory and neuropathic pain are rapidly suppressed by peripheral block of hyperpolarisation-activated cyclic nucleotide-gated ion channels.

    Science.gov (United States)

    Young, Gareth T; Emery, Edward C; Mooney, Elizabeth R; Tsantoulas, Christoforos; McNaughton, Peter A

    2014-09-01

    Previous studies have shown that hyperpolarisation-activated cyclic nucleotide-gated (HCN)-2 ion channels regulate the firing frequency of nociceptive sensory neurons and thus play a central role in both inflammatory and neuropathic pain conditions. Here we use ivabradine, a clinically approved anti-anginal agent that blocks all HCN channel isoforms approximately equally, to investigate the effect on inflammatory and neuropathic pain of HCN ion channel block. We show that ivabradine does not have major off-target effects on a sample group of Na, Ca, and K ion channels, and that it is peripherally restricted because it is a substrate for the P-glycoprotein (PgP) multidrug transporter that is expressed in the blood-brain barrier. Its effects are therefore likely to be due to an action on HCN ion channels in peripheral sensory neurons. Using patch clamp electrophysiology, we found that ivabradine was a use-dependent blocker of native HCN channels expressed in small sensory neurons. Ivabradine suppressed the action potential firing that is induced in nociceptive neurons by elevation of intracellular cAMP. In the formalin model of inflammatory pain, ivabradine reduced pain behaviour only in the second (inflammatory) phase. In nerve injury and chemotherapy models of neuropathic pain, we observed rapid and effective analgesia as effective as that with gabapentin. We conclude that both inflammatory and neuropathic pain are rapidly inhibited by blocking HCN-dependent repetitive firing in peripheral nociceptive neurons. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  4. Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: Engagement of antioxidant mechanisms and spinal GABAA receptors.

    Science.gov (United States)

    Zhao, Xin; Li, Xin-Lin; Liu, Xin; Wang, Chuang; Zhou, Dong-Sheng; Ma, Qing; Zhou, Wen-Hua; Hu, Zhen-Yu

    2015-12-01

    Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Fisetin, a naturally occurring flavonoid, has been reported to exert antidepressant-like effect in previous studies. As antidepressant drugs are employed clinically to treat neuropathic pain, this work aimed to investigate whether fisetin possess beneficial effect on diabetic neuropathic pain and explore the mechanism(s). We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (200mg/kg), and von Frey test or Hargreaves test was used to assess mechanical allodynia or thermal hyperalgesia, respectively. Chronic treatment of diabetic mice with fisetin not only ameliorated the established symptoms of thermal hyperalgesia and mechanical allodynia, but also arrested the development of neuropathic pain when given at low doses. Although chronic fisetin administration did not impact on the symptom of hyperglycemia in diabetic mice, it reduced exacerbated oxidative stress in tissues of spinal cord, dorsal root ganglion (DRG) and sciatic verve. Furthermore, the analgesic actions of fisetin were abolished by repetitive co-treatment with the reactive oxygen species (ROS) donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the ROS scavenger phenyl-N-tert-butylnitrone (PBN). Finally, acute blockade of spinal GABAA receptors by bicuculline totally counteracted such fisetin analgesia. These findings indicate that chronic fisetin treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the present fisetin analgesia may be associated with its antioxidant activity, and spinal GABAA receptors are likely rendered as downstream targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice.

    Science.gov (United States)

    Zhang, Qian; Cao, De-Li; Zhang, Zhi-Jun; Jiang, Bao-Chun; Gao, Yong-Jing

    2016-07-11

    Trigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of spinal nerve ligation-induced neuropathic pain. Whether and how CXCL13/CXCR5 in the trigeminal ganglion (TG) mediates orofacial pain are unknown. The partial infraorbital nerve ligation (pIONL) was used to induce trigeminal neuropathic pain in mice. The expression of ATF3, CXCL13, CXCR5, and phosphorylated extracellular signal-regulated kinase (pERK) in the TG was detected by immunofluorescence staining and western blot. The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing. pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG. Inhibition of CXCL13 or CXCR5 by shRNA lentivirus attenuated pIONL-induced mechanical allodynia. Additionally, pIONL-induced neuropathic pain and the activation of ERK in the TG were reduced in Cxcr5 (-/-) mice. Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL. TNF-α inhibitor (Etanercept) and IL-1β inhibitor (Diacerein) attenuated pIONL-induced orofacial pain. Finally, intra-TG injection of CXCL13 induced mechanical allodynia, increased the activation of ERK and the production of TNF-α and IL-1β in the TG of WT mice, but not in Cxcr5 (-/-) mice. Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation. CXCL13 and CXCR5 contribute to orofacial pain via ERK-mediated proinflammatory cytokines production. Targeting CXCL13/CXCR5/ERK/TNF-α and IL-1β pathway in the trigeminal ganglion may offer effective treatment for orofacial neuropathic pain.

  6. Neuropathic pain in people with cancer (part 2): pharmacological and non-pharmacological management.

    Science.gov (United States)

    Taverner, Tarnia

    2015-08-01

    The aim of this paper is to provide an overview of the management of neuropathic pain associated with cancer and to provide helpful clinical advice for nurses working with patients who may have neuropathic pain. While cancer pain is a mixed-mechanism pain, this article will focus only on neuropathic pain management. The impact of neuropathic pain on patients' quality of life is great and while many patients recover from their cancer, a significant number continue to suffer from a neuropathic pain syndrome. Management of neuropathic pain is significantly different from management of nociceptive pain with respect to pharmacological and non-pharmacological strategies. Neuropathic pain is complex, and as such requires complex management using pharmacological as well as non-pharmacological approaches. Specific drugs for neuropathic pain may be effective for some patients, but not all; therefore, ongoing and comprehensive assessment and management are required. Furthermore, these patients may require trials of several drugs before they find one that works for them. It is important for nurses to understand neuropathic pain, its manifestation, impact on quality of life and management when nursing patients with neuropathic pain associated with cancer.

  7. Combined bone scintigraphy and indium-111 leukocyte scans in neuropathic foot disease

    Energy Technology Data Exchange (ETDEWEB)

    Schauwecker, D.S.; Park, H.M.; Burt, R.W.; Mock, B.H.; Wellman, H.N.

    1988-10-01

    It is difficult to diagnose osteomyelitis in the presence of neurotrophic osteoarthropathy. We performed combined (99mTc)MDP bone scans and indium-111 (111In) leukocyte studies on 35 patients who had radiographic evidence of neuropathic foot disease and clinically suspected osteomyelitis. The (111In)leukocyte study determined if there was an infection and the bone scan provided the anatomic landmarks so that the infection could be localized to the bone or the adjacent soft tissue. Seventeen patients had osteomyelitis and all showed increased (111In)leukocyte activity localized to the bone, giving a sensitivity of 100%. Among the 18 patients without osteomyelitis, eight had no accumulation of (111In)leukocytes, seven had the (111In)leukocyte activity correctly localized to the soft tissue, two had (111In)leukocyte activity mistakenly attributed to the bone, and one had (111In)leukocyte accumulation in a proven neuroma which was mistakenly attributed to bone. These three false-positive results for osteomyelitis reduced the specificity to 83%. Considering only the 27 patients with a positive (111In)leukocyte study, the combined bone scan and (111In)leukocyte study correctly localized the infection to the soft tissues or bone in 89%. Uninfected neurotrophic osteoarthropathy does not accumulate (111In)leukocytes. We found the combined bone scan and (111In) leukocyte study useful for the detection and localization of infection to soft tissue or bone in patients with neuropathic foot disease.

  8. Dysfunction of cortical dendritic integration in neuropathic pain reversed by serotoninergic neuromodulation.

    Science.gov (United States)

    Santello, Mirko; Nevian, Thomas

    2015-04-08

    Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.

  9. Neuropathic pain as part of chronic widespread pain: environmental and genetic influences.

    Science.gov (United States)

    Momi, Sukhleen K; Fabiane, Stella Maris; Lachance, Genevieve; Livshits, Gregory; Williams, Frances M K

    2015-10-01

    Chronic widespread pain (CWP) has complex aetiology and forms part of the fibromyalgia syndrome. Recent evidence suggests a higher frequency of neuropathic pain features in those with CWP than previously thought. The aim of this study was to determine the prevalence of neuropathic pain features in individuals with CWP and to estimate the influence of genetic and environmental factors on neuropathic pain in CWP. Validated questionnaires (the London Fibromyalgia Screening Study questionnaire and PainDETECT questionnaire) were used to classify twins as having CWP and neuropathic pain, respectively. The prevalence of CWP was 14.7% (n = 4324), and of the 1357 twins invited to complete neuropathic pain screening, 15.9% of those having CWP demonstrated features of neuropathic pain. Neuropathic pain was found to be heritable (A = 37%; 95% confidence interval [CI]: 23%-50%) with unique environmental factors accounting for 63% (95% CI: 49%-79%) of the variance. Heritability of neuropathic pain and CWP were found to be correlated, 0.54 (95% CI: 0.42-0.65). Increasing age, raised body mass index, female gender, and smoking were all risk factors for neuropathic pain (P neuropathic pain (P = 0.003) and CWP (P = 0.001). Bivariate analysis of the 2 pain traits revealed that genetic predisposition to neuropathic pain is shared with that for CWP. This is the first study to provide formal heritability estimates for neuropathic pain in CWP. The findings suggest that at least some of the genetic factors underlying the development of neuropathic pain and CWP are the same.

  10. Depressing Interleukin-1β Contributed to the Synergistic Effects of Tramadol and Minocycline on Spinal Nerve Ligation-Induced Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Xiao-Peng Mei

    2013-10-01

    Full Text Available Our previous study indicated that coadministration of tramadol and minocycline exerted synergistic effects on spinal nerve ligation (SNL-induced neuropathic mechanical allodynia. However, the underlying mechanisms are still unclear. Recent reports indicated that spinal proinflammatory factor interleukin-1β (IL-1β contributed to the development of neuropathic pain and the positive feedback communication between neuron and glia. Therefore, the present research is to confirm whether spinal IL-1β-related pathway response contributes to the synergistic effects of tramadol and minocycline on SNL-induced neuropathic pain. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn 3 days after lesion, which could be significantly decreased by tramadol and minocycline coadministration. Immunofluorescence and Western blot indicated that SNL-induced microglial phosphorylated p38 (p-p38 upregulation was also inhibited by tramadol and minocycline coapplication. Meanwhile, intrathecal administration of p38 inhibitor SB203580 markedly alleviated mechanical allodynia whilst reducing IL-1β and Fos expression induced by SNL. Moreover, intrathecal neutralized antibody of IL-1β could depress SNL-induced mechanical allodynia and Fos expression. These results suggest that depressing SNL-induced aberrant activation of the spinal dorsal horn IL-1β-related pathway contributes to the underlying mechanism of the synergistic effects of tramadol and minocycline coadministration on SNL-induced neuropathic mechanical allodynia. © 2013 S. Karger AG, Basel

  11. The influence of microglia activation on the efficacy of amitriptyline, doxepin, milnacipran, venlafaxine and fluoxetine in a rat model of neuropathic pain.

    Science.gov (United States)

    Zychowska, Magdalena; Rojewska, Ewelina; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2015-02-15

    The analgesic properties of antidepressants are often used in the treatment of neuropathy; however their influence on glial cells in maintaining neuropathic pain is unknown. Our studies examined the neuropathic pain-relieving properties after intraperitoneal injection of amitriptyline, doxepin, milnacipran, venlafaxine and fluoxetine 7 days after sciatic nerve injury (CCI) in rats and its influence on microglia/macrophages (IBA-1) and astroglia (GFAP) activation in the spinal cord and dorsal root ganglia (DRG) using Western blot. All tested antidepressants significantly reduced CCI-induced allodynia but hyperalgesia was only antagonised by fluoxetine, doxepine and venlafaxine. The strongest analgesia was observed after fluoxetine administration. Western blot analysis showed the upregulation of the IBA-1 in the lumbar spinal cord and DRG after amitriptyline or milnacipran administration in CCI-exposed rats, whereas after fluoxetine the downregulation was observed. The administration of doxepin did not change the IBA-1 protein level in both studied structures; however venlafaxine decreased the IBA-1 only in the DRG. No changes in the GFAP level in both structures were observed after any of listed above antidepressants administration. Chronic minocycline treatment enhanced amitriptyline and milnacipran, but did not fluoxetine analgesia under neuropathic pain in rats. Our results suggest that nerve injury-induced pain is related with the activation of microglia, which is diminished by fluoxetine treatment in the neuropathic pain model.

  12. Antiallodynic effect of tianeptine via modulation of the 5-HT7 receptor of GABAergic interneurons in the spinal cord of neuropathic rats.

    Science.gov (United States)

    Lin, Hai; Heo, Bong Ha; Kim, Woong Mo; Kim, Yong Chul; Yoon, Myung Ha

    2015-06-26

    Although tianeptine, an atypical antidepressant has been reported to have antinociceptive effects, the mode of action is different from that of tricyclic antidepressants despite structural similarities. We examined the antiallodynic effect of intrathecal tianeptine in neuropathic pain rats and determined the involvement of 5-hydroxytryptamine type 7 (5-HT7) receptor of the GABAergic interneurons in the spinal cord. Neuropathic pain was induced by spinal nerve ligation (SNL). After observation of the effect from intrathecal tianeptine, a 5-HT7 receptor antagonist (SB-269970) was administered intrathecally 10 min before delivery of tianeptine, to determine the contribution of spinal 5-HT7 receptor on the activity of tianeptine. GAD expression and GABA concentrations were assessed. Intrathecal tianeptine dose-dependently attenuated mechanical allodynia in SNL rats. Pre-treatment with intrathecal SB-269970 reversed the antiallodynic effect of tianeptine. Both GAD65 expression and the GABA concentration in the spinal cord were decreased in neuropathic rats but were increased by tianeptine. Additionally, 5-HT7 receptor and GAD65 were co-localized in the spinal cord. Intrathecal tianeptine reduces neuropathic pain. 5-HT7 receptor of the GABAergic interneurons together with GAD65 plays a role in the activity of tianeptine at the spinal cord level.

  13. Inhibitory Effects of Scolopendra Pharmacopuncture on the Development and Maintenance of Neuropathic Pain in Rats: Possible Involvement of Spinal Glial Cells.

    Science.gov (United States)

    Li, Chengjin; Ji, Byeong Uk; Lee, Ji Eun; Park, Min Young; Kim, Sungchul; Kim, Seung Tae; Koo, Sungtae

    2015-10-01

    Scolopendra extracts were used for pharmacopuncture at the Kidney 1 acupoint to investigate the role of Scolopendra pharmacopuncture (SPP) in both the development and maintenance of neuropathic pain induced by L5 spinal nerve ligation in rats and the contribution of spinal glial cells. A single treatment and five once-daily treatments with SPP were given to evaluate its effects on the development and maintenance stages of neuropathic pain, respectively, which was followed by behavioral tests. Immunohistochemistry and Western blotting tests were also carried out. A single treatment of SPP delayed spinal nerve ligation-induced mechanical allodynia and thermal hyperalgesia and induced a profound decrease in the expression of ionized calcium binding adaptor protein in the lumbar spinal cord. Repeated SPP treatments reliably suppressed mechanical allodynia and thermal hyperalgesia at later time points, and these results correlated mainly with decreases in glial fibrillary acidic protein. Intriguingly, ionized calcium binding adaptor protein expression was also reduced after repeated SPP. These results illustrate that neuropathic pain in the development and maintenance stages is alleviated by SPP treatment, which may be ascribed principally to deactivations of microglia and astroglia, respectively. Additionally, microglial inactivation seems to be partially involved in preventing neuropathic pain in the maintenance stage.

  14. Ultrasound-Guided Nerve Block with Botulinum Toxin Type A for Intractable Neuropathic Pain

    OpenAIRE

    Young Eun Moon; Jung Hyun Choi; Hue Jung Park; Ji Hye Park; Ji Hyun Kim

    2016-01-01

    Neuropathic pain includes postherpetic neuralgia (PHN), painful diabetic neuropathy (PDN), and trigeminal neuralgia, and so on. Although various drugs have been tried to treat neuropathic pain, the effectiveness of the drugs sometimes may be limited for chronic intractable neuropathic pain, especially when they cannot be used at an adequate dose, due to undesirable severe side effects and the underlying disease itself. Botulinum toxin type A (BoNT-A) has been known for its analgesic effect in...

  15. A retrospective analysis of the efficacy of treatment of neuropathic peripheral pain

    OpenAIRE

    Pinto, Joana Manuela Tenreiro

    2016-01-01

    Tese de mestrado, apresentado á Faculdade de Medicina da Universidade de Coimbra Introduction: Neuropathic pain is defined as pain arising from a direct consequence of lesion or disease affecting the somatosensory system. Although there are several guidelines for neuropathic pain managent and various effective drugs are accessible, neuropathic pain remains untreated or undertreated. The goal of this study was to evaluate retrospectively efficacy of combining topic capsaicin 8% ...

  16. Neuropathic pain in the community: more under-treated than refractory?

    Science.gov (United States)

    Torrance, Nicola; Ferguson, Janice A; Afolabi, Ebenezer; Bennett, Michael I; Serpell, Michael G; Dunn, Kate M; Smith, Blair H

    2013-05-01

    Best current estimates of neuropathic pain prevalence come from studies using screening tools detecting pain with probable neuropathic features; the proportion experiencing significant, long-term neuropathic pain, and the proportion not responding to standard treatment are unknown. These "refractory" cases are the most clinically important to detect, being the most severe, requiring specialist treatment. The aim of this study was to estimate the proportion of neuropathic pain in the population that is "refractory," and to quantify associated clinical and demographic features. We posted self-administered questionnaires to 10,000 adult patients randomly selected from 10 general practitioner practices in 5 UK locations. The questionnaire contained chronic pain identification and severity questions, cause of pain, SF-12, EQ-5D, S-LANSS (Self-administered Leeds Assessment of Neuropathic Signs and Symptoms), PSEQ (Pain Self-Efficacy Questionnaire), use of neuropathic pain medications, and health care utilisation. These data were combined to determine the presence and characteristics of "refractory" neuropathic pain according to the defining features identified by a Delphi survey of international experts. Graded categories of chronic pain with and without neuropathic characteristics were generated, incorporating the refractory criteria. Completed questionnaires were returned by 4451 individuals (response rate 47%); 399 had "chronic pain with neuropathic characteristics" (S-LANSS positive, 8.9% of the study sample); 215 (53.9%) also reported a positive relevant history ("Possible neuropathic pain"); and 98 (4.5% of all Chronic Pain) also reported an "adequate" trial of at least one neuropathic pain drug ("Treated possible neuropathic pain"). The most refractory cases were associated with dramatically poorer physical and mental health, lower pain self-efficacy, higher pain intensity and pain-related disability, and greater health care service use. Copyright © 2013

  17. Neuropathic pain as part of chronic widespread pain: environmental and genetic influences

    OpenAIRE

    Momi, Sukhleen K.; Fabiane, Stella Maris; Lachance, Genevieve; Livshits, Gregory; Williams, Frances M. K.

    2015-01-01

    Abstract Chronic widespread pain (CWP) has complex aetiology and forms part of the fibromyalgia syndrome. Recent evidence suggests a higher frequency of neuropathic pain features in those with CWP than previously thought. The aim of this study was to determine the prevalence of neuropathic pain features in individuals with CWP and to estimate the influence of genetic and environmental factors on neuropathic pain in CWP. Validated questionnaires (the London Fibromyalgia Screening Study questio...

  18. [Personality and coping in neuropathic chronic pain: a predictable divorce].

    Science.gov (United States)

    Soriano Pastor, José F; Monsalve Dolz, Vicente; Ibáñez Guerra, Elena; Gómez Carretero, Patricia

    2010-11-01

    We approach the problem about relationships between personality dimensions and the use of coping strategies in chronic pain patients. The most frequently used theoretical model in the area of stress and its relation to pain is the transactional model, taking into account that the incorporation of personality traits improves predictions via coping in the stress process. Following the Big Five model, the relationships between personality and coping strategies in patients with chronical neuropathic pain were established. The results showed slight relationships between the Big-Five dimensions and coping. A vulnerable personality profile in patients with chronic neuropathic pain was obtained, consisting of high neuroticism, low extraversion, openness to experience and responsibility, and moderate agreeableness.

  19. Neuromodulation of neuropathic pain syndrome induced by elapidae (cobra) envenomation.

    Science.gov (United States)

    Stretanski, Michael F

    2009-01-01

    Objectives.  This study aims to demonstrate the utility of spinal cord stimulation in a neuropathic pain syndrome and overall decline in health and functional independence following elapid envenomation in a morbidly obese, insulin-dependent diabetic. Materials and Methods.  A two-lead, 16-electrode constant-current, independently controlled system is placed in the mid-cervical spine. Results.  Noted were a improvement in overall health status with better glycemic control and return to work status in response to adequate pain control. Conclusions.  The case serves as a model for other orphan pain cases with a seemingly esoteric etiology and adds to the existing body of literature that spinal cord stimulation and neuromodulation, in general, has a wide-ranging applicability peripheral neuropathic pain syndromes.

  20. Validation of the Greek Version of the DN4 Diagnostic Questionnaire for Neuropathic Pain.

    Science.gov (United States)

    Sykioti, Panagiota; Zis, Panagiotis; Vadalouca, Athina; Siafaka, Ioanna; Argyra, Eriphili; Bouhassira, Didier; Stavropoulou, Evmorfia; Karandreas, Nikolaos

    2015-09-01

    The Douleur Neuropathique 4 questionnaire (DN4) was developed by the French Neuropathic Pain Group and is a simple and objective tool, primarily designed to screen for neuropathic pain. The aim of our study is to validate the DN4 in the Greek language. The study was set up as a prospective observational study. Two pain specialists independently examined patients and diagnosed them with neuropathic, nociceptive, or mixed pain, according to the International Association for the Study of Pain (IASP) definitions. A third and a fourth physician administered the DN4 questionnaire to the patients. Out of the 237 patients who met our inclusion criteria and had identical diagnoses regarding the type of pain, 123 were diagnosed with neuropathic, 59 with nociceptive, and 55 with mixed pain. Among patients with identical diagnoses of neuropathic or nociceptive pain, using a receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.92. A cutoff point of equal or greater than 4 resulted in a sensitivity of 93% and a specificity of 78%. Among patients suffering from pain with neuropathic element (neuropathic or mixed pain) or pain with no neuropathic element (nociceptive pain), using a ROC curve analysis, the AUC was 0.89. A cutoff point of equal or greater than 4 resulted in a sensitivity of 89% and a specificity of 78%. The Greek version of DN4 is a valid tool for discriminating between neuropathic and nociceptive pain conditions in daily practice. © 2014 World Institute of Pain.

  1. Complex Regional Pain Syndrome (CRPS/RSD and Neuropathic Pain: Role of Intravenous Bisphosphonates as Analgesics

    Directory of Open Access Journals (Sweden)

    Jennifer Yanow

    2008-01-01

    Full Text Available Neuropathic pain is a sequela of dysfunction, injuries, or diseases of the peripheral and/or central nervous system pain pathways, which has historically been extremely difficult to treat. Complex regional pain syndrome (CRPS types 1 and 2 are neuropathic pain conditions that have a long history in the medical literature but whose pathophysiology remains elusive and whose available treatment options remain few. While an exact animal model for CRPS doesn't yet exist, there are several animal models of neuropathic pain that develop behaviors of hypersensitivity, one of the hallmark signs of neuropathic pain in humans.

  2. Case Report: Neuropathic Arthropathy of the Hip as a Sequela of Undiagnosed Tertiary Syphilis

    National Research Council Canada - National Science Library

    Viens, Nicholas A; Watters, Tyler Steven; Vinson, Emily N; Brigman, Brian E

    2010-01-01

    .... Neuropathic arthropathy can be associated with tabes dorsalis, a unique manifestation of late, tertiary neurosyphilis that may arise in individuals with untreated syphilis many years after initial...

  3. Pharmacological treatment of neuropathic pain in older persons

    OpenAIRE

    2008-01-01

    Clair Haslam1, Turo Nurmikko21The Walton Centre for Neurology and Neurosurgery, Liverpool, England, UK; 2The Pain Research Institute, Division of Neurological Science, University of Liverpool, Liverpool, England, UKAbstract: Interest and research into the mechanisms and treatment of neuropathic pain have increased during recent years, but current treatment is still far from satisfactory (Dworkin et al 2003; Attal et al 2006). The European Federation of Neurological Societies (EFNS) Task Force...

  4. Hemiplegic shoulder pain: evidence of a neuropathic origin.

    Science.gov (United States)

    Zeilig, Gabi; Rivel, Michal; Weingarden, Harold; Gaidoukov, Evgeni; Defrin, Ruth

    2013-02-01

    Hemiplegic shoulder pain (HSP) is common after stroke. Whereas most studies have concentrated on the possible musculoskeletal factors underlying HSP, neuropathic aspects have hardly been studied. Our aim was to explore the possible neuropathic components in HSP, and if identified, whether they are specific to the shoulder or characteristic of the entire affected side. Participants included 30 poststroke patients, 16 with and 14 without HSP, and 15 healthy controls. The thresholds of warmth, cold, heat-pain, touch, and graphesthesia were measured in the intact and affected shoulder and in the affected lower leg. They were also assessed for the presence of allodynia and hyperpathia, and computed tomography/magnetic resonance imaging scans of the brain were reviewed. In addition, chronic pain was characterized. Participants with HSP exhibited higher rates of parietal lobe damage (P<0.05) compared to those without HSP. Both poststroke groups exhibited higher sensory thresholds than healthy controls. Those with HSP had higher heat-pain thresholds in both the affected shoulder (P<0.001) and leg (P<0.01), exhibited higher rates of hyperpathia in both these regions (each P<0.001), and more often reported chronic pain throughout the affected side (P<0.001) than those without HSP. The more prominent sensory alterations in the shoulder region suggest that neuropathic factors play a role in HSP. The clinical evidence of damage to the spinothalamic-thalamocortical system in the affected shoulder and leg, the presence of chronic pain throughout the affected side, and the more frequent involvement of the parietal cortex all suggest that the neuropathic component is of central origin.

  5. Surgical animal models of neuropathic pain: Pros and Cons.

    Science.gov (United States)

    Challa, Siva Reddy

    2015-03-01

    One of the biggest challenges for discovering more efficacious drugs for the control of neuropathic pain has been the diversity of chronic pain states in humans. It is now acceptable that different mechanisms contribute to normal physiologic pain, pain arising from tissue damage and pain arising from injury to the nervous system. To study pain transmission, spot novel pain targets and characterize the potential analgesic profile of new chemical entities, numerous experimental animal pain models have been developed that attempt to simulate the many human pain conditions. Among the neuropathic pain models, surgical models have paramount importance in the induction of pain states. Many surgical animal models exist, like the chronic constriction injury (CCI) to the sciatic nerve, partial sciatic nerve ligation (pSNL), spinal nerve ligation (SNL), spared nerve injury (SNI), brachial plexus avulsion (BPA), sciatic nerve transaction (SNT) and sciatic nerve trisection. Most of these models induce responses similar to those found in causalgia, a syndrome of sustained burning pain often seen in the distal extremity after partial peripheral nerve injury in humans. Researchers most commonly use these surgical models in both rats and mice during drug discovery to screen new chemical entities for efficacy in the area of neuropathic pain. However, there is scant literature that provides a comparative discussion of all these surgical models. Each surgical model has its own benefits and limitations. It is very difficult for a researcher to choose a suitable surgical animal model to suit their experimental set-up. Therefore, particular attention has been given in this review to comparatively provide the pros and cons of each model of surgically induced neuropathic pain.

  6. Use of 5% lidocaine medicated plaster to treat localized neuropathic pain secondary to traumatic injury of peripheral nerves

    Directory of Open Access Journals (Sweden)

    Correa-Illanes G

    2012-07-01

    Full Text Available Gerardo Correa-Illanes,1 Ricardo Roa,2 José Luis Piñeros,2 Wilfredo Calderón31Rehabilitation Department, 2Burns and Plastic Surgery Department, Hospital del Trabajador, 3Plastic Surgery Department, Hospital del Salvador, Santiago, ChileObjective: The efficacy of 5% lidocaine medicated plaster (LMP has previously been demonstrated in post-traumatic localized neuropathic pain. This study evaluated the use of LMP in localized neuropathic pain secondary to traumatic peripheral nerve injury.Patients and methods: This prospective observational study enrolled patients with traumatic injuries to peripheral nerves that were accompanied by localized neuropathic pain of more than 3 months duration. Demographic variables, pain intensity (measured using the numeric rating scale; NRS, answers to the Douleur Neuropathique 4 (DN4 questionnaire, and the size of the painful area were recorded.Results: Nineteen patients were included, aged (mean ± standard deviation 41.4 ± 15.7 years. Nerve injuries affected the upper (eight patients or lower (11 patients limbs. The mean duration of pain before starting treatment with LMP was 22.6 ± 43.5 months (median 8 months. Mean baseline values included: NRS 6.7 ± 1.6, painful area 17.8 ± 10.4 cm2 (median 18 cm2, and DN4 score 6.7 ± 1.4. The mean duration of treatment with LMP was 19.5 ± 10.0 weeks (median 17.4 weeks. Mean values after treatment were: NRS 2.8 ± 1.5 (≥3 point reduction in 79% of patients, ≥50% reduction in 57.9% of patients and painful area 2.1 ± 2.3 cm2 (median 1 cm2, ≥50% reduction in 94.7% of patients. Functional improvement after treatment was observed in 14/19 patients (73.7%.Conclusion: LMP effectively treated traumatic injuries of peripheral nerves which presented with chronic localized neuropathic pain, reducing both pain intensity and the size of the painful area.Keywords: chronic post-surgical pain, chronic post-traumatic pain, 5% lidocaine medicated plaster, neuropathic pain

  7. Spinal Interleukin-10 Therapy to Treat Peripheral Neuropathic Pain

    Science.gov (United States)

    Milligan, Erin D.; Penzkover, Kathryn R.; Soderquist, Ryan G.; Mahoney, Melissa J.

    2012-01-01

    Introduction Current research indicates that chronic peripheral neuropathic pain includes a role for glia and the actions of proinflammatory factors. This review briefly discusses the glial and cytokine responses that occur following peripheral nerve damage in support of utilizing anti-inflammatory cytokine interleukin-10 therapy to suppress chronic peripheral neuropathic pain. Spinal Non-viral Interleukin-10 Gene Therapy IL-10 is one of the most powerful endogenous counter-regulators of pro-inflammatory cytokine function that acts in the nervous system. Subarachnoid (intrathecal) spinal injection of the gene encoding IL-10 delivered by non-viral vectors has several advantages over virally-mediated gene transfer methods and leads to profound pain relief in several animal models. Non-viral gene delivery Lastly, data are reviewed that non-viral DNA encapsulated by a biologically safe co-polymer, poly(lactic-co-glycolic) acid (PLGA), thought to protect DNA, leads to significantly improved therapeutic gene transfer in animal models, which additionally and significantly extends pain relief. Conclusions The impact of these early studies exploring anti-inflammatory genes emphasizes the exceptional therapeutic potential of new biocompatible intrathecal non-viral gene delivery approaches such as PLGA microparticles. Ultimately, ongoing expression of therapeutic genes are a viable option to treat chronic neuropathic pain in the clinic. PMID:22672183

  8. Neuropathic Pain Following Spinal Cord Injury: Mechanism, Assessment and Treatment

    Directory of Open Access Journals (Sweden)

    Gul Mete Civelek

    2016-04-01

    Full Text Available Spinal cord injury (SCI is a devastating disease which may cause physical, psychological and social dysfunction. Neuropathic pain (NP after SCI is common, can be seen in varying degrees and is one of the most difficultly treated problems developing after SCI. With the addition of the NP to loss of function after SCI, sleep patterns, moods and daily activities of patients are adversely affected. In order to treat pain effectively, classification of pain after SCI must be done carefully and correctly. According to classification of International Pain Study Group, pain after SCI is divided into two main groups as nociceptive and neuropathic pain. Neuropathic pain is defined as %u201Cpain occuring as a direct result of a disease or lesion directly affecting somato-sensorial system%u201D. NP after SCI can be classified according to anatomical region (above the level of lesion, at the level of lesion, below the level of lesion. Treatment of NP after SCI is often challenging and receiving response to treatment may take long time. Therefore, treatment of NP after SCI should be multifactorial. Treatment options include pharmochologic treatment, application of transcutanous electrical nerve stimulation, psychiatric treatment approaches, and surgical approaches in selected cases. In pharmachologic treatment, first line agents are tricyclic antidepresants, pregabalin and gabapentin. In this review, mechanisms and assessment and treatment of NP after SCI is discussed with the guide of current literature.

  9. Efficient assessment of efficacy in post-traumatic peripheral neuropathic pain patients: pregabalin in a randomized, placebo-controlled, crossover study

    Directory of Open Access Journals (Sweden)

    Jenkins TM

    2012-07-01

    Full Text Available Tim M Jenkins, Trevor S Smart, Frances Hackman, Carol Cooke, Keith KC TanClinical Research, Pfizer Worldwide Research and Development, Sandwich, Kent, UKBackground: Detecting the efficacy of novel analgesic agents in neuropathic pain is challenging. There is a critical need for study designs with the desirable characteristics of assay sensitivity, low placebo response, reliable pain recordings, low cost, short duration of exposure to test drug and placebo, and relevant and recruitable population.Methods: We designed a proof-of-concept, double-blind, randomized, placebo-controlled, crossover study in patients with post-traumatic peripheral neuropathic pain (PTNP to evaluate whether such a study design had the potential to detect efficacious agents. Pregabalin, known to be efficacious in neuropathic pain, was used as the active analgesic. We also assessed physical activity throughout the study.Results: Twenty-five adults (20–70 years of age with PTNP for ≥3 months entered a screening week and were then randomized to one of the two following treatment sequences: (1 pregabalin followed by placebo or (2 placebo followed by pregabalin. These 2-week treatment periods were separated by a 2-week washout period. Patients on pregabalin treatment received escalating doses to a final dosage of 300 mg/day (days 5–15. In an attempt to minimize placebo response, patients received placebo treatment during the screening week and the 2-week washout period. Average daily pain scores (primary endpoint were significantly reduced for pregabalin versus placebo, with a mean treatment difference of -0.81 (95% confidence interval: -1.45 to -0.17; P = 0.015.Conclusion: The efficacy of pregabalin was similar to that identified in a large, parallel group trial in PTNP. Therefore, this efficient crossover study design has potential utility for future proof-of-concept studies in neuropathic pain.Keywords: pregabalin, post-traumatic peripheral neuropathic pain, randomized

  10. Involvement of pro- and antinociceptive factors in minocycline analgesia in rat neuropathic pain model.

    Science.gov (United States)

    Rojewska, Ewelina; Popiolek-Barczyk, Katarzyna; Jurga, Agnieszka M; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2014-12-15

    In neuropathic pain the repeated minocycline treatment inhibited the mRNA and protein expression of the microglial markers and metalloproteinase-9 (MMP-9). The minocycline diminished the pronociceptive (IL-6, IL-18), but not antinociceptive (IL-1alpha, IL-4, IL-10) cytokines at the spinal cord level. In vitro primary cell culture studies have shown that MMP-9, TIMP-1, IL-1beta, IL-1alpha, IL-6, IL-10, and IL-18 are of microglial origin. Minocycline reduces the production of pronociceptive factors, resulting in a more potent antinociceptive effect. This change in the ratio between pro- and antinociceptive factors, in favour of the latter may be the mechanism of minocycline analgesia in neuropathy.

  11. Reversal of TRESK Downregulation Alleviates Neuropathic Pain by Inhibiting Activation of Gliocytes in the Spinal Cord.

    Science.gov (United States)

    Zhou, Jun; Chen, Hongtao; Yang, Chengxiang; Zhong, Jiying; He, Wanyou; Xiong, Qingming

    2017-02-03

    Despite the consensus that activation of TWIK-related spinal cord K(+) (TRESK) might contribute to the pathogenesis of chronic pain, the specific mechanisms underlying the transfer and development of pain signals still remain obscure. In the present study, we validated that TRESK was expressed in neurons instead of glial cells. Furthermore, in the SNI model of neuropathic pain (NP), downregulation of TRESK in spinal cord neurons resulted in upregulation of connexin 36 (Cx36) and connexin 43 (Cx43), both being subtypes of gap junctions in the spinal cord, with gliocytes in the spinal cord activated ultimately. Compared with SNI rats, intrathecal injection of TRESK gene recombinant adenovirus significantly downregulated the expression levels of Cx36 and Cx43 and suppressed the activation of gliocytes in the spinal cord, with hyperalgesia significantly reduced. In conclusion, TRESK contributes to the pathogenesis of NP by upregulation of synaptic transmission and activation of gliocytes.

  12. Inhibition of YAP/TAZ Activity in Spinal Cord Suppresses Neuropathic Pain.

    Science.gov (United States)

    Xu, Ni; Wu, Ming-Zheng; Deng, Xue-Ting; Ma, Ping-Chuan; Li, Ze-Hua; Liang, Lei; Xia, Meng-Fan; Cui, Dong; He, Duan-Duan; Zong, Yuan; Xie, Zhong; Song, Xue-Jun

    2016-09-28

    Neuropathic pain, often caused by nerve injury, is a major clinical challenge. Mechanisms that underlie neuropathic pain remain elusive and effective medications are limited. Numerous investigations of pain mechanisms have focused on alterations and phenotypic switches of the nociceptive transmitters and modulators, as well as on their receptors and downstream signaling pathways that have already exerted roles in the pain processes of mature nervous systems. We have demonstrated recently that nerve injury may elicit neuronal alterations that recapitulate events occurring during development. Signaling of the representative activated molecule Wnt thus becomes a trigger for the development of neuropathic pain and is a potential therapeutic target. We report that the transcriptional regulators YAP and TAZ, which orchestrate Wnt response via incorporation in the β-catenin destruction complex, are key in the pathogenesis of neuropathic pain and may serve as an "ON-OFF" switch for neuropathic pain status in rats. Peripheral nerve injury causes rapid-onset and long-lasting nuclear accumulation of YAP/TAZ/β-catenin in the spinal dorsal horn. Spinal inhibition or knock-down of either YAP or TAZ suppresses mechanical allodynia induced by nerve injury or the pain initiators lysophosphatidic acid and Wnt3a. Promoting the nuclear accumulation of YAP/TAZ leads to mechanical hypersensitivity in naive animals. Further, we discovered a new small molecule, dCTB, which targets YAP/TAZ/β-catenin and can greatly suppress neuropathic pain and the associated neurochemical alterations. Our study reveals that YAP and TAZ are core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening for potent analgesics for the treatment of neuropathic pain. Mechanisms that underlie neuropathic pain remain elusive. We have demonstrated recently that nerve injury can activate Wnt signaling, which becomes a trigger for the development of neuropathic pain. We report

  13. Diagnosis and medical treatment of neuropathic pain in leprosy.

    Science.gov (United States)

    Arco, Rogerio Del; Nardi, Susilene Maria Tonelli; Bassi, Thiago Gasperini; Paschoal, Vania Del Arco

    2016-08-08

    to identify the difficulties in diagnosing and treating neuropathic pain caused by leprosy and to understand the main characteristics of this situation. 85 patients were treated in outpatient units with reference to leprosy and the accompanying pain. We used a questionnaire known as the Douleur Neuropathic 4 test and we conducted detailed neurological exams. As a result, 42 patients were excluded from the study for not having proved their pain. Out of the 37 patients that experienced pain, 22 (59.5%) had neuropathic pain (or a mixture of this pain and their existing pain) and of these 90.8% considered this pain to be moderate or severe. 81.8% of the sample suffered with this pain for more than 6 months. Only 12 (54.5%) of the patients had been diagnosed with neuropathic pain and in almost half of these cases, this pain had not been diagnosed. With reference to medical treatment (n=12) for neuropathic pain, 5 (41.6%) responded that they became better. For the other 7 (58.4%) there were no changes in relation to the pain or in some cases the pain worsened in comparison to their previous state. Statistical analysis comparing improvements in relation to the pain amongst the patients that were treated (n=12) and those that were not, showed significant differences (value p=0.020). we noted difficulties in diagnosing neuropathic pain for leprosy in that almost half of the patients that were studied had not had their pain diagnosed. We attributed this to some factors such as the non-adoption of the appropriate protocols which led to inadequate diagnosis and treatment that overlooked the true picture. identificar as dificuldades em diagnosticar e tratar a dor neuropática causada pela hanseníase, bem como determinar as características principais dessa situação. examinaram-se 85 pacientes tratados no ambulatório de referência para hanseníase e referiam dor. Aplicou-se questionário, o teste Douleur Neuropathic 4, e criterioso exame neurológico pelo qual exclu

  14. Patient-reported neuropathic pain in adolescent and young adult cancer patients.

    Science.gov (United States)

    Acquazzino, Melissa A; Igler, Eva C; Dasgupta, Mahua; Simpson, Pippa; Browning, Meghen B; Brandow, Amanda M

    2017-03-01

    Neuropathic pain, a known complication of cancer and its treatments, negatively impacts quality of life. There are limited data using screening tools to aid in the diagnosis of neuropathic pain in cancer patients. Our primary objective was to determine the proportion of adolescent and young adult cancer patients reporting neuropathic pain on a patient-completed, neuropathic pain screening tool. This prospective, cohort study enrolled patients 14-39 years of age who were receiving therapy for primary cancer diagnosis, cancer relapse, or had recently completed treatment. The painDETECT, a patient-completed, neuropathic pain screening tool used down to age 14, was administered a maximum of three times in on-therapy patients and once in off-therapy patients. Provider documentation of neuropathic pain at the corresponding visit was abstracted from the medical record. Seventy-eight patients participated. Median (interquartile range) age at study enrollment was 18.1 (16-19.4) years and 47% were female. Cancer diagnoses included 41% leukemia, 26% solid tumor, 23% lymphoma, and 10% central nervous system tumor. The proportion of patients reporting neuropathic pain was 26% (95% confidence interval [CI] 16-40%) in on-therapy patients and 11% (95% CI 3-27%) in off-therapy patients. In patients reporting neuropathic pain, only 26% had a clinical diagnosis of neuropathic pain documented in the medical record at the corresponding visit. Neuropathic pain occurs in one in four adolescents and young adults receiving cancer therapy. Use of screening tools may increase the detection of neuropathic pain in adolescents and young adults receiving cancer therapy and could ultimately improve pain treatment. © 2016 Wiley Periodicals, Inc.

  15. The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population.

    Science.gov (United States)

    Yawn, Barbara P; Wollan, Peter C; Weingarten, Toby N; Watson, James C; Hooten, W Michael; Melton, L Joseph

    2009-04-01

    Neuropathic pain is reported to be common based on studies from specialty centers and survey studies. However, few prevalence estimates have been completed in a community population using clinical evaluation. To develop an estimate of the prevalence of neuropathic pain in community-dwelling adults. Data from a mailed survey (N = 3,575 community respondents), telephone interview (N = 907), and a clinical examination (N = 205) were linked to estimate the population prevalence of neuropathic pain. Using the clinical examination as the "gold" standard, estimates from several screening tools were developed and adjusted to the Olmsted County, MN adult population. The estimated community prevalence of neuropathic pain from the clinical examination (gold standard) was 9.8%. Most other estimates were lower, including a 3.0% population prevalence using the Berger criteria and 8.8% using the Leeds Assessment of Neuropathic Symptoms and Signs. Only the prevalence rate based on self-report of nerve pain was higher (12.4%). Overlap among the groups each tool identified as having "neuropathic predominant pain" was only modest and the groups had significantly different rates of depressive symptoms, anxiety, limited functional ability, and use of complementary and alternative medicine. The estimated rates and personal characteristics of community residents with "neuropathic pain" vary widely depending on the tools used to identify neuropathic pain. None of the screening tools compared well with clinical evaluation. The differences in the groups identified by alternative screening methods become of major importance when reporting neuropathic pain epidemiology, studying therapies for neuropathic pain, or attempting to translate neuropathic pain research into clinical practice.

  16. Spinal anandamide produces analgesia in neuropathic rats: possible CB(1)- and TRPV1-mediated mechanisms.

    Science.gov (United States)

    Starowicz, K; Makuch, W; Osikowicz, M; Piscitelli, F; Petrosino, S; Di Marzo, V; Przewlocka, B

    2012-03-01

    The endocannabinoid anandamide (AEA) activates also transient receptor potential vanilloid-1 (TRPV1) channels. However, no data exist on the potential role of spinal TRPV1 activation by AEA in neuropathic pain. We tested the effect of: 1) AEA (5-100 μg), alone or in the presence of an inhibitor of its hydrolysis, and 2) elevated levels of endogenous AEA (following inhibition of AEA hydrolysis), in CCI rats, and the involvement of TRPV1 or cannabinoid CB(1) receptors in the observed effects. Levels of AEA in the spinal cord of CCI rats were measured following all treatments. AEA (50 μg) displayed anti-allodynic and anti-hyperalgesic effects which were abolished by previous antagonism of TRPV1, but not CB(1), receptors. Depending on the administered dose, the selective inhibitor of AEA enzymatic hydrolysis, URB597 (10-100 μg), reduced thermal and tactile nociception via CB(1) or CB(1)/TRPV1 receptors. The anti-nociceptive effects of co-administered per se ineffective doses of AEA (5 μg) and URB597 (5 μg) was abolished by antagonism of CB(1), but not TRPV1, receptors. Spinal AEA levels were increased after CCI, slightly increased further by URB597, 10 μg i.t., and strongly elevated by URB597, 100 μg. Injection of AEA (50 μg) into the lumbar spinal cord led to its dramatic elevation in this tissue, whereas, when a lower dose was used (5 μg) AEA endogenous levels were elevated only in the presence of URB597 (5 μg). We suggest that spinal AEA reduces neuropathic pain via CB(1) or TRPV1, depending on its local concentration.

  17. Effects of Melatonin and Vitamin E on Peripheral Neuropathic Pain in Streptozotocin-Induced Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2010-04-01

    Full Text Available Objective(sPrevious studies have indicated that diabetes mellitus might be accompanied by neuropathic pain. Oxidative stress is implicated as a final common pathway in development of diabetic neuropathy. Pharmacological interventions targeted at inhibiting free radical production have shown beneficial effects in diabetic neuropathy. The aim of this study was to investigate and compare the possible analgesic effects of melatonin and vitamin E in diabetic rats.Materials and MethodsThis study was performed on 32 male Wistar rats divided into 4 groups: control, diabetic, melatonin-treated diabetic and vitamin E-treated diabetic. Experimental diabetes was induced by intraperitoneal streptozotocin (50 mg/kg injection. Melatonin (10 mg/kg, i.p. and vitamin E (100 mg/kg, i.p. were injected for 2 weeks after 21st day of diabetes induction. At the end of administration period, pain-related behavior was assessed using 0.5% formalin test according to two spontaneous flinching and licking responses. The levels of lipid peroxidation as well as glutathione-peroxidase and catalase activities were evaluated in lumbosacral dorsal root ganglia.ResultsFormalin-evoked flinching and total time of licking were increased in both acute and chronic phases of pain in diabetic rats as compared to control rats, whereas treatment with melatonin or vitamin E significantly reduced the pain indices. Furthermore, lipid peroxidation levels increased and glutathione-peroxidase and catalase activities decreased in diabetic rats. Both antioxidants reversed the biochemical parameters toward their control values.ConclusionThese results suggest that oxidative stress may contribute to induction of pain in diabetes and further suggest that antioxidants, melatonin and vitamin E, can reduce peripheral neuropathic pain in streptozotocin-induced diabetic rats.

  18. Motor cortex stimulation for the treatment of refractory peripheral neuropathic pain.

    Science.gov (United States)

    Lefaucheur, Jean-Pascal; Drouot, Xavier; Cunin, Patrick; Bruckert, Rémy; Lepetit, Hélène; Créange, Alain; Wolkenstein, Pierre; Maison, Patrick; Keravel, Yves; Nguyen, Jean-Paul

    2009-06-01

    Epidural motor cortex stimulation (MCS) has been proposed as a treatment for chronic, drug-resistant neuropathic pain of various origins. Regarding pain syndromes due to peripheral nerve lesion, only case series have previously been reported. We present the results of the first randomized controlled trial using chronic MCS in this indication. Sixteen patients were included with pain origin as follows: trigeminal neuralgia (n = 4), brachial plexus lesion (n = 4), neurofibromatosis type-1 (n = 3), upper limb amputation (n = 2), herpes zoster ophthalmicus (n = 1), atypical orofacial pain secondary to dental extraction (n = 1) and traumatic nerve trunk transection in a lower limb (n = 1). A quadripolar lead was implanted, under radiological and electrophysiological guidance, for epidural cortical stimulation. A randomized crossover trial was performed between 1 and 3 months postoperative, during which the stimulator was alternatively switched 'on' and 'off' for 1 month, followed by an open phase during which the stimulator was switched 'on' in all patients. Clinical assessment was performed up to 1 year after implantation and was based on the following evaluations: visual analogue scale (VAS), brief pain inventory, McGill Pain questionnaire, sickness impact profile and medication quantification scale. The crossover trial included 13 patients and showed a reduction of the McGill Pain questionnaire-pain rating index (P = 0.0166, Wilcoxon test) and McGill Pain questionnaire sensory subscore (P = 0.01) when the stimulator was switched 'on' compared to the 'off-stimulation' condition. However, these differences did not persist after adjustment for multiple comparisons. In the 12 patients who completed the open study, the VAS and sickness impact profile scores varied significantly in the follow-up and were reduced at 9-12 months postoperative, compared to the preoperative baseline. At final examination, the mean rate of pain relief on VAS scores was 48% (individual results

  19. Diagnosing neuropathic pain in patients with cancer: comparative analysis of recommendations in national guidelines from European countries

    NARCIS (Netherlands)

    Piano, V.M.; Verhagen, S.; Schalkwijk, A.; Burgers, J.S.; Kress, H.; Treede, R.D.; Hekster, Y.A.; Lanteri-Minet, M.; Engels, Y.M.; Vissers, K.

    2013-01-01

    BACKGROUND: Neuropathic pain is a prevalent symptom in patients with cancer, which needs a more specific algorithm than nociceptive pain or neuropathic pain from other origin. Clinical practice guidelines (CPGs) can be helpful in optimizing the diagnosis of neuropathic pain in patients with cancer.

  20. Charcot Neuropathic Arthropathy of the Foot: A Literature Review and Single-Center Experience

    Science.gov (United States)

    Shaikh, Haroun Hassan

    2016-01-01

    Charcot neuropathic osteoarthropathy of the foot is a relatively common complication of diabetic neuropathy. Incorrect diagnosis and improper treatment often result in the extremity having to be amputated. This paper summarises the current view on the etiology, diagnostics, and treatment of diabetic Charcot neuropathic osteoarthropathy, with particular focus on preserving the extremity through surgical intervention from our own experiences. PMID:27656656

  1. Charcot Neuropathic Arthropathy of the Foot: A Literature Review and Single-Center Experience

    OpenAIRE

    Tomas Kucera; Haroun Hassan Shaikh; Pavel Sponer

    2016-01-01

    Charcot neuropathic osteoarthropathy of the foot is a relatively common complication of diabetic neuropathy. Incorrect diagnosis and improper treatment often result in the extremity having to be amputated. This paper summarises the current view on the etiology, diagnostics, and treatment of diabetic Charcot neuropathic osteoarthropathy, with particular focus on preserving the extremity through surgical intervention from our own experiences.

  2. Charcot Neuropathic Arthropathy of the Foot: A Literature Review and Single-Center Experience

    Directory of Open Access Journals (Sweden)

    Tomas Kucera

    2016-01-01

    Full Text Available Charcot neuropathic osteoarthropathy of the foot is a relatively common complication of diabetic neuropathy. Incorrect diagnosis and improper treatment often result in the extremity having to be amputated. This paper summarises the current view on the etiology, diagnostics, and treatment of diabetic Charcot neuropathic osteoarthropathy, with particular focus on preserving the extremity through surgical intervention from our own experiences.

  3. Conceptual adequacy of the neuropathic pain symptom inventory in six countries

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    Wong Audrey

    2008-08-01

    Full Text Available Abstract Background Neuropathic pain results from a nerve lesion or nerve damage. Because it is a subjective experience, patient-reported outcomes may measure both the symptoms and impact on the patient's life. The purpose of this study was to determine whether the Neuropathic Pain Symptom Inventory (NPSI adequately assesses neuropathic pain symptoms in patients with diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and sciatica across multiple cultures. Methods From data collected from 132 subjects in 6 countries, qualitative research methods identified their most important symptoms (and verbal descriptions associated with neuropathic pain. A core set of commonly described symptoms spanning multiple cultures was also described. Moderators using a semi-structured discussion guide conducted focus groups consisting of patients in the U.S., Brazil, Japan, China, Finland, and Spain to elicit concepts that were most important and relevant (concept elicitation phase. Study subjects ranked the importance of each neuropathic pain symptom, completed the NPSI, and commented on its ability to capture key symptoms (face and content validation phase. Results Descriptive terms for sensations of neuropathic pain were similar in all countries; burning, electric shocks, and pins and needles were among the most-common sensations. Individuals with neuropathic pain experienced all sensations that were included in the NPSI. They also tended to describe pins and needles and numbness interchangeably, perhaps reflecting the relative number of DPN subjects on study. Conclusion Based on data from these focus groups, the NPSI is an acceptable instrument for assessing neuropathic pain.

  4. KLF15 regulates dopamine D2 receptor and participates in mouse models of neuropathic pain.

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    Zhou, Junfei; Wang, Fang; Xu, Chang; Zhou, Zipeng; Zhang, Wei

    2017-10-14

    Neuropathic pain is caused by damage to the nervous system, resulting in aberrant pain. The mechanism underlying neuropathic pain remains largely unknown. Krüppel-like factor 15 (KLF15) is a member of the Krüppel-like factor family of transcriptional factors. Here in this study, we aimed to investigate the potential role of the transcriptional factor KLF15 in neuropathic pain. The mRNA and protein levels of Klf15 were significantly increased in the neurons of mouse undergoing neuropathic pain induced by sciatic nerve chronic constrictive injury (CCI) or unilateral spared nerve injury (SNI). In neurons, the upregulation of Klf15 was triggered by the inflammatory factor tumor necrosis factor alpha (TNF-α). As a transcriptional factor, KLF15 promoted the expression of dopamine D2 receptor (Drd2), which is a receptor essentially involved in neuropathic pain. KLF15 bound to the promoter of Drd2 directly and promoted the promoter activity of Drd2. Finally, we showed that knockout of Klf15 repressed the sensitivity in neuropathic pain induced by CCI or SNI. In conclusion, KLF15 is induced in neuropathic pain via a TNF-α-dependent manner and contributes to neuropathic pain partially through promoting the expression of dopamine D2 receptor. Copyright © 2017. Published by Elsevier Inc.

  5. Neuropathic-like pain features and cross-sectional associations in rheumatoid arthritis

    NARCIS (Netherlands)

    Koop, Sanne M.W.; ten Klooster, Peter M.; Vonkeman, Harald Erwin; Steunebrink, Laura Margaretha Maria; van de Laar, Mart A F J

    2015-01-01

    Introduction Increasing evidence indicates that features suggestive of neuropathic pain may also be present in patients with common rheumatic conditions. The objective of this study was to examine neuropathic-like pain symptoms and associated factors in patients with rheumatoid arthritis. Methods We

  6. Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain

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    Lim, Eun Yeong

    2016-01-01

    Neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory nervous system, is characterized by dysesthesia, hyperalgesia, and allodynia. The number of patients with this type of pain has increased rapidly in recent years. Yet, available neuropathic pain medicines have undesired side effects, such as tolerance and physical dependence, and do not fully alleviate the pain. The mechanisms of neuropathic pain are still not fully understood. Injury causes inflammation and immune responses and changed expression and activity of receptors and ion channels in peripheral nerve terminals. Additionally, neuroinflammation is a known factor in the development and maintenance of neuropathic pain. During neuropathic pain development, the C-C motif chemokine receptor 2 (CCR2) acts as an important signaling mediator. Traditional plant treatments have been used throughout the world for treating diseases. We and others have identified food-derived compounds that alleviate neuropathic pain. Here, we review the natural compounds for neuropathic pain relief, their mechanisms of action, and the potential benefits of natural compounds with antagonistic effects on GPCRs, especially those containing CCR2, for neuropathic pain treatment. PMID:27891521

  7. Thalamic activity and biochemical changes in individuals with neuropathic pain following spinal cord injury

    Science.gov (United States)

    Gustin, S.M.; Wrigley, P.J.; Youssef, A.M.; McIndoe, L.; Wilcox, S.L.; Rae, C.D.; Edden, R; Siddall, P.J.; Henderson, L.A.

    2015-01-01

    There is increasing evidence relating thalamic changes to the generation and/or maintenance of neuropathic pain. We have recently reported that neuropathic orofacial pain is associated with altered thalamic anatomy, biochemistry and activity, which may result in disturbed thalamocortical oscillatory circuits. Despite this evidence, it is possible that these thalamic changes are not responsible for the presence of pain per se, but result as a consequence of the injury. To clarify this subject, we compared brain activity and biochemistry in 12 people with below-level neuropathic pain after complete thoracic spinal cord injury to 11 people with similar injuries and no neuropathic pain and 21 age and gender matched healthy controls. Quantitative arterial spinal labelling was used to measure thalamic activity and magnetic resonance spectroscopy was used to determine changes in neuronal variability quantifying N-acetylaspartate and alterations in inhibitory function quantifying gamma amino butyric acid. This study revealed that the presence of neuropathic pain is associated with significant changes in thalamic biochemistry and neuronal activity. More specifically, the presence of neuropathic pain following spinal cord injury is associated with significant reductions in thalamic N-acetylaspartate, gamma amino butyric acid content and blood flow in the region of the thalamic reticular nucleus. Spinal cord injury on its own did not account for these changes. These findings support the hypothesis that neuropathic pain is associated with altered thalamic structure and function, which may disturb central processing and play a key role in the experience of neuropathic pain. PMID:24530612

  8. Cognitive behavioural treatment programme for chronic neuropathic pain after spinal cord injury

    NARCIS (Netherlands)

    Heutink, M.

    2014-01-01

    People with spinal cord injury (SCI) often face serious secondary health conditions, including different types of pain. Neuropathic pain is often rated by them as the most severe type of pain. Pharmacological interventions are often insufficiently effective in providing neuropathic pain relief and,

  9. Neuropathic-like pain features and cross-sectional associations in rheumatoid arthritis

    NARCIS (Netherlands)

    Koop, Sanne M.W.; Klooster, ten P.; Vonkeman, H.E.; Steunebrink, L.M.M.; Laar, van de M.A.F.J.

    2015-01-01

    Introduction Increasing evidence indicates that features suggestive of neuropathic pain may also be present in patients with common rheumatic conditions. The objective of this study was to examine neuropathic-like pain symptoms and associated factors in patients with rheumatoid arthritis. Methods

  10. Ethanolic extract of Aloe vera ameliorates sciatic nerve ligation induced neuropathic pain

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    Swetha Kanyadhara

    2014-01-01

    Conclusion: The results of the present study validate the use of EEAV to treat neuropathic pain. This effect may be attributed to the decreased migration of neutrophils and due to the anti-oxidant properties of A. vera. Further studies to confirm the mechanism of action will help develop suitable A. vera formulations for neuropathic pain therapy .

  11. Agmatine reversed mechanical allodynia in a rat model of neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    YANGHong-Ju; ZhAONan; GONGZheng-Hua; YUANWei-Xiou; LIYunFeng; LI-Jin; LUOZhi-Pu

    2004-01-01

    AIM: Agmatine is an endogenous neuromodulator present in the brain and spinal cord, agmatine has both NMDA receptor antagonist and NOS inhibitor activities, which may participate the pathological process in the neuropathic pain. The effect of agmatine on the mechanical allodynia in a rat model of the neuropathic pain was investigated in this experiment.

  12. Gabapentin for chronic neuropathic pain and fibromyalgia in adults

    Science.gov (United States)

    Moore, R Andrew; Wiffen, Philip J; Derry, Sheena; McQuay, Henry J

    2014-01-01

    Background This review updates parts of two earlier Cochrane reviews investigating effects of gabapentin in chronic neuropathic pain (pain due to nerve damage). Antiepileptic drugs are used to manage pain, predominantly for chronic neuropathic pain, especially when the pain is lancinating or burning. Objectives To evaluate the analgesic effectiveness and adverse effects of gabapentin for chronic neuropathic pain management. Search methods We identified randomised trials of gabapentin in acute, chronic or cancer pain from MEDLINE, EMBASE, and CENTRAL. We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources. The date of the most recent search was January 2011. Selection criteria Randomised, double-blind studies reporting the analgesic and adverse effects of gabapentin in neuropathic pain with assessment of pain intensity and/or pain relief, using validated scales. Participants were adults aged 18 and over. Data collection and analysis Two review authors independently extracted data. We calculated numbers needed to treat to benefit (NNTs), concentrating on IMM-PACT (Initiative on Methods, Measurement and Pain Assessment in Clinical Trials) definitions of at least moderate and substantial benefit, and to harm (NNH) for adverse effects and withdrawal. Meta-analysis was undertaken using a fixed-effect model. Main results Twenty-nine studies (3571 participants), studied gabapentin at daily doses of 1200 mg or more in 12 chronic pain conditions; 78% of participants were in studies of postherpetic neuralgia, painful diabetic neuropathy or mixed neuropathic pain. Using the IMMPACT definition of at least moderate benefit, gabapentin was superior to placebo in 14 studies with 2831 participants, 43% improving with gabapentin and 26% with placebo; the NNT was 5.8 (4.8 to 7.2). Using the IMMPACT definition of substantial benefit, gabapentin was superior to placebo in 13 studies with 2627 participants, 31% improving with

  13. TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain.

    Science.gov (United States)

    Kobayashi, Masaaki; Konishi, Hiroyuki; Sayo, Akira; Takai, Toshiyuki; Kiyama, Hiroshi

    2016-10-26

    Neuropathic pain afflicts millions of people, and the development of an effective treatment for this intractable pain is an urgent issue. Recent evidence has implicated microglia in neuropathic pain. The present study showed that the DNAX-activating protein of 12 kDa (DAP12) and its associated "triggering receptor expressed on myeloid cells 2" (TREM2) were predominantly expressed by microglia in the dorsal horn after spinal nerve injury, revealing a role for TREM2/DAP12 signaling in neuropathic pain. Nerve injury-induced proinflammatory cytokine expression in microglia and pain behaviors were significantly suppressed in Dap12-deficient mice. Furthermore, intrathecal administration of TREM2 agonistic antibody induced proinflammatory cytokine expression, as well as neuropathic pain, in mice without nerve injury. The agonistic antibody induced proinflammatory responses and neuropathic pain was not observed in Dap12-deficient mice. Together, these results suggest that TREM2/DAP12-mediated signals in microglia exacerbate nerve injury-induced neuropathic pain by inducing proinflammatory cytokine secretion from microglia. Suppression of DAP12-mediated signals could be a therapeutic target for neuropathic pain. Recent studies have revealed that activated microglia in the spinal dorsal horn exacerbate neuropathic pain, which has suggested that suppression of microglial activity should be considered as a therapeutic target. However, only a few molecules have been identified as regulators of microglial activity. In this study, we focused on a receptor complex of TREM2 and DAP12, both of which are expressed by microglia and have been implicated in the pathogenesis of Alzheimer's disease, and demonstrated that TREM2/DAP12 signaling promoted proinflammatory responses in microglia and exacerbates neuropathic pain. The present results revealed the functional significance of TREM2/DAP12 signaling in microglial activation after neuronal injury, and could help in the development of

  14. Prevalence of neuropathic pain in cases with chronic pain related to spinal disorders.

    Science.gov (United States)

    Yamashita, Toshihiko; Takahashi, Kazuhisa; Yonenobu, Kazuo; Kikuchi, Shin-ichi

    2014-01-01

    The incidence and characteristics of neuropathic pain associated with spinal disorders have not yet been fully clarified. The purpose of this study was to investigate the prevalence of neuropathic pain and the degree of deterioration of quality of life (QOL) in patients with chronic pain associated with spinal disorders who visited orthopedic outpatient clinics. This cross-sectional study was conducted in 1,857 patients recruited from 137 medical institutions nationwide. Participants were men and women aged 20-79 years with a history of spine-related pain for at least 3 months and a visual analog scale (VAS) score of at least 30 in the previous week. Patients were screened using a neuropathic pain screening questionnaire. The degree of QOL deterioration and its correlation with the presence of neuropathic pain were assessed using the Short Form Health Survey with 36 questions (SF-36). Overall prevalence of neuropathic pain was 53.3%. It was relatively high in patients with cervical spondylotic myelopathy (77.3%) and ligament ossification (75.7%) and relatively low in those with low back pain (29.4%) and spondylolysis (40.4%). Only 56.9% of patients with radiculopathy were diagnosed with neuropathic pain. Logistic regression analysis identified several risk factors, including advanced age, severe pain, disease duration of at least 6 months, and cervical lesions. In QOL assessment, physical functioning, role-physical, role-emotional, and social functioning were severely affected, and this trend was more pronounced in patients who were more likely to have neuropathic pain. The frequency of neuropathic pain tended to be higher in patients with diseases associated with spinal cord damage and lower in patients with diseases that primarily manifested as somatic pain. A bias toward allodynia symptoms in the screening questionnaire may have resulted in the failure to diagnose neuropathic pain in some patients with radiculopathy. Poor QOL, primarily from the aspect of

  15. IL-1 receptor antagonist improves morphine and buprenorphine efficacy in a rat neuropathic pain model.

    Science.gov (United States)

    Pilat, Dominika; Rojewska, Ewelina; Jurga, Agnieszka M; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2015-10-05

    An interesting research and therapeutic problem is the reduced beneficial efficacy of opioids in the treatment of neuropathic pain. The present study sought to investigate the potential role of IL-1 family members in this phenomenon. We studied the time course of changes in IL-1alpha, IL-1beta, IL-1 receptor type I and IL-1 receptor antagonist mRNA and protein levels experienced by rats after chronic constriction injury (CCI) of the sciatic nerve using qRT-PCR and Western blot analysis. In CCI-exposed rats, spinal levels of IL-1alpha mRNA were slightly downregulated on the 7th day, and protein levels were not changed on the 7th and 14th days. Levels of IL-1 receptor antagonist and IL-1 receptor type I were slightly upregulated in the ipsilateral part of the spinal cord on the 7th and 14th days; however, protein levels were not changed at those time points. Interestingly, we observed that IL-1beta mRNA and protein levels were strongly elevated in the ipsilateral part of the dorsal spinal cord on the 7th and 14th days following CCI. Moreover, in rats exposed to a single intrathecal administration of an IL-1 receptor antagonist (100 ng i.t.) on the 7th and 14th day following CCI, symptoms of neuropathic pain were attenuated, and the analgesic effects of morphine (2.5 µg i.t.) and buprenorphine (2.5 µg i.t.) were enhanced. In summary, restoration of the analgesic activity of morphine and buprenorphine by blockade of IL-1 signaling suggests that increased IL-1beta responses may account for the decreased analgesic efficacy of opioids observed in the treatment of neuropathy.

  16. Histamine in the locus coeruleus promotes descending noradrenergic inhibition of neuropathic hypersensitivity.

    Science.gov (United States)

    Wei, Hong; Jin, Cong-Yu; Viisanen, Hanna; You, Hao-Jun; Pertovaara, Antti

    2014-12-01

    Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1-10μg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.

  17. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone.

    Science.gov (United States)

    Hughes, Sam; Hickey, Louise; Donaldson, Lucy F; Lumb, Bridget M; Pickering, Anthony E

    2015-02-01

    The descending noradrenergic (NAergic) projection to the spinal cord forms part of an endogenous analgesic system. After nerve injury, a localised failure in this compensatory system has been implicated as a permissive factor in the development of neuropathic sensitisation. We investigated whether restoring descending NAergic tone with intrathecal reboxetine can oppose the development of the neuropathic pain phenotype after tibial nerve transection (TNT). Rats had a lumbar intrathecal catheter implanted at the time of nerve injury for administration of reboxetine (10 μg) in both acute and chronic dosing experiments. In acute dosing experiments, both intrathecal and systemic (30 mg/kg) reboxetine partially reversed mechanical allodynia. This antiallodynic effect of intrathecal reboxetine was blocked by prior administration of yohimbine (α2-adrenoceptor antagonist, 30 μg) but not by prazosin (α1-adrenoceptor antagonist, 30 μg) or propranolol (β-adrenoceptor antagonist, 100 μg). Chronic intrathecal reboxetine (10 μg, intrathecally, twice daily for 2 weeks) suppressed the development of cold and mechanical allodynia. Nerve-injured animals demonstrated a place preference for intrathecal reboxetine, suggesting that it also reduced spontaneous pain. In contrast, an equivalent antiallodynic dose of systemic reboxetine (30 mg/kg) was aversive in both naive and TNT rats. On cessation of chronic intrathecal reboxetine, there was a gradual development of allodynic sensitisation that was indistinguishable from control TNT animals by 7 days after the end of dosing. Our results suggest that pharmacological restoration of spinal NAergic tone with intrathecal reboxetine can suppress both allodynia and spontaneous pain in the TNT model.

  18. Pharmacological evaluation of tacrolimus (FK-506 on ischemia reperfusion induced vasculatic neuropathic pain in rats

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    Sood Shailja

    2010-06-01

    Full Text Available Abstract Background Ischemia reperfusion (I/R is common in various pathological conditions like diabetic complication, rheumatic arthritis, necrotizing vascular occlusive disease and trauma. Methods We have evaluated the effect of tacrolimus (1, 2 and 3 mg/kg, p.o. for 10 consecutive days on femoral arterial ischemic reperfusion (I/R induced neuropathic pain in rats. Behavioral parameters (i.e. hot plate, radiant heat, acetone drop, tail heat hyperalgesia, tail flick and tail cold allodynia tests were assessed at different time intervals (i.e. 0, 1, 4, 7, 10, 13 and 16th day and biochemical analysis in serum and tissue samples were also performed along with histopathological studies. Results Behavioral pain assessment revealed increase in the paw and tail withdrawal threshold in tacrolimus treated groups against hyperalgesic and allodynic stimuli as compared to the sham control group. We observed a decrease in the serum nitrate and thiobarbituric acid reactive substance (TBARS levels along with reduction in tissue myeloperoxidase (MPO and total calcium levels, whereas, rise in tissue reduced glutathione levels in tacrolimus treated groups. However, significant results were obtained in medium and high dose treated group as compared to sham control group. Histopathological study had revealed the increase in the neuronal edema and axonal degeneration in the I/R group whereas, tacrolimus ameliorate these effects. Conclusion Our results indicate the anti-oxidative, anti-inflammatory and calcium modulatory actions of tacrolimus. Therefore, it can be used as a therapeutic agent for the treatment of vascular inflammatory related neuropathic pain.

  19. Local peripheral opioid effects and expression of opioid genes in the spinal cord and dorsal root ganglia in neuropathic and inflammatory pain.

    Science.gov (United States)

    Obara, Ilona; Parkitna, Jan Rodriguez; Korostynski, Michal; Makuch, Wioletta; Kaminska, Dorota; Przewlocka, Barbara; Przewlocki, Ryszard

    2009-02-01

    We investigated the efficacy of local intraplantar (i.pl.) injection of peptide and non-peptide mu-, delta- and kappa-opioid receptor agonists in rat models of inflammatory and neuropathic pain. Locally applied agonists dose-dependently reduced formalin-induced flinching of the inflamed paw and induced antiallodynic and antihyperalgesic effects in sciatic nerve ligation-induced neuropathic pain. These effects were mediated by peripheral opioid receptors localized at the side of tissue/nerve injury, as was demonstrated by selective and non-selective opioid receptors antagonists. The ED(50) dose range of mu- and kappa-agonists required to induce analgesia in neuropathy was much higher than the ED(50) for inflammation; moreover, only delta-agonists were effective in the same dose range in both pain models. Additionally, effective antinociception was achieved at a lower dose of peptide, compared to non-peptide, opioids. Such findings support the use of the peripheral administration of opioid peptides, especially delta-agonists, in treating chronic pain. Furthermore, in order to assess whether adaptations in the expression of opioid genes could underlie the clinical observation of reduced opioid effectiveness in neuropathic pain, we analyzed the abundance of opioid transcripts in the spinal cord and dorsal root ganglia (DRG) during the neuropathy and inflammation. Nerve injury down-regulated mRNA for all types of opioid receptors in the DRG, which is predicted to decrease in the synthesis of opioid receptors to possibly account for the reduced effectiveness of locally administered opioids in neuropathy. The obtained results differentiate inflammatory and neuropathic pain and provide a novel insight into the peripheral effectiveness of opioids in both types of pain.

  20. Reduction of painful area as new possible therapeutic target in post-herpetic neuropathic pain treated with 5% lidocaine medicated plaster: a case series.

    Science.gov (United States)

    Casale, Roberto; Di Matteo, Maria; Minella, Cristina E; Fanelli, Guido; Allegri, Massimo

    2014-01-01

    Post-herpetic neuralgia (PHN) is neuropathic pain persisting after an acute episode of herpes zoster, and is associated with severe pain and sensory abnormalities that adversely affect the patient's quality of life and increase health care costs. Up to 83% of patients with PHN describe localized neuropathic pain, defined as "a type of neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain". Topical treatments have been suggested as a first-line treatment for localized neuropathic pain. Use of 5% lidocaine medicated plaster could reduce abnormal nervous peripheral discharge and via the plaster could have a "protective" function in the affected area. It has been suggested that use of this plaster could reduce pain as well as the size of the painful area. To evaluate this possible outcome, we retrospectively reviewed eight patients with PHN, treated using 5% lidocaine medicated plaster. During a follow-up period of 3 months, we observed good pain relief, which was associated with a 46% reduction in size of the painful area after one month (from 236.38±140.34 cm(2) to 128.80±95.7 cm(2)) and a 66% reduction after 3 months (81.38±59.19 cm(2)). Our study cohort was composed mainly of elderly patients taking multiple drugs to treat comorbidities, who have a high risk of drug-drug interactions. Such patients benefit greatly from topical treatment of PHN. Our observations confirm the effectiveness of lidocaine plasters in the treatment of PHN, indicating that 5% lidocaine medicated plaster could reduce the size of the painful area. This last observation has to be confirmed and the mechanisms clarified in appropriate larger randomized controlled trials.

  1. Neuropathic diabetic foot ulcers – evidence-to-practice

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    Ndip A

    2012-02-01

    Full Text Available Agbor Ndip1–3, Leonard Ebah3,4, Aloysius Mbako51Department of Diabetes and Medicine, Manchester Royal Infirmary, Central Manchester Foundation Trust, UK; 2Department of Medicine, Royal Bolton Hospital, Bolton, UK; 3Cardiovascular Research Group, School of Biomedicine, University of Manchester, UK; 4Department of Renal Medicine, Manchester Royal Infirmary, Central Manchester Foundation Trust, UK; 5Department of Orthopaedic Surgery, Wrexham Maelor Hospital, Wales, UKAbstract: Foot ulcers and their attendant complications are disquietingly high in people with diabetes, a majority of whom have underlying neuropathy. This review examines the evidence base underpinning the prevention and management of neuropathic diabetic foot ulcers in order to inform best clinical practice. Since it may be impractical to ask patients not to weight-bear at all, relief of pressure through the use of offloading casting devices remains the mainstay for management of neuropathic ulcers, whilst provision of appropriate footwear is essential in ulcer prevention. Simple non-surgical debridement and application of hydrogels are both effective in preparing the wound bed for healthy granulation and therefore enhancing healing. Initial empirical antibiotic therapy for infected ulcers should cover the most common bacterial flora. There is limited evidence supporting the use of adjunctive therapies such as hyperbaric oxygen and cytokines or growth factors. In selected cases, recombinant human platelet-derived growth factor has been shown to enhance healing; however, its widespread use cannot be advised due to the availability of more cost-effective approaches. While patient education may be beneficial, the evidence base remains thin and conflicting. In conclusion, best management of foot ulcers is achieved by what is taken out of the foot (pressure, callus, infection, and slough rather than what is put on the foot (adjuvant treatment.Keywords: diabetic foot ulcers, neuropathic

  2. Effect of DSP4 and desipramine in the sensorial and affective component of neuropathic pain in rats.

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    Bravo, Lidia; Mico, Juan A; Rey-Brea, Raquel; Camarena-Delgado, Carmen; Berrocoso, Esther

    2016-10-03

    Previous findings suggest that neuropathic pain induces characteristic changes in the noradrenergic system that may modify the sensorial and affective dimensions of pain. We raise the hypothesis that different drugs that manipulate the noradrenergic system can modify specific domains of pain. In the chronic constriction injury (CCI) model of neuropathic pain, the sensorial (von Frey and acetone tests) and the affective (place escape/avoidance paradigm) domains of pain were evaluated in rats 1 and 2weeks after administering the noradrenergic neurotoxin [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] (DSP4, 50mg/kg). In other animals, we evaluated the effect of enhancing noradrenergic tone in the 2weeks after injury by administering the antidepressant desipramine (10mg/kg/day, delivered by osmotic minipumps) during this period, a noradrenaline reuptake inhibitor. Moreover, the phosphorylation of the extracellular signal regulated kinases (p-ERK) in the anterior cingulate cortex (ACC) was also assessed. The ACC receives direct inputs from the main noradrenergic nucleus, the locus coeruleus, and ERK activation has been related with the expression of pain-related negative affect. These studies revealed that DSP4 almost depleted noradrenergic axons in the ACC and halved noradrenergic neurons in the locus coeruleus along with a decrease in the affective dimension and an increased of p-ERK in the ACC. However, it did not modify sensorial pain perception. By contrast, desipramine reduced pain hypersensitivity, while completely impeding the reduction of the affective pain dimension and without modifying the amount of p-ERK. Together results suggest that the noradrenergic system may regulate the sensorial and affective sphere of neuropathic pain independently.

  3. Mechanisms of neuropathic pain in patients with Charcot-Marie-Tooth 1 A: a laser-evoked potential study.

    Science.gov (United States)

    Pazzaglia, Costanza; Vollono, Catello; Ferraro, Diana; Virdis, Daniela; Lupi, Valentina; Le Pera, Domenica; Tonali, Pietro; Padua, Luca; Valeriani, Massimiliano

    2010-05-01

    Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy. The CMT1A type can be considered the typical phenotype of this disease. Although pain is not considered a relevant symptom in CMT patients by physicians and no study assessed it comprehensively, this symptom is frequently complained by patients. The objective of the present study was to investigate the nociceptive system in a sample of CMT1A patients suffering from pain by laser-evoked potentials (LEPs). Moreover, we also used a pain specific questionnaire in order to obtain patient-oriented data about their painful symptoms, the Neuropathic Pain Diagnostic Questionnaire (DN4). We evaluated 16 patients affected by CMT1A and 14 controls. All subjects underwent a standard LEP recording session (foot, hand, and face stimulation) and filled in the DN4. While the N2/P2 amplitude to foot stimulation was lower in CMT patients than in controls (p=0.003), no difference in LEP amplitude to both hand and face stimulation was found between patients and healthy subjects (p>0.05). This result is probably due to a length-dependent Adelta-fiber loss which involves mostly the longer fibers coming from the lower limb. In our patients, there was a significant association between a reduced N2/P2 amplitude to foot stimulation and a high DN4 score (p=0.03), meaning that patients with highly probable neuropathic pain had also low N2/P2 amplitude values to painful foot stimulation. This suggests that in our CMT1A patients neuropathic pain is probably related to a reduction of the Adelta afferents. Copyright 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  4. The RS504393 Influences the Level of Nociceptive Factors and Enhances Opioid Analgesic Potency in Neuropathic Rats.

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    Kwiatkowski, Klaudia; Piotrowska, Anna; Rojewska, Ewelina; Makuch, Wioletta; Mika, Joanna

    2017-09-01

    Increasing evidence has indicated that activated glial cells releasing nociceptive factors, such as interleukins and chemokines, are of key importance for neuropathic pain. Significant changes in the production of nociceptive factors are associated with the low effectiveness of opioids in neuropathic pain. Recently, it has been suggested that CCL2/CCR2 signaling is important for nociception. Here, we studied the time course changes in the mRNA/protein level of CD40/Iba-1, CCL2 and CCR2 in the spinal cord/dorsal root ganglia (DRG) in rats following chronic constriction injury (CCI) of the sciatic nerve. Moreover, we examined the influence of intrathecal preemptive and repeated (daily for 7 days) administration of RS504393, CCR2 antagonist, on pain-related behavior and the associated biochemical changes of some nociceptive factors as well as its influence on opioid effectiveness. We observed simultaneous upregulation of Iba-1, CCL2, CCR2 in the spinal cord on 7th day after CCI. Additionally, we demonstrated that repeated administration of RS504393 not only attenuated tactile/thermal hypersensitivity but also enhanced the analgesic properties of morphine and buprenorphine under neuropathy. Our results proof that repeated administration of RS504393 reduced the mRNA and/or protein levels of pronociceptive factors, such as IL-1beta, IL-18, IL-6 and inducible nitric oxide synthase (iNOS), and some of their receptors in the spinal cord and/or DRG. Furthermore, RS504393 elevated the spinal protein level of antinociceptive IL-1alpha and IL-18 binding protein. Our data provide new evidence that CCR2 is a promising target for diminishing neuropathic pain and enhancing the opioid analgesic effects.

  5. Effect of a polyherbal formulation cream on diabetic neuropathic pain among patients with type 2 diabetes - A pilot study.

    Science.gov (United States)

    Viswanathan, Vijay; Rajsekar, Seena; Selvaraj, Bamila; Kumpatla, Satyavani

    2016-08-01

    Painful diabetic neuropathy is a common complication of diabetes and can severely limit patients' daily functions. The aim of this pilot study was to evaluate the safety and effect of using a polyherbal formulation in reducing the symptoms of diabetic neuropathic pain in comparison with placebo among patients with type 2 diabetes. A total of 50 (M:F = 33:17) consecutive type 2 diabetes patients with painful diabetic neuropathy were enrolled in this study. All these patients had either two or more symptoms of diabetic neuropathy such as pain, burning and pricking sensations and numbness in their feet. They were randomly assigned to two groups: group 1 (n = 26) patients were treated with polyherbal formulation cream and group 2 (n = 24) patients were administered placebo. The patients were followed up for six months. Changes in the symptoms of painful diabetic neuropathy of each patient were recorded at baseline, third and sixth month using the Diabetic Neuropathic Score. The mean age of the patients, duration of diabetes and glycated haemoglobin (HbA 1c ) were similar in both groups at baseline. During follow up visits, there was a decrease in the HbA 1c levels in the study and control groups. The symptoms of painful diabetic neuropathy were also similar in both groups at baseline. A significant decrease in symptoms of neuropathic pain was observed among the group of patients treated with polyherbal formulation cream (76.9 per cent) compared to the placebo-treated group (12.5 per cent) (Pcream was found to be effective as well as safe to treat painful diabetic neuropathy. However, its long term use needs to be evaluated for any further effectiveness and side effects.

  6. Effect of a polyherbal formulation cream on diabetic neuropathic pain among patients with type 2 diabetes - A pilot study

    Directory of Open Access Journals (Sweden)

    Vijay Viswanathan

    2016-01-01

    Full Text Available Background & objectives: Painful diabetic neuropathy is a common complication of diabetes and can severely limit patients′ daily functions. The aim of this pilot study was to evaluate the safety and effect of using a polyherbal formulation in reducing the symptoms of diabetic neuropathic pain in comparison with placebo among patients with type 2 diabetes. Methods: A total of 50 (M:F = 33:17 consecutive type 2 diabetes patients with painful diabetic neuropathy were enrolled in this study. All these patients had either two or more symptoms of diabetic neuropathy such as pain, burning and pricking sensations and numbness in their feet. They were randomly assigned to two groups: group 1 (n = 26 patients were treated with polyherbal formulation cream and group 2 (n = 24 patients were administered placebo. The patients were followed up for six months. Changes in the symptoms of painful diabetic neuropathy of each patient were recorded at baseline, third and sixth month using the Diabetic Neuropathic Score. Results: The mean age of the patients, duration of diabetes and glycated haemoglobin (HbA 1c were similar in both groups at baseline. During follow up visits, there was a decrease in the HbA 1c levels in the study and control groups. The symptoms of painful diabetic neuropathy were also similar in both groups at baseline. A significant decrease in symptoms of neuropathic pain was observed among the group of patients treated with polyherbal formulation cream (76.9 per cent compared to the placebo-treated group (12.5 per cent (P<0.001, at the end of the final follow up. Interpretation & conclusions: In this pilot study polyherbal formulation cream was found to be effective as well as safe to treat painful diabetic neuropathy. However, its long term use needs to be evaluated for any further effectiveness and side effects.

  7. The cannabinoid CB₂ receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain.

    Science.gov (United States)

    Klauke, A-L; Racz, I; Pradier, B; Markert, A; Zimmer, A M; Gertsch, J; Zimmer, A

    2014-04-01

    The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB₂). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB₂ is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, we have investigated the analgesic effects of BCP in animal models of inflammatory and neuropathic pain. We demonstrate that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB₂ receptor-dependent manner, while it had no effect on acute (early phase) responses. In a neuropathic pain model the chronic oral administration of BCP attenuated thermal hyperalgesia and mechanical allodynia, and reduced spinal neuroinflammation. Importantly, we found no signs of tolerance to the anti-hyperalgesic effects of BCP after prolonged treatment. Oral BCP was more effective than the subcutaneously injected synthetic CB₂ agonist JWH-133. Thus, the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.

  8. Prokineticin 2 Upregulation in the Peripheral Nervous System Has a Major Role in Triggering and Maintaining Neuropathic Pain in the Chronic Constriction Injury Model

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    Roberta Lattanzi

    2015-01-01

    Full Text Available The new chemokine Prokineticin 2 (PROK2 and its receptors (PKR1 and PKR2 have a role in inflammatory pain and immunomodulation. Here we identified PROK2 as a critical mediator of neuropathic pain in the chronic constriction injury (CCI of the sciatic nerve in mice and demonstrated that blocking the prokineticin receptors with two PKR1-preferring antagonists (PC1 and PC7 reduces pain and nerve damage. PROK2 mRNA expression was upregulated in the injured nerve since day 3 post injury (dpi and in the ipsilateral DRG since 6 dpi. PROK2 protein overexpression was evident in Schwann Cells, infiltrating macrophages and axons in the peripheral nerve and in the neuronal bodies and some satellite cells in the DRG. Therapeutic treatment of neuropathic mice with the PKR-antagonist, PC1, impaired the PROK2 upregulation and signalling. This fact, besides alleviating pain, brought down the burden of proinflammatory cytokines in the damaged nerve and prompted an anti-inflammatory repair program. Such a treatment also reduced intraneural oedema and axon degeneration as demonstrated by the physiological skin innervation and thickness conserved in CCI-PC1 mice. These findings suggest that PROK2 plays a crucial role in neuropathic pain and might represent a novel target of treatment for this disease.

  9. Prokineticin 2 Upregulation in the Peripheral Nervous System Has a Major Role in Triggering and Maintaining Neuropathic Pain in the Chronic Constriction Injury Model

    Science.gov (United States)

    Lattanzi, Roberta; Maftei, Daniela; Marconi, Veronica; Florenzano, Fulvio; Franchi, Silvia; Borsani, Elisa; Rodella, Luigi Fabrizio; Balboni, Gianfranco; Salvadori, Severo; Sacerdote, Paola; Negri, Lucia

    2015-01-01

    The new chemokine Prokineticin 2 (PROK2) and its receptors (PKR1 and PKR2) have a role in inflammatory pain and immunomodulation. Here we identified PROK2 as a critical mediator of neuropathic pain in the chronic constriction injury (CCI) of the sciatic nerve in mice and demonstrated that blocking the prokineticin receptors with two PKR1-preferring antagonists (PC1 and PC7) reduces pain and nerve damage. PROK2 mRNA expression was upregulated in the injured nerve since day 3 post injury (dpi) and in the ipsilateral DRG since 6 dpi. PROK2 protein overexpression was evident in Schwann Cells, infiltrating macrophages and axons in the peripheral nerve and in the neuronal bodies and some satellite cells in the DRG. Therapeutic treatment of neuropathic mice with the PKR-antagonist, PC1, impaired the PROK2 upregulation and signalling. This fact, besides alleviating pain, brought down the burden of proinflammatory cytokines in the damaged nerve and prompted an anti-inflammatory repair program. Such a treatment also reduced intraneural oedema and axon degeneration as demonstrated by the physiological skin innervation and thickness conserved in CCI-PC1 mice. These findings suggest that PROK2 plays a crucial role in neuropathic pain and might represent a novel target of treatment for this disease. PMID:25685780

  10. Role of COX-1 in the process of neuropathic pain and its mechanism Zhi-hong LU, Qi - bing MEI

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    AIM In neuropathic pain the peripheral or central nervous systems are malfunctioning and become the cause of the pain. Unlike other pain styles, most neuropathic pain responds poorly to opioid analgesics. The mainstay of treatment is predominantly the tricyclic antidepressants, the anticonvulsants and the systemic local anesthetics of which the long- term use could lead to great side effects. Recently, proin-flammatory cytokines, such as IL-6, TNF-α, etc, have been proved to be involved in the process of neuropathic pain, indicating the cross - talking between neuropathic pain and inflammation. As an important member in inflammatory process, COX is expected to play a part in the process of neuropathic pain.In this study, we observed the change of COX-1 after neuropathic pain and further investigated thechange it caused in the brain. METHODS Spared nerve injury (SNI) is used to induce neuropathic painin mice.

  11. Successful spinal cord stimulation for neuropathic below-level spinal cord injury pain following complete paraplegia: a case report.

    Science.gov (United States)

    Reck, Tim A; Landmann, Gunther

    2017-01-01

    Neuropathic pain is common in patients with spinal cord injury (SCI) and often difficult to treat. We report a case where epidural spinal cord stimulation (SCS) below the level of injury has been successfully applied in a patient with a complete spinal cord lesion. A 53-year-old female presented with neuropathic below-level SCI pain of both lower legs and feet due to complete SCI below T5. Time and pain duration since injury was 2 years. Pain intensity was reported on numeric rating scale with an average of 7/10 (0 meaning no pain, 10 meaning the worst imaginable pain), but also with about 8-10 pain attacks during the day with an intensity of 9/10, which lasted between some minutes and half an hour. SCS was applied below the level of injury at-level T11-L1. After a successful 2 weeks testing period the pulse generator has been implanted permanently with a burst-stimulation pattern. The average pain was reduced to a bearable intensity of 4/10, in addition attacks could be reduced both in frequency and in intensity. This effects lasted for at least three months of follow-up. Even in case of complete SCI, SCS might be effective. Mechanisms of pain relief remain unclear. A modulation of suggested residual spinothalamic tract function may play a role. Further investigation has to be carried out to support this theory.

  12. Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief

    Science.gov (United States)

    Moriconi, Alessio; Cunha, Thiago M.; Souza, Guilherme R.; Lopes, Alexandre H.; Cunha, Fernando Q.; Carneiro, Victor L.; Pinto, Larissa G.; Brandolini, Laura; Aramini, Andrea; Bizzarri, Cinzia; Bianchini, Gianluca; Beccari, Andrea R.; Fanton, Marco; Bruno, Agostino; Costantino, Gabriele; Bertini, Riccardo; Galliera, Emanuela; Locati, Massimo; Ferreira, Sérgio H.; Teixeira, Mauro M.; Allegretti, Marcello

    2014-01-01

    Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent pronociceptive mediator in several models of inflammatory and neuropathic pain. Although there has long been interest in the identification of C5aR inhibitors, their development has been complicated, as for many peptidomimetic drugs, mostly by poor drug-like properties. Herein, we report the de novo design of a potent and selective C5aR noncompetitive allosteric inhibitor, DF2593A, guided by the hypothesis that an allosteric site, the “minor pocket,” previously characterized in CXC chemokine receptors-1 and -2, is functionally conserved in the GPCR class. In vitro, DF2593A potently inhibited C5a-induced migration of human and rodent neutrophils. In vivo, oral administration of DF2593A effectively reduced mechanical hyperalgesia in several models of acute and chronic inflammatory and neuropathic pain, without any apparent side effects. Mechanical hyperalgesia after spared nerve injury was also reduced in C5aR−/− mice compared with WT mice. Furthermore, treatment of C5aR−/− mice with DF2593A did not produce any further antinociceptive effect compared with C5aR−/− mice treated with vehicle. The successful medicinal chemistry strategy confirms that a conserved minor pocket is amenable for the rational design of selective inhibitors and the pharmacological results support that the allosteric blockade of the C5aR represents a highly promising therapeutic approach to control chronic inflammatory and neuropathic pain. PMID:25385614

  13. Topical moringin cream relieves neuropathic pain by suppression of inflammatory pathway and voltage-gated ion channels in murine model of multiple sclerosis

    Science.gov (United States)

    Giacoppo, Sabrina; Iori, Renato; Bramanti, Placido

    2017-01-01

    Background Neuropathic pain represents the major public health burden with a strong impact on quality life in multiple sclerosis patients. Although some advances have been obtained in the last years, the conventional therapies remain poorly effective. Thus, the discovery of innovative approaches to improve the outcomes for multiple sclerosis patients is a goal of primary importance. With this aim, we investigated the efficacy of the 4-(α−L-rhamnopyranosyloxy)benzyl isothiocyanate (moringin), purified from Moringa oleifera seeds and ready-to-use as topical treatment in experimental autoimmune encephalomyelitis, murine model of multiple sclerosis. Female C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG35–55) were topically treated with 2% moringin cream twice daily from the onset of the symptoms until the sacrifice occurred about 21 days after experimental autoimmune encephalomyelitis induction. Results Our observations showed the efficacy of 2% moringin cream treatment in reducing clinical and histological disease score, as well as in alleviating neuropathic pain with consequent recovering of the hind limbs and response to mechanical stimuli. In particular, Western blot analysis and immunohistochemical evaluations revealed that 2% moringin cream was able to counteract the inflammatory cascade by reducing the production of pro-inflammatory cytokines (interleukin-17 and interferon-γ) and in parallel by increasing the expression of anti-inflammatory cytokine (interleukin-10). Interestingly, 2% moringin cream treatment was found to modulate the expression of voltage-gated ion channels (results focused on P2X7, Nav 1.7, Nav 1.8 KV4.2, and α2δ-1) as well as metabotropic glutamate receptors (mGluR5 and xCT) involved in neuropathic pain initiation and maintenance. Conclusions Finally, our evidences suggest 2% moringin cream as a new pharmacological trend in the management of multiple sclerosis-induced neuropathic pain. PMID:28741431

  14. Acute neuropathic joint in diabetic foot: Plain radiographic findings

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    Yoon, Dae Young; Kang, Heung Sik; Sim, Jung Suk; Yoon, Yong Kyu; Kim, Chu Wan [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1994-05-15

    To determine the plain film findings of acute neuropathic joint in diabetic foot. Acute neuropathic joint in diabetic foot was considered when fragmentation of the articular ends of bone and subluxation of the affected joint developed within eight weeks after clinical onset of diabetic gangrene. Eight toes of six diabetics were satisfactory to our criteria. We analyzed plain radiographic findings of the affected joint and soft tissue, interval changes in followed-up radiographs, and deformities after healing. The time interval between clinical onset of gangrene and bone destruction ranges from 2 weeks to 4 weeks(mean 2.6 weeks). Plane radiographs showed fragmentation of the articular ends, subluxation, and soft tissue swelling of the metatarsophalangeal joint or interphalangeal joint. The significant feature of these patients was rapid progression of the lesions. Clinically, all patients had diabetic gangrene in affected toes, however, there was no evidence of osteomyelitis in our series. Amputation was done in 2 cases, and lesions in 3 of the remaining 4 cases were repaired spontaneously with regression of gangrene, leaving radiological residua such as pointed-end, tapered-end, and ball and socket deformity. Rapid disorganisation of the joint with associated evidence of soft tissue gangrene in plain radiograph is believed to be valuable for the diagnosis of diabetic osteoarthropathy.

  15. Botulinum Toxin for Neuropathic Pain: A Review of the Literature

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    Hyun-Mi Oh

    2015-08-01

    Full Text Available Botulinum neurotoxin (BoNT, derived from Clostridium botulinum, has been used therapeutically for focal dystonia, spasticity, and chronic migraine. Its spectrum as a potential treatment for neuropathic pain has grown. Recent opinions on the mechanism behind the antinociceptive effects of BoNT suggest that it inhibits the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. There is some evidence showing the axonal transport of BoNT, but it remains controversial. The aim of this review is to summarize the experimental and clinical evidence of the antinociceptive effects, mechanisms, and therapeutic applications of BoNT for neuropathic pain conditions, including postherpetic neuralgia, complex regional pain syndrome, and trigeminal neuralgia. The PubMed and OvidSP databases were searched from 1966 to May 2015. We assessed levels of evidence according to the American Academy of Neurology guidelines. Recent studies have suggested that BoNT injection is an effective treatment for postherpetic neuralgia and is likely efficient for trigeminal neuralgia and post-traumatic neuralgia. BoNT could also be effective as a treatment for diabetic neuropathy. It has not been proven to be an effective treatment for occipital neuralgia or complex regional pain syndrome.

  16. Sodium hydrosulfide relieves neuropathic pain in chronic constriction injured rats.

    Science.gov (United States)

    Lin, Jian-Qing; Luo, Hui-Qin; Lin, Cai-Zhu; Chen, Jin-Zhuan; Lin, Xian-Zhong

    2014-01-01

    Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain (NPP). Channel protein pCREB of that activity has been shown to mitigate the onset of associated molecular events in the nervous system, and sodium hydrosulfide (NaHS) could inhibit the expression of pCREB. However, whether NaHS could relieve the pain, it needs further experimental research. Furthermore, the clinical potential that NaHS was used to relieve pain was limited so it would be required. To address these issues, the rats of sciatic nerve chronic constriction injury (CCI) were given intraperitoneal injection of NaHS containing hydrogen sulfide (H2S). The experimental results showed that NaHS inhibited the reduction of paw withdrawal thermal latency (PWTL), mechanical withdrawal threshold (MWT), and the level of pCREB in CCI rats in a dose-dependent manner and they were greatly decreased in NaHSM group (P < 0.05). NaHS alleviates chronic neuropathic pain by inhibiting expression of pCREB in the spinal cord of Sprague-Dawley rats.

  17. Sodium Hydrosulfide Relieves Neuropathic Pain in Chronic Constriction Injured Rats

    Directory of Open Access Journals (Sweden)

    Jian-qing Lin

    2014-01-01

    Full Text Available Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain (NPP. Channel protein pCREB of that activity has been shown to mitigate the onset of associated molecular events in the nervous system, and sodium hydrosulfide (NaHS could inhibit the expression of pCREB. However, whether NaHS could relieve the pain, it needs further experimental research. Furthermore, the clinical potential that NaHS was used to relieve pain was limited so it would be required. To address these issues, the rats of sciatic nerve chronic constriction injury (CCI were given intraperitoneal injection of NaHS containing hydrogen sulfide (H2S. The experimental results showed that NaHS inhibited the reduction of paw withdrawal thermal latency (PWTL, mechanical withdrawal threshold (MWT, and the level of pCREB in CCI rats in a dose-dependent manner and they were greatly decreased in NaHSM group (P < 0.05. NaHS alleviates chronic neuropathic pain by inhibiting expression of pCREB in the spinal cord of Sprague-Dawley rats.

  18. Neuropathic pain referrals to a multidisciplinary pediatric cancer pain service.

    Science.gov (United States)

    Anghelescu, Doralina L; Faughnan, Lane G; Popenhagen, Mark P; Oakes, Linda L; Pei, Deqing; Burgoyne, Laura L

    2014-03-01

    Neuropathic pain (NP) in children with cancer is not well characterized. In a retrospective review of patient data from a 3.5-year period, we describe the prevalence of NP and the characteristics, duration of follow-up, and interventions provided for NP among patients referred to a pediatric oncology center's pain management service. Fifteen percent (66/439) of all referrals to our pain service were for NP (56/323 patients [17%]; 34 male, 22 female). The NP patient group had 1,401 clinical visits (778 inpatient visits [55.5%] and 623 outpatient visits [44.5%]). Patients with NP had a significantly greater mean number of pain visits per consultation (p = .008) and significantly more days of pain service follow-up (p cancer treatment rather than the underlying malignancy. Pharmacologic management of NP was complex, often comprising three medications. Nonpharmacologic approaches were used for 57.6% of NP referrals. Neuropathic pain is less frequently encountered than non-NP in children with cancer; nevertheless, it is more difficult to treat, requiring longer follow-up, more clinical visits, complex pharmacologic management, and the frequent addition of nonpharmacologic interventions.

  19. Walking with Neuropathic Pain: Paradoxical Shift from Burden to Support?

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    David J. Kopsky

    2015-01-01

    Full Text Available Baclofen 5% cream can be used for the treatment of neuropathic pain. We describe an unusual case of a neuropathic pain patient with spinal cord injury. A 71-year-old woman with a partial spinal cord injury lesion at L4 complained of tingling, pins and needles, and burning in her legs. She scored her pain as 6 before adding baclofen 5% cream to her pain medication (pregabalin 450 mg, acetaminophen 3000 mg, and diclofenac 150 mg daily. One month later she experienced complete pain relief, though experienced increased difficulties in walking, leading to frequent falls. Her steadier walking without stumbling and falling was more important to her than pain reduction. Thus she decided to stop using baclofen. This unusual case report discusses two important issues that relate to pain medicine and rehabilitation in patients with painful spinal cord lesions: (1 the presence of wide areas of sensory loss “covered” by the presence of painful sensations and (2 pathological sensations that can be used and integrated in the body schema to create an improved spatiovisual orientation and thus mobility. Both these aspects have to be taken into account when treating pain and design rehabilitation programs.

  20. Neuropathic diabetic foot ulcers - evidence-to-practice.

    Science.gov (United States)

    Ndip, Agbor; Ebah, Leonard; Mbako, Aloysius

    2012-01-01

    Foot ulcers and their attendant complications are disquietingly high in people with diabetes, a majority of whom have underlying neuropathy. This review examines the evidence base underpinning the prevention and management of neuropathic diabetic foot ulcers in order to inform best clinical practice. Since it may be impractical to ask patients not to weight-bear at all, relief of pressure through the use of offloading casting devices remains the mainstay for management of neuropathic ulcers, whilst provision of appropriate footwear is essential in ulcer prevention. Simple non-surgical debridement and application of hydrogels are both effective in preparing the wound bed for healthy granulation and therefore enhancing healing. Initial empirical antibiotic therapy for infected ulcers should cover the most common bacterial flora. There is limited evidence supporting the use of adjunctive therapies such as hyperbaric oxygen and cytokines or growth factors. In selected cases, recombinant human platelet-derived growth factor has been shown to enhance healing; however, its widespread use cannot be advised due to the availability of more cost-effective approaches. While patient education may be beneficial, the evidence base remains thin and conflicting. In conclusion, best management of foot ulcers is achieved by what is taken out of the foot (pressure, callus, infection, and slough) rather than what is put on the foot (adjuvant treatment).

  1. Nerve injury and neuropathic pain — A question of age

    Science.gov (United States)

    Fitzgerald, Maria; McKelvey, Rebecca

    2016-01-01

    The effects of peripheral nerve injury on somatosensory processing and pain are highly dependent upon the age at which the damage occurs. Adult nerve injury rapidly triggers neuropathic pain, but this is not so if the same nerve injury is performed in animals below postnatal day (P) 28, consistent with observations in paediatric patients. However, longitudinal studies show that pain hypersensitivity emerges later in life, when the animal reaches adolescence, an observation that could be of clinical importance. Here we discuss the evidence that the central consequences of nerve damage are critically determined by the status of neuroimmune regulation at different ages. In the first postnatal weeks, when spinal somatosensory circuits are undergoing synaptic reorganisation, the ‘default’ neuroimmune response is skewed in an anti-inflammatory direction, suppressing the excitation of dorsal horn neurons and preventing the onset of neuropathic pain. As animals grow up and the central nervous system matures, the neuroimmune profile shifts in a pro-inflammatory direction, unmasking a ‘latent’ pain response to an earlier nerve injury. The data predicts that nerve injury in infancy and childhood could go unnoticed at the time, but emerge as clinically ‘unexplained’ or ‘functional’ pain in adolescence. PMID:26220898

  2. Nerve injury and neuropathic pain - A question of age.

    Science.gov (United States)

    Fitzgerald, Maria; McKelvey, Rebecca

    2016-01-01

    The effects of peripheral nerve injury on somatosensory processing and pain are highly dependent upon the age at which the damage occurs. Adult nerve injury rapidly triggers neuropathic pain, but this is not so if the same nerve injury is performed in animals below postnatal day (P) 28, consistent with observations in paediatric patients. However, longitudinal studies show that pain hypersensitivity emerges later in life, when the animal reaches adolescence, an observation that could be of clinical importance. Here we discuss the evidence that the central consequences of nerve damage are critically determined by the status of neuroimmune regulation at different ages. In the first postnatal weeks, when spinal somatosensory circuits are undergoing synaptic reorganisation, the 'default' neuroimmune response is skewed in an anti-inflammatory direction, suppressing the excitation of dorsal horn neurons and preventing the onset of neuropathic pain. As animals grow up and the central nervous system matures, the neuroimmune profile shifts in a pro-inflammatory direction, unmasking a 'latent' pain response to an earlier nerve injury. The data predicts that nerve injury in infancy and childhood could go unnoticed at the time, but emerge as clinically 'unexplained' or 'functional' pain in adolescence.

  3. Interventional management of neuropathic pain: NeuPSIG recommendations.

    Science.gov (United States)

    Dworkin, Robert H; O'Connor, Alec B; Kent, Joel; Mackey, Sean C; Raja, Srinivasa N; Stacey, Brett R; Levy, Robert M; Backonja, Miroslav; Baron, Ralf; Harke, Henning; Loeser, John D; Treede, Rolf-Detlef; Turk, Dennis C; Wells, Christopher D

    2013-11-01

    Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long-term studies, and head-to-head comparisons among different interventional and noninterventional treatments.

  4. Autophagy impairment in a mouse model of neuropathic pain

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    Berliocchi Laura

    2011-10-01

    Full Text Available Abstract Autophagy is an intracellular membrane trafficking pathway controlling the delivery of cytoplasmic material to the lysosomes for degradation. It plays an important role in cell homeostasis in both normal settings and abnormal, stressful conditions. It is now recognised that an imbalance in the autophagic process can impact basal cell functions and this has recently been implicated in several human diseases, including neurodegeneration and cancer. Here, we investigated the consequences of nerve injury on the autophagic process in a commonly used model of neuropathic pain. The expression and modulation of the main autophagic marker, the microtubule-associated protein 1 light chain 3 (LC3, was evaluated in the L4-L5 cord segment seven days after spinal nerve ligation (SNL. Levels of LC3-II, the autophagosome-associated LC3 form, were markedly higher in the spinal cord ipsilateral to the ligation side, appeared to correlate with the upregulation of the calcium channel subunit α2δ-1 and were not present in mice that underwent sham surgery. However, LC3-I and Beclin 1 expression were only slightly increased. On the contrary, SNL promoted the accumulation of the ubiquitin- and LC3-binding protein p62, which inversely correlates with autophagic activity, thus pointing to a block of autophagosome turnover. Our data showed for the first time that basal autophagy is disrupted in a model of neuropathic pain.

  5. Ulnar nerve entrapment neuropathy at the elbow: relationship between the electrophysiological findings and neuropathic pain.

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    Halac, Gulistan; Topaloglu, Pinar; Demir, Saliha; Cıkrıkcıoglu, Mehmet Ali; Karadeli, Hasan Huseyin; Ozcan, Muhammet Emin; Asil, Talip

    2015-07-01

    [Purpose] Ulnar nerve neuropathies are the second most commonly seen entrapment neuropathies of the upper extremities after carpal tunnel syndrome. In this study, we aimed to evaluate pain among ulnar neuropathy patients by the Leeds assessment of neuropathic symptoms and signs pain scale and determine if it correlated with the severity of electrophysiologicalfindings. [Subjects and Methods] We studied 34 patients with clinical and electrophysiological ulnar nerve neuropathies at the elbow. After diagnosis of ulnar neuropathy at the elbow, all patients underwent the Turkish version of the Leeds assessment of neuropathic symptoms and signs pain scale. [Results] The ulnar entrapment neuropathy at the elbow was classified as class-2, class-3, class-4, and class-5 (Padua Distal Ulnar Neuropathy classification) for 15, 14, 4, and 1 patient, respectively. No patient included in class-1 was detected. According to Leeds assessment of neuropathic symptoms and signs pain scale, 24 patients scored under 12 points. The number of patients who achieved more than 12 points was 10. Groups were compared by using the χ(2) test, and no difference was detected. There was no correlation between the Leeds assessment of neuropathic symptoms and signs pain scale and electromyographic findings. [Conclusion] We found that the severity of electrophysiologic findings of ulnar nerve entrapment at the elbow did not differ between neuropathic and non-neuropathic groups as assessed by the Leeds assessment of neuropathic symptoms and signs pain scale.

  6. Combined approaches for the relief of spinal cord injury-induced neuropathic pain.

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    Gwak, Young S; Kim, Hee Young; Lee, Bong Hyo; Yang, Chae Ha

    2016-04-01

    The adequate treatment of spinal cord injury (SCI)-induced neuropathic pain still remains an unresolved problem. The current medications predominantly used in the SCI-induced neuropathic pain therapy are morphine, anticonvulsants, antidepressants, and antiepileptics, which suggests that psychiatric aspects might be important factors in the treatment of neuropathic pain. It is well documented that the modulation of the sensory events is not a unique way for achieving pain relief. In addition, pain patients still express dissatisfaction and complain of unwanted effects of the medications, suggesting that alternative approaches for the treatment of neuropathic pain are essential. In psychiatry, pain relief represents relaxation and a feeling of comfort and satisfaction, which suggests that cognitive and emotional motivations are important factors in the treatment of neuropathic pain. The comorbidity of chronic pain and psychiatric disorders, which is well recognized, suggests that the effective therapeutic relief for neuropathic pain induced by SCI can be achieved in conjunction with the management of the sensory and psychiatric aspects of patient. In this review, we address the feasibility of a combined acupuncture and pharmacotherapy treatment for the relief of neuropathic pain behavior following SCI. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Neuropathic Pain Components in Patients with Cancer: Prevalence, Treatment, and Interference with Daily Activities.

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    Oosterling, Anne; te Boveldt, Nienke; Verhagen, Constans; van der Graaf, Winette T; Van Ham, Maaike; Van der Drift, Miep; Vissers, Kris; Engels, Yvonne

    2016-04-01

    Pain and neuropathic symptoms impact quality of life of patients with cancer. To obtain more insight in the prevalence, severity, and treatment of neuropathic symptoms in patients with cancer and their interference with daily activities, we conducted a cross-sectional study at the outpatient clinic of a Dutch university hospital. A cross-sectional study among outpatients with cancer. To identify pain, its intensity, quality, and interference with daily activities, the Brief Pain Inventory (BPI) was used. Neuropathic symptoms were identified with the Douleur Neuropathique (DN4) interview and pain characteristics with the McGill Pain Questionnaire (MPQ). Pain medication and adjuvant analgesics were also collected with a prestructured questionnaire. Descriptives, chi-squared tests, t-tests, and a logistic regression analysis were conducted. 892 patients completed the questionnaires. Twenty-three percent (n = 204) reported moderate to severe pain, and 19% (n = 170) scored positive on neuropathic symptoms (DN4 ≥ 3). Particularly in patients with a rating on a numeric rating scale (NRS) neuropathic symptoms significantly increased interference with daily activities. Of patients with neuropathic symptoms, 8% received adjuvant pain treatment. Receiving curative treatment, using a systemic drug with neurotoxicity, having had an operation, and having had a lymph node dissection independently contributed to having neuropathic symptoms. This study shows that over 40% of the patients with moderate to severe pain also have neuropathic symptoms, causing increased interference with daily activities. Most of these patients do not receive adjuvant analgesics. There is a need to improve management of neuropathic symptoms in patients with cancer. © 2015 World Institute of Pain.

  8. Efficacy of Venlafaxine in Neuropathic Pain: A Narrative Review of Optimized Treatment.

    Science.gov (United States)

    Trouvin, Anne-Priscille; Perrot, Serge; Lloret-Linares, Célia

    2017-06-01

    The prevalence of neuropathic pain is high in the general population, and high priority is given to the management of this pain condition. The treatment of neuropathic pain remains challenging, despite the publication of national and international recommendations. The purpose of this narrative review of venlafaxine (VLX) is to provide a better knowledge of the pharmacology of this drug and a clearer view of its efficacy and tolerability in neuropathic pain. Two independent reviewers searched PubMed with the following search terms: serotonin and noradrenalin reuptake inhibitors OR VLX hydrochloride AND pain. The reviewers included all clinical studies that investigated VLX in neuropathic pain conditions and excluded animal studies, studies on fibromyalgia, studies that focused on the prevention of neuropathic pain, case reports, and studies that did not clearly describe neuropathic pain in the included patients. We describe the 13 studies that we analyzed. Eleven were randomized clinical trials, and the comparator was placebo in 8 studies. Nine studies reported that VLX was effective against neuropathic pain. However, among the trials, only one against placebo included a large number of patients with >200 participants and one against prégabaline and carbamazepine had >200 patients. Most of the adverse events reported in the selected studies were consistent with known adverse events of VLX, and most were mild to moderate. However, most studies were of very short duration. Most of the clinical studies found that VLX was effective and well tolerated. However, given the limited number of study and the limitations of all these studies, further large clinical trials are needed. Currently, considering the limited therapeutic options for treating neuropathic pain and the highly variable nature of responses to all drugs, VLX has a place as a treatment option for neuropathic pain. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

  9. Neuropathic pain in the general population: a systematic review of epidemiological studies.

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    van Hecke, O; Austin, Sophie K; Khan, Rafi A; Smith, B H; Torrance, N

    2014-04-01

    Most patients with neuropathic pain symptoms present and are managed in primary care, with only a minority being referred for specialist clinical assessment and diagnoses. Previous reviews have focused mainly on specific neuropathic pain conditions based in specialist settings. This is the first systematic review of epidemiological studies of neuropathic pain in the general population. Electronic databases were searched from January 1966 to December 2012, and studies were included where the main focus was on neuropathic pain prevalence and/or incidence, either as part of a specific neuropathic pain-related condition or as a global entity in the general population. We excluded studies in which data were extracted from pain or other specialist clinics or focusing on specific population subgroups. Twenty-one articles were identified and underwent quality assessment and data extraction. Included studies differed in 3 main ways: method of data retrieval, case ascertainment tool used, and presentation of prevalence/incidence rates. This heterogeneity precluded any meta-analysis. We categorised comparable incidence and prevalence rates into 2 main subgroups: (1) chronic pain with neuropathic characteristics (range 3-17%), and (2) neuropathic pain associated with a specific condition, including postherpetic neuralgia (3.9-42.0/100,000 person-years [PY]), trigeminal neuralgia (12.6-28.9/100,000 PY), painful diabetic peripheral neuropathy (15.3-72.3/100,000 PY), glossopharyngeal neuralgia (0.2-0.4/100,000 PY). These differences highlight the importance of a standardised approach for identifying neuropathic pain in future epidemiological studies. A best estimate of population prevalence of pain with neuropathic characteristics is likely to lie between 6.9% and 10%. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  10. The effect of Normast (PEA) in neuropathic pain in spinal cord injury

    DEFF Research Database (Denmark)

    Andresen, Sven Robert; Bing, Jette; Hansen, Rikke Bod Middelhede

    2015-01-01

    Introduction: Neuropathic pain and spasticity after spinal cord injury represent significant problems. Palmitoylethanolamide (PEA) is a fatty acid that is produced in many cells in the body, and it is thought to potentiate the body's own cannabis-like substances (endocannabinoids). PEA is suggested...... and psychological functioning in patients with spinal cord injury. Methods: A randomized, double-blind, placebo-controlled parallel multicenter study. We have included 66 patients with neuropathic pain due to spinal cord injury. Questionnaires regarding neuropathic pain, spasticity, insomnia, anxiety and depression...

  11. Histone deacetylase inhibitors relieve morphine resistance in neuropathic pain after peripheral nerve injury.

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    Uchida, Hitoshi; Matsushita, Yosuke; Araki, Kohei; Mukae, Takehiro; Ueda, Hiroshi

    2015-08-01

    Neuropathic pain is often insensitive to morphine. Our previous study has demonstrated that neuron-restrictive silencer factor represses mu opioid receptor (MOP) gene expression in the dorsal root ganglion (DRG) via histone hypoacetylation-mediated mechanisms after peripheral nerve injury, thereby causing loss of peripheral morphine analgesia. Here, we showed that histone deacetylase (HDAC) inhibitors, such as trichostatin A and valproic acid, restored peripheral and systemic morphine analgesia in neuropathic pain. Also, these agents blocked nerve injury-induced MOP down-regulation in the DRG. These results suggest that HDAC inhibitors could serve as adjuvant analgesics to morphine for the management of neuropathic pain.

  12. Fatty acid amide hydrolase (FAAH) inhibitors exert pharmacological effects, but lack antinociceptive efficacy in rats with neuropathic spinal cord injury pain.

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    Hama, Aldric T; Germano, Peter; Varghese, Matthew S; Cravatt, Benjamin F; Milne, G Todd; Pearson, James P; Sagen, Jacqueline

    2014-01-01

    Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.

  13. Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation.

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    Padi, Satyanarayana S V; Shi, Xiang Q; Zhao, Yuan Q; Ruff, Michael R; Baichoo, Noel; Pert, Candace B; Zhang, Ji

    2012-01-01

    Chemokine signaling is important in neuropathic pain, with microglial cells expressing CCR2 playing a well-established key role. DAPTA, a HIV gp120-derived CCR5 entry inhibitor, has been shown to inhibit CCR5-mediated monocyte migration and to attenuate neuroinflammation. We report here that as a stabilized analog of DAPTA, the short peptide RAP-103 exhibits potent antagonism for both CCR2 (half maximal inhibitory concentration [IC50] 4.2 pM) and CCR5 (IC50 0.18 pM) in monocyte chemotaxis. Oral administration of RAP-103 (0.05-1 mg/kg) for 7 days fully prevents mechanical allodynia and inhibits the development of thermal hyperalgesia after partial ligation of the sciatic nerve in rats. Administered from days 8 to 12, RAP-103 (0.2-1 mg/kg) reverses already established hypersensitivity. RAP-103 relieves behavioral hypersensitivity, probably through either or both CCR2 and CCR5 blockade, because by using genetically deficient animals, we demonstrated that in addition to CCR2, CCR5 is also required for the development of neuropathic pain. Moreover, RAP-103 is able to reduce spinal microglial activation and monocyte infiltration, and to inhibit inflammatory responses evoked by peripheral nerve injury that cause chronic pain. Our findings suggest that targeting CCR2/CCR5 should provide greater efficacy than targeting CCR2 or CCR5 alone, and that dual CCR2/CCR5 antagonist RAP-103 has the potential for broad clinical use in neuropathic pain treatment.

  14. Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state.

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    Suter, Marc R; Kirschmann, Guylène; Laedermann, Cedric J; Abriel, Hugues; Decosterd, Isabelle

    2013-01-01

    Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

  15. Effects of 660- and 980-nm low-level laser therapy on neuropathic pain relief following chronic constriction injury in rat sciatic nerve.

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    Masoumipoor, M; Jameie, S B; Janzadeh, A; Nasirinezhad, F; Soleimani, M; Kerdary, M

    2014-09-01

    Neuropathic pain (NP) is one of the most suffered conditions in medical disciplines. The role of reactive oxygen species (ROS) and oxidative stress in the induction of NP was studied by many researchers. Neuropathies lead to medical, social, and economic isolation of the patient, so various therapies were used to treat or reduce it. During the recent years, low-level laser therapy (LLLT) has been used in certain areas of medicine and rehabilitation. Chronic constriction injury (CCI) is a well-known model for neuropathic pain studies. In order to find the effects of different wavelengths of LLLT on the injured sciatic nerve, the present research was done. Thirty Wistar adult male rats (230-320 g) were used in this study. The animals were randomly divided into three groups (n = 10). To induce neuropathic pain for the sciatic nerve, the CCI technique was used. Low-level laser of 660 and 980 nm was used for two consecutive weeks. Thermal and mechanical hyperalgesia was done before and after surgery on days 7 and 14, respectively. Paw withdrawal thresholds were also evaluated. CCI decreased the pain threshold, whereas both wavelengths of LLLT for 2 weeks increased mechanical and thermal threshold significantly. A comparison of the mechanical and thermal threshold showed a significant difference between the therapeutic effects of the two groups that received LLLT. Based on our findings, the laser with a 660-nm wavelength had better therapeutic effects than the laser with a 980-nm wavelength, so the former one may be used for clinical application in neuropathic cases; however, it needs more future studies.

  16. Neuropathic Pain and Psychological Morbidity in Patients with Treated Leprosy: A Cross-Sectional Prevalence Study in Mumbai

    Science.gov (United States)

    Lasry-Levy, Estrella; Hietaharju, Aki; Pai, Vivek; Ganapati, Ramaswamy; Rice, Andrew S. C.; Haanpää, Maija; Lockwood, Diana N. J.

    2011-01-01

    Background Neuropathic pain has been little studied in leprosy. We assessed the prevalence and clinical characteristics of neuropathic pain and the validity of the Douleur Neuropathique 4 questionnaire as a screening tool for neuropathic pain in patients with treated leprosy. The association of neuropathic pain with psychological morbidity was also evaluated. Methodology/Principal Findings Adult patients who had completed multi-drug therapy for leprosy were recruited from several Bombay Leprosy Project clinics. Clinical neurological examination, assessment of leprosy affected skin and nerves and pain evaluation were performed for all patients. Patients completed the Douleur Neuropathique 4 and the 12-item General Health Questionnaire to identify neuropathic pain and psychological morbidity. Conclusions/Significance One hundred and one patients were recruited, and 22 (21.8%) had neuropathic pain. The main sensory symptoms were numbness (86.4%), tingling (68.2%), hypoesthesia to touch (81.2%) and pinprick (72.7%). Neuropathic pain was associated with nerve enlargement and tenderness, painful skin lesions and with psychological morbidity. The Douleur Neuropathique 4 had a sensitivity of 100% and specificity of 92% in diagnosing neuropathic pain. The Douleur Neuropathique 4 is a simple tool for the screening of neuropathic pain in leprosy patients. Psychological morbidity was detected in 15% of the patients and 41% of the patients with neuropathic pain had psychological morbidity. PMID:21408111

  17. Neuropathic pain and psychological morbidity in patients with treated leprosy: a cross-sectional prevalence study in Mumbai.

    Directory of Open Access Journals (Sweden)

    Estrella Lasry-Levy

    Full Text Available BACKGROUND: Neuropathic pain has been little studied in leprosy. We assessed the prevalence and clinical characteristics of neuropathic pain and the validity of the Douleur Neuropathique 4 questionnaire as a screening tool for neuropathic pain in patients with treated leprosy. The association of neuropathic pain with psychological morbidity was also evaluated. METHODOLOGY/PRINCIPAL FINDINGS: Adult patients who had completed multi-drug therapy for leprosy were recruited from several Bombay Leprosy Project clinics. Clinical neurological examination, assessment of leprosy affected skin and nerves and pain evaluation were performed for all patients. Patients completed the Douleur Neuropathique 4 and the 12-item General Health Questionnaire to identify neuropathic pain and psychological morbidity. CONCLUSIONS/SIGNIFICANCE: One hundred and one patients were recruited, and 22 (21.8% had neuropathic pain. The main sensory symptoms were numbness (86.4%, tingling (68.2%, hypoesthesia to touch (81.2% and pinprick (72.7%. Neuropathic pain was associated with nerve enlargement and tenderness, painful skin lesions and with psychological morbidity. The Douleur Neuropathique 4 had a sensitivity of 100% and specificity of 92% in diagnosing neuropathic pain. The Douleur Neuropathique 4 is a simple tool for the screening of neuropathic pain in leprosy patients. Psychological morbidity was detected in 15% of the patients and 41% of the patients with neuropathic pain had psychological morbidity.

  18. An improved behavioural assay demonstrates that ultrasound vocalizations constitute a reliable indicator of chronic cancer pain and neuropathic pain

    Directory of Open Access Journals (Sweden)

    Selvaraj Deepitha

    2010-03-01

    Full Text Available Abstract Background On-going pain is one of the most debilitating symptoms associated with a variety of chronic pain disorders. An understanding of mechanisms underlying on-going pain, i.e. stimulus-independent pain has been hampered so far by a lack of behavioural parameters which enable studying it in experimental animals. Ultrasound vocalizations (USVs have been proposed to correlate with pain evoked by an acute activation of nociceptors. However, literature on the utility of USVs as an indicator of chronic pain is very controversial. A majority of these inconsistencies arise from parameters confounding behavioural experiments, which include novelty, fear and stress due to restrain, amongst others. Results We have developed an improved assay which overcomes these confounding factors and enables studying USVs in freely moving mice repetitively over several weeks. Using this improved assay, we report here that USVs increase significantly in mice with bone metastases-induced cancer pain or neuropathic pain for several weeks, in comparison to sham-treated mice. Importantly, analgesic drugs which are known to alleviate tumour pain or neuropathic pain in human patients significantly reduce USVs as well as mechanical allodynia in corresponding mouse models. Conclusions We show that studying USVs and mechanical allodynia in the same cohort of mice enables comparing the temporal progression of on-going pain (i.e. stimulus-independent pain and stimulus-evoked pain in these clinically highly-relevant forms of chronic pain.

  19. Ameliorative potential of Vernonia cinerea on chronic constriction injury of sciatic nerve induced neuropathic pain in rats

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    VENKATA R.K. THIAGARAJAN

    2014-09-01

    Full Text Available The aim of the present study is to investigate the ameliorative potential of ethanolic extract of whole plant of Vernonia cinerea in the chronic constriction injury (CCI of sciatic nerve induced neuropathic pain in rats. Behavioral parameters such as a hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal, chemical and mechanical hyperalgesia and allodynia. Biochemical changes in sciatic nerve tissue were ruled out by estimating thiobarbituric acid reactive substances (TBARS, reduced glutathione (GSH and total calcium levels. Ethanolic extract of Vernonia cinerea and pregabalin were administered for 14 consecutive days starting from the day of surgery. CCI of sciatic nerve has been shown to induce significant changes in behavioral, biochemical and histopathological assessments when compared to the sham control group. Vernonia cinerea attenuated in a dose dependent manner the above pathological changes induced by CCI of the sciatic nerve, which is similar to attenuation of the pregabalin pretreated group. The ameliorating effect of ethanolic extract of Vernonia cinerea against CCI of sciatic nerve induced neuropathic pain may be due to the presence of flavonoids and this effect is attributed to anti-oxidative, neuroprotective and calcium channel modulator actions of these compounds.

  20. Synthesis and Analgesic Effects of μ-TRTX-Hhn1b on Models of Inflammatory and Neuropathic Pain

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    Yu Liu

    2014-08-01

    Full Text Available μ-TRTX-Hhn1b (HNTX-IV is a 35-amino acid peptide isolated from the venom of the spider, Ornithoctonus hainana. It inhibits voltage-gated sodium channel Nav1.7, which has been considered as a therapeutic target for pain. The goal of the present study is to elucidate the analgesic effects of synthetic μ-TRTX-Hhn1b on animal models of pain. The peptide was first synthesized and then successfully refolded/oxidized. The synthetic peptide had the same inhibitory effect on human Nav1.7 current transiently expressed in HEK 293 cells as the native toxin. Furthermore, the analgesic potentials of the synthetic peptide were examined on models of inflammatory pain and neuropathic pain. μ-TRTX-Hhn1b produced an efficient reversal of acute nociceptive pain in the abdominal constriction model, and significantly reduced the pain scores over the 40-min period in the formalin model. The efficiency of μ-TRTX-Hhn1b on both models was equivalent to that of morphine. In the spinal nerve model, the reversal effect of μ-TRTX-Hhn1b on allodynia was longer and higher than mexiletine. These results demonstrated that μ-TRTX-Hhn1b efficiently alleviated acute inflammatory pain and chronic neuropathic pain in animals and provided an attractive template for further clinical analgesic drug design.

  1. Neuron-Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region.

    Science.gov (United States)

    Hossain, Mohammad Zakir; Unno, Shumpei; Ando, Hiroshi; Masuda, Yuji; Kitagawa, Junichi

    2017-09-26

    Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate-glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron-glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

  2. An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain from Spinal Cord Injury and Disease

    Science.gov (United States)

    Wilsey, Barth; Marcotte, Thomas D.; Deutsch, Reena; Zhao, Holly; Prasad, Hannah; Phan, Amy

    2016-01-01

    Using eight hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, the majority of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta-9-tetrahydrocannabinol on three separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was utilized to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model demonstrated a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (e.g., good drug effect, feeling high, etc.) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all p<0.0004). Psychoactive and subjective effects were dose dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. As the two active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord. PMID:27286745

  3. Outcome predictors for treatment success with 5% lidocaine medicated plaster in low back pain with neuropathic components and neuropathic pain after surgical and nonsurgical trauma

    Science.gov (United States)

    Nicolaou, Andrew; Nicholson, Bruce; Hans, Guy; Brasseur, Louis

    2011-01-01

    Five percent lidocaine medicated plaster has been proven efficacious for the symptomatic relief of neuropathic pain in diverse pain conditions which might be attributed to a common localized symptomatology in these indications, possibly with common predictors of treatment success. To discuss potential symptoms and other factors predicting response to treatment with lidocaine plaster for the indications of low back pain with neuropathic components and neuropathic pain after surgical and nonsurgical trauma, 44 pain specialists from 17 countries attended a two-day conference meeting in December 2009. Discussions were based on the retrospective analysis of case reports (sent in by participants in the four weeks prior to the meeting) and the practical experience of the participants. The results indicate some predictors for success with 5% lidocaine medicated plaster for the two indications. Localized pain, hyperalgesia and/or allodynia, and other positive sensory symptoms, such as dysesthesia, were considered positive predictors, whereas widespread pain and negative sensory symptoms were regarded as negative predictors. Paresthesia, diagnosis, and site of pain were considered to be of no predictive value. Common symptomatology with other neurologic pathologies suggests that treatment of localized neuropathic pain symptoms with the plaster can be considered across different neuropathic pain indications. PMID:21386952

  4. An evidence-based algorithm for the treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Finnerup, Nanna Brix; Otto, Marit; Jensen, Troels Staehelin;

    2007-01-01

    OBJECTIVE: The purpose of this article is to discuss an evidence-based algorithm that can be implemented by the primary care physician in his/her daily clinical practice for the treatment of patients with neuropathic pain conditions. METHOD: A treatment algorithm for neuropathic pain was formulated...... on the basis of a review of 105 high-quality, randomized, placebo-controlled clinical trials. The number needed to treat (NNT) and number needed to harm (NNH) were used to compare the safety and effectiveness of current treatments for neuropathic pain syndromes. Most of the clinical trials reviewed...... with different experimental designs and outcomes. CONCLUSION: Patients presenting with neuropathic pain are becoming a more frequent occurrence for the primary care physician as the population ages. Evidence-based treatment options allow for the most efficient and effective pharmacotherapy regimen...

  5. An evidence-based algorithm for the treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Finnerup, Nanna B; Otto, Marit; Jensen, Troels S

    2007-01-01

    OBJECTIVE: The purpose of this article is to discuss an evidence-based algorithm that can be implemented by the primary care physician in his/her daily clinical practice for the treatment of patients with neuropathic pain conditions. METHOD: A treatment algorithm for neuropathic pain was formulated...... on the basis of a review of 105 high-quality, randomized, placebo-controlled clinical trials. The number needed to treat (NNT) and number needed to harm (NNH) were used to compare the safety and effectiveness of current treatments for neuropathic pain syndromes. Most of the clinical trials reviewed...... with different experimental designs and outcomes. CONCLUSION: Patients presenting with neuropathic pain are becoming a more frequent occurrence for the primary care physician as the population ages. Evidence-based treatment options allow for the most efficient and effective pharmacotherapy regimen...

  6. Effectiveness of transcranial direct current stimulation and visual illusion on neuropathic pain in spinal cord injury

    National Research Council Canada - National Science Library

    Soler, Maria Dolors; Kumru, Hatice; Pelayo, Raul; Vidal, Joan; Tormos, Josep Maria; Fregni, Felipe; Navarro, Xavier; Pascual-Leone, Alvaro

    2010-01-01

    ... with neuropathic pain following spinal cord injury. In a sham controlled, double-blind, parallel group design, 39 patients were randomized into four groups receiving transcranial direct current stimulation with walking visual illusion or with control...

  7. TMEM16F Regulates Spinal Microglial Function in Neuropathic Pain States

    Directory of Open Access Journals (Sweden)

    Laura Batti

    2016-06-01

    Full Text Available Neuropathic pain is a widespread chronic pain state that results from injury to the nervous system. Spinal microglia play a causative role in the pathogenesis of neuropathic pain through secretion of growth factors and cytokines. Here, we investigated the contribution of TMEM16F, a protein that functions as a Ca2+-dependent ion channel and a phospholipid scramblase, to microglial activity during neuropathic pain. We demonstrate that mice with a conditional ablation of TMEM16F in microglia do not develop mechanical hypersensitivity upon nerve injury. In the absence of TMEM16F, microglia display deficits in process motility and phagocytosis. Moreover, loss of GABA immunoreactivity upon injury is spared in TMEM16F conditional knockout mice. Collectively, these data indicate that TMEM16F is an essential component of the microglial response to injury and suggest the importance of microglial phagocytosis in the pathogenesis of neuropathic pain.

  8. Effects of silymarin on neuropathic pain and formalin-induced nociception in mice

    Directory of Open Access Journals (Sweden)

    Faezeh Vahdati Hassani

    2015-07-01

    Conclusion:Results of the present study indicated that repeated administration of silymarin prevents the formalin-induced nociceptive behavior. However, it is not effective in the treatment of sciatic neuropathic pain.

  9. The pharmacogenomics of escitalopram in the treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Andersen, Charlotte Brasch; Møller, Malik U; Sindrup, Søren Hein

    of neuropathic pain is still unsatisfactory. The effects of a selective serotonin reuptake inhibitor (SSRI), escitalopram, on pain in polyneuropathy was tested in an earlier randomized, placebo-controlled, double- blinded cross-over trial including  41 patients who were treated with 20 mg escitalopram...... and placebo. The clinical study showed a moderate, good or complete pain relief for escitalopram in 11 patients ("responders") but at only a slight or no relief  in 30 patients ("non-responders"). The difference in response to escitalopram may be caused by genetic differences between the responders...... and effect of escitalopram when dichotomizing the patients into responders and non-responders. Using quantitative assessment of pain might add more information to the association studies....

  10. Neuropathic arthropathy (Charcot's joint) in dialysis patients

    Energy Technology Data Exchange (ETDEWEB)

    Meneghello, A.; Bertoli, M.

    1984-08-01

    To the author's knowledge, uraemic neuropathy has not been previously reported as a cause of Charcot's joint. In this paper they present three cases in which the association between clinical and radiographic patterns suggest the diagnosis of neuropathic arthropathy. The features of uraemic neuropathy are stressed and the role of secondary hyperparathyroidism in the development of this type of arthropathy is discussed. The extremely severe hyperparathyroidism reported here, may cause tendon and ligament disease, especially at the site of their bone insertion. Uraemic tendon and ligament failures weaken joints and produce further instability, which may be a precipitating factor of uraemic Charcot's joint in patients undergoing chronic haemodialysis. 5 figs.

  11. Combination of pregabalin and palmitoylethanolamide (PEA for neuropathic pain treatment

    Directory of Open Access Journals (Sweden)

    Paolo Desio

    2010-12-01

    Full Text Available 30 patients ranging between 32 to 78 years, suffering from neuropathicpain, were treated with pregabalin and palmitoylethanolamide for 45 days. All patients have completed the study and no side effect was reported; in all patients it has been observed a significant reduction of pain intensity that was associated to a better quality of the sleep. The improvement of the clinical symptomatology was associated to a recovery of quality of sleep and to a good subjective evaluation of the effectiveness of the therapy. In conclusion, the efficacy of a new multitherapeutic approach for neuropathic pain, based on pregabalin + palmitoylethanolamide has been proved; the therapy showed to be safe and allows patients to have a better quality of life.

  12. Management of diabetic neuropathic foot and ankle malunions and nonunions

    Directory of Open Access Journals (Sweden)

    John J. Stapleton

    2011-05-01

    Full Text Available The management of diabetic neuropathic foot and ankle malunions and/or nonunions is often complicated by the presence of broken or loosened hardware, Charcot joints, infection, osteomyelitis, avascular bone necrosis, unstable deformities, bone loss, disuse and pathologic osteopenia, and ulcerations. The author discusses a rational approach to functional limb salvage with various surgical techniques that are aimed at achieving anatomic alignment, long-term osseous stability, and adequate soft tissue coverage. Emphasis is placed on techniques to overcome the inherent challenges that are encountered when surgically managing a diabetic nonunion and/or malunion. Particular attention is directed to the management of deep infection and Charcot neuroarthropathy in the majority of the cases presented.

  13. Neuropathic Pain due to Small Fiber Neuropathy in Aging: Current Management and Future Prospects

    OpenAIRE

    Brouwer, Brigitte A.; de Greef, Bianca T. A.; Hoeijmakers, Janneke G. J.; Geerts, Margot; van Kleef, Maarten; Merkies, Ingemar S. J.; Faber, Catharina G.

    2015-01-01

    Over the last 10 years, the diagnosis small fiber neuropathy (SFN) has gained recognition worldwide. Patients often suffer from severe neuropathic pain that may be difficult to treat. A substantial subset of patients with SFN is aged 65 years or older, and these patients often exhibit comorbidities and usage of multiple drugs, making neuropathic pain treatment more challenging. In this review, we highlight relevant pathophysiological aspects and discuss currently used therapeutic strategies f...

  14. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone

    OpenAIRE

    Hughes, Sam; Hickey, Louise; Donaldson, Lucy F.; Lumb, Bridget M; Pickering, Anthony E.

    2015-01-01

    The descending noradrenergic (NAergic) projection to the spinal cord forms part of an endogenous analgesic system. After nerve injury, a localised failure in this compensatory system has been implicated as a permissive factor in the development of neuropathic sensitisation. We investigated whether restoring descending NAergic tone with intrathecal reboxetine can oppose the development of the neuropathic pain phenotype after tibial nerve transection (TNT). Rats had a lumbar intrathecal cathete...

  15. Tramadol and Propentofylline Coadministration Exerted Synergistic Effects on Rat Spinal Nerve Ligation-Induced Neuropathic Pain

    Science.gov (United States)

    Wang, Huan; Wang, Wei; Zhang, Hui; Liu, Rui; Xu, Li-Xian; Mei, Xiao-Peng

    2013-01-01

    Neuropathic pain is an intractable clinical problem. Drug treatments such as tramadol have been reported to effectively decrease neuropathic pain by inhibiting the activity of nociceptive neurons. It has also been reported that modulating glial activation could also prevent or reverse neuropathic pain via the administration of a glial modulator or inhibitor, such as propentofylline. Thus far, there has been no clinical strategy incorporating both neuronal and glial participation for treating neuropathic pain. Therefore, the present research study was designed to assess whether coadministration of tramadol and propentofylline, as neuronal and glial activation inhibitors, respectively, would exert a synergistic effect on the reduction of rat spinal nerve ligation (SNL)-induced neuropathic pain. Rats underwent SNL surgery to induce neuropathic pain. Pain behavioral tests were conducted to ascertain the effect of drugs on SNL-induced mechanical allodynia with von-Frey hairs. Proinflammatory factor interleukin-1β (IL-1β) expression was also detected by Real-time RT-PCR. Intrathecal tramadol and propentofylline administered alone relieved SNL-induced mechanical allodynia in a dose-dependent manner. Tramadol and propentofylline coadministration exerted a more potent effect in a synergistic and dose dependent manner than the intrathecal administration of either drug alone. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn after the lesion, which was significantly decreased by tramadol and propentofylline coadministration. Inhibiting proinflammatory factor IL-1β contributed to the synergistic effects of tramadol and propentofylline coadministration on rat peripheral nerve injury-induced neuropathic pain. Thus, our study provided a rationale for utilizing a novel strategy for treating neuropathic pain by blocking the proinflammatory factor related pathways in the central nervous system. PMID:24009718

  16. Is neuropathic pain underdiagnosed in musculoskeletal pain conditions? The Danish PainDETECTive study

    DEFF Research Database (Denmark)

    2010-01-01

    In all, 19-22% of the adult Danish population suffer from chronic pain - most frequently in the musculoskeletal system. Different pain management strategies depending on pain mechanism (neuropathic/nociceptive) make diagnosing the pain condition especially important.......In all, 19-22% of the adult Danish population suffer from chronic pain - most frequently in the musculoskeletal system. Different pain management strategies depending on pain mechanism (neuropathic/nociceptive) make diagnosing the pain condition especially important....

  17. The importance of TRPV1-sensitisation factors for the development of neuropathic pain.

    Science.gov (United States)

    Malek, Natalia; Pajak, Agnieszka; Kolosowska, Natalia; Kucharczyk, Mateusz; Starowicz, Katarzyna

    2015-03-01

    Transient receptor potential vanilloid type 1 (TRPV1), classically associated with transduction of high-temperature and low-pH pain, underlies pain hypersensitivity in neuropathic pain. The molecular regulation of TRPV1 channel activity is not yet fully understood. Therefore, we investigated factors regulating sensitisation of this receptor during development of neuropathic pain in a rat model of chronic construction injury (CCI) in the dorsal root ganglia (DRG). In the rat CCI model, elevated levels of pro-inflammatory cytokines (TNFα, IL-1β and IL-6) in DRG corresponded to development of neuropathic pain. We assessed the expression of known kinases influencing TRPV1 sensitisation at the mRNA and/or protein level. Protein kinase C ε (PKCε) showed the strongest upregulation at the mRNA and protein levels among all tested kinases. Co-expression of PKCε and TRPV1 in L5 DRG of CCI animals was high during the development of neuropathic pain. The number of neurons expressing PKCε increased throughout the experiment. We provide complex data on the expression of a variety of factors involved in TRPV1 sensitisation in a CCI model of neuropathic pain. Our study supports evidence for involvement of TRPV1 in the development of neuropathic pain, by showing increased expression of interleukins and kinases responsible for the channel sensitisation. TNFα and NGF seem to play a role in the transition from acute to neuropathic pain, while PKCε in its maintenance. Further studies might confirm their significance as novel targets for the treatment of neuropathic pain. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Thalamic activity and biochemical changes in individuals with neuropathic pain after spinal cord injury.

    Science.gov (United States)

    Gustin, S M; Wrigley, P J; Youssef, A M; McIndoe, L; Wilcox, S L; Rae, C D; Edden, R A E; Siddall, P J; Henderson, L A

    2014-05-01

    There is increasing evidence relating thalamic changes to the generation and/or maintenance of neuropathic pain. We have recently reported that neuropathic orofacial pain is associated with altered thalamic anatomy, biochemistry, and activity, which may result in disturbed thalamocortical oscillatory circuits. Despite this evidence, it is possible that these thalamic changes are not responsible for the presence of pain per se, but result as a consequence of the injury. To clarify this subject, we compared brain activity and biochemistry in 12 people with below-level neuropathic pain after complete thoracic spinal cord injury with 11 people with similar injuries and no neuropathic pain and 21 age- and gender-matched healthy control subjects. Quantitative arterial spinal labelling was used to measure thalamic activity, and magnetic resonance spectroscopy was used to determine changes in neuronal variability quantifying N-acetylaspartate and alterations in inhibitory function quantifying gamma amino butyric acid. This study revealed that the presence of neuropathic pain is associated with significant changes in thalamic biochemistry and neuronal activity. More specifically, the presence of neuropathic pain after spinal cord injury is associated with significant reductions in thalamic N-acetylaspartate, gamma amino butyric acid content, and blood flow in the region of the thalamic reticular nucleus. Spinal cord injury on its own did not account for these changes. These findings support the hypothesis that neuropathic pain is associated with altered thalamic structure and function, which may disturb central processing and play a key role in the experience of neuropathic pain. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  19. Analgesic Effect of Indian Gooseberry (Emblica officinalis Fruit Extracts on Postoperative and Neuropathic Pain in Rats

    Directory of Open Access Journals (Sweden)

    Dong Wook Lim

    2016-11-01

    Full Text Available Indian gooseberry (Emblica officinalis fruit, also known as “Amla” is one of the oldest edible fruits known in India. It has also traditionally been used to treat inflammation, and as an analgesic to treat wounds. However, experimental evidence for the analgesic effects of E. officinalis has been lacking. The present study investigated whether E. officinalis extracts exhibit analgesic effects in the plantar incision (PI and spared nerve injury (SNI pain-model rats. We evaluated the mechanical withdrawal threshold (MWT using von Frey filaments, and pain-related behavior was determined after surgery based on ultrasonic vocalization (USV. The group treated with E. officinalis extracts at 300 mg/kg had significantly increased MWT values at 6 h and 24 h after the PI, and had a significantly reduced number of 22–27-kHz USVs at 6 h and 24 h after PI. Moreover, after 15 days of continuous treatment with E. officinalis extracts, the treated group showed significantly alleviated SNI-induced hypersensitivity and reduced pro-inflammatory cytokine levels. Thus, E. officinalis extracts have potential analgesic effects in both postoperative and neuropathic pain models in vivo.

  20. Analgesic Effect of Indian Gooseberry (Emblica officinalis Fruit) Extracts on Postoperative and Neuropathic Pain in Rats

    Science.gov (United States)

    Lim, Dong Wook; Kim, Jae Goo; Kim, Yun Tai

    2016-01-01

    Indian gooseberry (Emblica officinalis fruit), also known as “Amla” is one of the oldest edible fruits known in India. It has also traditionally been used to treat inflammation, and as an analgesic to treat wounds. However, experimental evidence for the analgesic effects of E. officinalis has been lacking. The present study investigated whether E. officinalis extracts exhibit analgesic effects in the plantar incision (PI) and spared nerve injury (SNI) pain-model rats. We evaluated the mechanical withdrawal threshold (MWT) using von Frey filaments, and pain-related behavior was determined after surgery based on ultrasonic vocalization (USV). The group treated with E. officinalis extracts at 300 mg/kg had significantly increased MWT values at 6 h and 24 h after the PI, and had a significantly reduced number of 22–27-kHz USVs at 6 h and 24 h after PI. Moreover, after 15 days of continuous treatment with E. officinalis extracts, the treated group showed significantly alleviated SNI-induced hypersensitivity and reduced pro-inflammatory cytokine levels. Thus, E. officinalis extracts have potential analgesic effects in both postoperative and neuropathic pain models in vivo. PMID:27898027

  1. Analgesic Effect of Indian Gooseberry (Emblica officinalis Fruit) Extracts on Postoperative and Neuropathic Pain in Rats.

    Science.gov (United States)

    Lim, Dong Wook; Kim, Jae Goo; Kim, Yun Tai

    2016-11-26

    Indian gooseberry (Emblica officinalis fruit), also known as "Amla" is one of the oldest edible fruits known in India. It has also traditionally been used to treat inflammation, and as an analgesic to treat wounds. However, experimental evidence for the analgesic effects of E. officinalis has been lacking. The present study investigated whether E. officinalis extracts exhibit analgesic effects in the plantar incision (PI) and spared nerve injury (SNI) pain-model rats. We evaluated the mechanical withdrawal threshold (MWT) using von Frey filaments, and pain-related behavior was determined after surgery based on ultrasonic vocalization (USV). The group treated with E. officinalis extracts at 300 mg/kg had significantly increased MWT values at 6 h and 24 h after the PI, and had a significantly reduced number of 22-27-kHz USVs at 6 h and 24 h after PI. Moreover, after 15 days of continuous treatment with E. officinalis extracts, the treated group showed significantly alleviated SNI-induced hypersensitivity and reduced pro-inflammatory cytokine levels. Thus, E. officinalis extracts have potential analgesic effects in both postoperative and neuropathic pain models in vivo.

  2. Effects of natural and synthetic isothiocyanate-based H2S-releasers against chemotherapy-induced neuropathic pain: Role of Kv7 potassium channels.

    Science.gov (United States)

    Di Cesare Mannelli, Lorenzo; Lucarini, Elena; Micheli, Laura; Mosca, Ilaria; Ambrosino, Paolo; Soldovieri, Maria Virginia; Martelli, Alma; Testai, Lara; Taglialatela, Maurizio; Calderone, Vincenzo; Ghelardini, Carla

    2017-07-15

    Hydrogen sulfide (H2S) is a crucial signaling molecule involved in several physiological and pathological processes. Nonetheless, the role of this gasotransmitter in the pathogenesis and treatment of neuropathic pain is controversial. The aim of the present study was to investigate the pain relieving profile of a series of slow releasing H2S donors (the natural allyl-isothiocyanate and the synthetics phenyl- and carboxyphenyl-isothiocyanate) in animal models of neuropathic pain induced by paclitaxel or oxaliplatin, anticancer drugs characterized by a dose-limiting neurotoxicity. The potential contribution of Kv7 potassium channels modulation was also studied. Mice were treated with paclitaxel (2.0 mg kg(-1)) i.p. on days 1, 3, 5 and 7; oxaliplatin (2.4 mg kg(-1)) was administered i.p. on days 1-2, 5-9, 12-14. Behavioral tests were performed on day 15. In both models, single subcutaneous administrations of H2S donors (1.33, 4.43, 13.31 μmol kg(-1)) reduced the hypersensitivity to cold non-noxious stimuli (allodynia-related measurement). The prototypical H2S donor NaHS was also effective. Activity was maintained after i.c.v. administrations. On the contrary, the S-lacking molecule allyl-isocyanate did not increase pain threshold; the H2S-binding molecule hemoglobin abolished the pain-relieving effects of isothiocyanates and NaHS. The anti-neuropathic properties of H2S donors were reverted by the Kv7 potassium channel blocker XE991. Currents carried by Kv7.2 homomers and Kv7.2/Kv7.3 heteromers expressed in CHO cells were potentiated by H2S donors. Sistemically- or centrally-administered isothiocyanates reduced chemotherapy-induced neuropathic pain by releasing H2S. Activation of Kv7 channels largely mediate the anti-neuropathic effect. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Role of Drp1, a key mitochondrial fission protein, in neuropathic pain.

    Science.gov (United States)

    Ferrari, Luiz F; Chum, Adrienne; Bogen, Oliver; Reichling, David B; Levine, Jon D

    2011-08-03

    While oxidative stress has been implicated in small-fiber painful peripheral neuropathies, antioxidants are only partially effective to treat patients. We have tested the hypothesis that Drp1 (dynamin-related protein 1), a GTPase that catalyzes the process of mitochondrial fission, which is a mechanism central for the effect and production of reactive oxygen species (ROS), plays a central role in these neuropathic pain syndromes. Intrathecal administration of oligodeoxynucleotide antisense against Drp1 produced a decrease in its expression in peripheral nerve and markedly attenuated neuropathic mechanical hyperalgesia caused by HIV/AIDS antiretroviral [ddC (2',3'-dideoxycytidine)] and anticancer (oxaliplatin) chemotherapy in male Sprague Dawley rats. To confirm the role of Drp1 in these models of neuropathic pain, as well as to demonstrate its contribution at the site of sensory transduction, we injected a highly selective Drp1 inhibitor, mdivi-1, at the site of nociceptive testing on the dorsum of the rat's hindpaw. mdivi-1 attenuated both forms of neuropathic pain. To evaluate the role of Drp1 in hyperalgesia induced by ROS, we demonstrated that intradermal hydrogen peroxide produced dose-dependent hyperalgesia that was inhibited by mdivi-1. Finally, mechanical hyperalgesia induced by diverse pronociceptive mediators involved in inflammatory and neuropathic pain-tumor necrosis factor α, glial-derived neurotrophic factor, and nitric oxide-was also inhibited by mdivi-1. These studies provide support for a substantial role of mitochondrial fission in preclinical models of inflammatory and neuropathic pain.

  4. Effect of Gabapentin and Baclofen on Histology Study in Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Fifteen A. Fajrin

    2015-12-01

    Full Text Available Neuropathic pain resulted from injury to nerves is often resistant to current treatments and can seriously cause chronic pain if no appropriate treatment is given. This study was designed to prove the effectiveness of gabapentin and baclofen in increasing latency time toward thermal stimulus and recovering the morphology of dorsal horn of spinal cord in neuropathic-induced chronic pain. Forty mice were divided into 8 groups i.e sham, negative control, gabapentin at three different doses (10, 30, 100 nmol and baclofen at three different doses (1, 10, 30 nmol. Neuropathic condition was induced by ligation of sciatic nerve with Partial Sciatic Nerve Ligation (PSNL method. Gabapentin and baclofen were administrated intrathecally once a day for seven days, a week after neuropathic induction. Latency time toward thermal stimulus was measured on days 0, 1, 3, 5, 7, 8, 10, 12 and 14 after induction. Histology of the dorsal horn of spinal cord tissue was examined by haematoxylline-eosin staining. The results showed that intrathecal injection of gabapentin and baclofen significantly increased latency time of mice toward thermal stimulus compared with negative control. Gabapentin and baclofen are effective as treatment for neuropathic pain. They can also help the recovery process of the histology in dorsal horn in neuropathic pain.

  5. Neuropathic pain: an updated grading system for research and clinical practice.

    Science.gov (United States)

    Finnerup, Nanna B; Haroutounian, Simon; Kamerman, Peter; Baron, Ralf; Bennett, David L H; Bouhassira, Didier; Cruccu, Giorgio; Freeman, Roy; Hansson, Per; Nurmikko, Turo; Raja, Srinivasa N; Rice, Andrew S C; Serra, Jordi; Smith, Blair H; Treede, Rolf-Detlef; Jensen, Troels S

    2016-08-01

    The redefinition of neuropathic pain as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system," which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the "definite" level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research.

  6. Quality of life and functional capacity are adversely affected in osteoarthritis patients with neuropathic pain.

    Science.gov (United States)

    Aşkın, Ayhan; Özkan, Ayten; Tosun, Aliye; Demirdal, Ümit Seçil; İsnaç, Fethi

    2017-03-01

    The aim of this study was to examine the neuropathic pain component of knee osteoarthritis (OA) patients and to investigate the relationship between neuropathic pain, disease stage, functional state, depression, anxiety, and quality of life. This study included 60 patients with knee OA. All demographic data and radiological results were recorded. Visual Analog Scale (VAS), Timed Up and Go Test, Chair Stand Test, Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC), PainDETECT questionnaire, DN4 questionnaire, Short form-36 questionnaire, and Hospital Anxiety Depression Scale were performed for each patient. Neuropathic pain was detected in 66.7% of patients based on the PainDETECT scale and in 46.7% of patients based on DN4 scale. VAS-resting, OA grade, WOMAC scores, and SF-scores showed a significant difference in patients that detected neuropathic pain with PainDETECT (pneuropathic pain had significantly higher WOMAC scores and significantly lower SF-36 scores (ppain may have a neuropathic component involved in the clinical condition. Quality of life and functional capacity are adversely affected in patients with knee OA who have neuropathic pain. This should be taken into account while planning the treatment of these patients. Copyright © 2017. Published by Elsevier Taiwan.

  7. Reliability and validity of quantitative sensory testing in persons with spinal cord injury and neuropathic pain.

    Science.gov (United States)

    Felix, Elizabeth R; Widerström-Noga, Eva G

    2009-01-01

    Quantitative sensory testing (QST) has been used to assess neurological function in various chronic pain patient populations. In the present study, we investigated the ability of QST to reliably characterize somatosensory dysfunction in subjects with spinal cord injury (SCI) and neuropathic pain by measuring mechanical, vibration, and thermal detection and pain thresholds. Test-retest reliability was determined based on data collected from 10 subjects with SCI and neuropathic pain who underwent QST on two occasions approximately 3 weeks apart. The intraclass correlation coefficients for mechanical, vibration, warm, and cool detection thresholds were in the "substantial" range, while thresholds for cold pain and hot pain demonstrated "fair" stability in this sample of patients. To determine the validity of QST in persons with SCI-related neuropathic pain, we evaluated the relationship between somatosensory thresholds and severity of neuropathic pain symptoms with multiple linear regression analysis. Thermal pain threshold was the only QST variable significantly related to the severity of neuropathic pain symptoms. The present study provides preliminary evidence that QST is a reliable and valid adjunct measurement strategy for quantifying the neurological dysfunction associated with neuropathic pain in persons with SCI.

  8. Sciatic nerve cuffing in mice: a model of sustained neuropathic pain.

    Science.gov (United States)

    Benbouzid, Malika; Pallage, Viviane; Rajalu, Mathieu; Waltisperger, Elisabeth; Doridot, Stéphane; Poisbeau, Pierrick; Freund-Mercier, Marie José; Barrot, Michel

    2008-07-01

    Because of its severity, chronicity, resistance to usual therapy and its consequences on quality of life, neuropathic pain represents a real clinical challenge. Fundamental research on this pathology uses metabolic, pharmacological or traumatic models in rodents that reproduce the characteristic human pain symptoms. In 1996, Mosconi and Kruger morphologically described a model of peripheral neuropathy in which a cuff of polyethylene tubing was placed around the sciatic nerve in rats. In the present study, we evaluated the behavioral consequences of this neuropathic pain model in C57Bl/6J mice which is the main genetic background used for studies in transgenic mice. A short cuff of polyethylene tubing was unilaterally placed around the main branch of the sciatic nerve. It induced an ipsilateral heat thermal hyperalgesia lasting around 3 weeks, and a sustained ipsilateral mechanical allodynia lasting at least 2 months. We showed that this neuropathic pain model is insensitive to ketoprofen, a non-steroidal anti-inflammatory drug. Morphine treatment acutely suppressed the mechanical allodynia, but tolerance to this effect rapidly developed. The analysis of video recordings revealed that most aspects of spontaneous behavior remained unaffected on the long term, excepted for a decrease in the time spent at social interaction for the neuropathic mice. Using the elevated plus-maze and the marble-burying test, we also showed that neuropathic mice develop an anxiety phenotype. Our data indicate that sciatic nerve cuffing in mice is a pertinent model for the study of nociceptive and emotional consequences of sustained neuropathic pain.

  9. Effects of fisetin on oxaliplatin-induced neuropathic pain in mice

    Directory of Open Access Journals (Sweden)

    Hong Liu

    2015-03-01

    Full Text Available Common chemotherapeutic agents such as oxaliplatin often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is difficult to treat and responds poorly to common analgesics, which represents a challenging clinical issue. Fisetin is a naturally occurring flavonoid and this study tested the potential anti-hyperalgesic effects of fisetin in a mice model of oxaliplatin-induced neuropathic pain. Fisetin (1-4 mg/kg, i.p. did not significantly alter the mechanical hypersensitivity in oxaliplatin-treated mice but produced a dose-dependent anti-hyperalgesic effect during repeated treatment. Repeated treatment with fisetin also prevented chronic neuropathic pain-induced depressive-like behavior in a forced swimming test. Both the antihyperalgesic and the antidepressant-like effects of fisetin can be blocked by a selective 5-HT1A receptor antagonist WAY100635 (1 mg/kg. Together, these results demonstrate that fisetin has significant analgesic efficacy against chronic neuropathic pain, which could be a useful analgesic in the management of neuropathic pain.

  10. Nerve Regenerative Effects of GABA-B Ligands in a Model of Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Valerio Magnaghi

    2014-01-01

    Full Text Available Neuropathic pain arises as a direct consequence of a lesion or disease affecting the peripheral somatosensory system. It may be associated with allodynia and increased pain sensitivity. Few studies correlated neuropathic pain with nerve morphology and myelin proteins expression. Our aim was to test if neuropathic pain is related to nerve degeneration, speculating whether the modulation of peripheral GABA-B receptors may promote nerve regeneration and decrease neuropathic pain. We used the partial sciatic ligation- (PSL- induced neuropathic model. The biochemical, morphological, and behavioural outcomes of sciatic nerve were analysed following GABA-B ligands treatments. Simultaneous 7-days coadministration of baclofen (10 mg/kg and CGP56433 (3 mg/kg alters tactile hypersensitivity. Concomitantly, specific changes of peripheral nerve morphology, nerve structure, and myelin proteins (P0 and PMP22 expression were observed. Nerve macrophage recruitment decreased and step coordination was improved. The PSL-induced changes in nociception correlate with altered nerve morphology and myelin protein expression. Peripheral synergic effects, via GABA-B receptor activation, promote nerve regeneration and likely ameliorate neuropathic pain.

  11. Long-term outcomes of cutaneous vesicostomy in patients with neuropathic bladder caused by spina bifida.

    Science.gov (United States)

    Dönmez, M İrfan; Carrasco, Alonso; Saltzman, Amanda F; Vemulakonda, Vijaya; Wilcox, Duncan T

    2017-06-16

    To evaluate the outcomes of patients who underwent cutaneous vesicostomy for management of neuropathic bladder secondary to spina bifida. We hypothesize that vesicostomy, in select patients, is beneficial to prevent upper urinary tract deterioration (UTD), reduce febrile urinary tract infections (UTIs), and preserve renal function. We performed a retrospective chart review on patients with spina bifida who underwent cutaneous vesicostomy at our institution between 2000 and 2016. Demographic information, indication for vesicostomy, pre and postoperative laboratory/radiologic studies, incidence of febrile UTIs, and urodynamic findings were abstracted. A total of 14 patients (eight females and six males) were identified. The indication for vesicostomy was UTD in four, recurrent febrile UTIs in five, parental request in two, both UTD and recurrent febrile UTIs in two, and both UTI and parental request in one patient. Seven patients had a median of three (range one to five) febrile UTI prior to surgery for cutaneous vesicostomy. Median creatinine level before surgery was 0.26 mg/dL (range 0.16-0.97). Either unilateral or bilateral ≥SFU Grade 2 hydronephrosis was present in six patients. Median age at vesicostomy creation was 26.5 months (range 4-96). Mean functional bladder capacity assessed during preoperative urodynamic studies was 107 mL (range 20-279), and detrusor sphincter dysynergia was present in all patients. High-grade vesicoureteral reflux (grade ≥3) was present in three patients, all with UTD. Mean follow-up after vesicostomy was 62.4 ± 39.3 months. After vesicostomy, only two of the seven patients with history of febrile UTIs experienced an additional febrile UTI. The median serum creatinine level was 0.36 mg/dL (range 0.2-0.58) at last follow-up. Moreover, 11/14 patients had no hydronephrosis and just two patients had unilateral SFU grade 1 hydronephrosis (Table). Worsening UTD, recurrent febrile UTIs, and high-pressure bladder despite maximal

  12. Evaluation of NR2B peptide as subunit vaccines against experimental neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    WANG Gong-ming; TIAN Yu-ke; CHEN Jian-ping; TIAN Xu-bi; GAO Feng; YANG Hui; AN Ke; MA Guo-ping

    2007-01-01

    Background NR2B containing N-methyl-D-aspartate (NMDA) receptor plays an important role in the facilitation and maintenance of neuropathic pain. The discrete distribution of NR2B subunit in the central nervous system (CNS) may support reduced side effects of agents that act selectively at this site. Therefore, we investigated the hypothesis that a humoral autoimmune response targeting the NR2B subunit of NMDA receptor relieves pain like behaviours produced by peripheral injury.Methods Rats were immunized subcutaneously with NR2B-Keyhole Limpet Hemocyanin (NR2B-KLH) three times at two-week intervals. NR2B specific IgG titres in sera and cerebrospinal fluid were determined by indirect ELISA. Seven days after the third immunization, 2 of the 3 terminal branches of the sciatic nerve (tibial and common peroneal nerves) were tightly ligated. Behavioural testing was carried out on every other day after surgery, until 7 days after surgery. The lumbar spinal cord (L4-6) was removed on day 7 after ligation. The expression of NR2B protein in the lumbar spinal cord was determined using Western blotting.Results After the second vaccination, NR2B specific IgG in sera was detected to be >0.5 μg/ml in six of nine rats. After the third vaccination, all the immunized rats had >2.2 μg/ml. Titres of NR2B specific IgG in sera peaked 42 days post initial immunization and persisted for over 70 days. No NR2B specific IgG was detected in sera from PBS or KLH group.The behavioural thresholds in NR2B group were significantly higher than those in PBS and KLH groups on day 7 after ligation. NR2B specific IgG in CSF in NR2B group could not be detected on day 1 before spinal dissection; but could be detected on day 7 after surgery. The expression of NR2B protein in group NR2B was significantly lower than in PBS and KLH groups on day 7 after surgery.Conclusion The NR2B peptide could be used as a vaccine against neuropathic pain, which could be associated with reduction of NR2B protein in

  13. Involvement of EphB1 receptors signalling in models of inflammatory and neuropathic pain.

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    Vincent Cibert-Goton

    Full Text Available EphB receptors tyrosine kinases and ephrinB ligands were first identified as guidance molecules involved in the establishment of topographical mapping and connectivity in the nervous system during development. Later in development and into adulthood their primary role would switch from guidance to activity-dependent modulation of synaptic efficacy. In sensory systems, they play a role in both the onset of inflammatory and neuropathic pain, and in the establishment of central sensitisation, an NMDA-mediated form of synaptic plasticity thought to underlie most forms of chronic pain. We studied wild type and EphB1 knockout mice in a range of inflammatory and neuropathic pain models to determine 1, whether EphB1 expression is necessary for the onset and/or maintenance of persistent pain, regardless of origin; 2, whether in these models cellular and molecular changes, e.g. phosphorylation of the NR2B subunit of the NMDA receptor, increased c-fos expression or microglial activation, associated with the onset of pain, are affected by the lack of functional EphB1 receptors. Differences in phenotype were examined behaviourally, anatomically, biochemically and electrophysiologically. Our results establish firstly, that functional EphB1 receptors are not essential for the development of normal nociception, thermal or mechanical sensitivity. Secondly, they demonstrate a widespread involvement of EphB1 receptors in chronic pain. NR2B phosphorylation, c-fos expression and microglial activation are all reduced in EphB1 knockout mice. This last finding is intriguing, since microglial activation is supposedly triggered directly by primary afferents, therefore it was not expected to be affected. Interestingly, in some models of long-term pain (days, mechanical and thermal hyperalgesia develop both in wild type and EphB1 knockout mice, but recovery is faster in the latter, indicating that in particular models these receptors are required for the maintenance

  14. Effect of percutaneous radiofrequency thermocoagulation on different neuropathic pains

    Institute of Scientific and Technical Information of China (English)

    Youcai Shi; Xiaoxia Hu

    2006-01-01

    BACKGROUND: The clinical treatment of neuropathic pain is very troublesome ,and the physical method of radiofrequency thermocoagulation is a good choice for its treatment.OBJECTIVE: To observe the curative effact of percutaneous radiofrequency thermocoagulation on neuropathic neuralgia.DESIGN:A case follow-up analysis.SETTING: Minimally Invasive Surgery Room,Department of Neurosurgery,Urumqi General Hospital of Lanzhou Military Area Command of Chinese PLA.PARTICIPANTS: Totally 131 patients were selected from the Department of Neurosurgery,Urumqi General Hospital of Lanzhou Military Area Command of Chinese PLA from December 2000 to June 2006,including 73 males and 58 females,aging 37-72 years old,AND the disease course was 2-15 years.①Drug treatment failed to alleviate the pain or induced obvious side the pain or induced obvious side effects; ②With the same pathological changes as pain and effective in the nerve block test; Had signed the informed consents before treatment.Distribution of the neuropathic pain:①Trigeminal neuralgia,which were lighting attack,located at V2 in 28 cases,V3 in 46 cases,V1+V2 in 3 cases,V2+V3 in 28 cases,and V1+V2+V3 in 1 cases;②Migraine located at(except the frontal branch of trigeminal nerve)greater and lesser occipital nerves in 6 cases,auriculotemporal nerve in 3 cases,temporal and zygomatic nerves in 3 cases;③Unilateral neuralgia of C2 and C3 following herpes zoster in 1 case,and chest intercostals neuralgia in 2 cases;④Lasting burning pain in the operative area after thoracotomy was in 1 case of lung cancer.METHODS: ①All the enrolled patients were treated with percutaneous puncture at trigeminal ganglion or peripheral nerve,then nerve block was performed firstly for anesthesia,and the pain disappeared immediately at this moment,there was hypoesthesia or numbness in the area of innervation,which manifested the puncture apposition was correct.then electrostimulation of 50 Hz with the current of 0.1-0.5 V was given for

  15. A COMBINED EFFECT OF DEXTROMETHORPHAN AND MELATONIN ON NEUROPATHIC PAIN BEHAVIOR IN RATS

    Science.gov (United States)

    Wang, Shuxing; Zhang, Lin; Lim, Grewo; Sung, Backil; Tian, Yinghong; Chou, Chiu-Wen; Hernstadt, Hayley; Rusanescu, Gabriel; Ma, Yuxin; Mao, Jianren

    2009-01-01

    Previous study has shown that administration of melatonin into the anterior cingulate cortex contralateral to peripheral nerve injury prevented exacerbation of mechanical allodynia with a concurrent improvement of depression-like behavior in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats. In the present study, we examined the effect of the individual versus combined treatment of melatonin and/or dextromethorphan (DM), a clinically available N-methyl-D-aspartate (NMDA) receptor antagonist, on pain behaviors in WKY rats with chronic constriction sciatic nerve injury (CCI). Pain behaviors (thermal hyperalgesia and mechanical allodynia) were established at one week after CCI. WKY rats were then treated intraperitoneally with various doses of melatonin, DM or their combination once daily for the following week. At the end of this one-week treatment, behavioral tests were repeated in these same rats. While DM alone was effective in reducing thermal hyperalgesia at three tested doses (15, 30 or 60 mg/kg), it reduced mechanical allodynia only at high doses (30 or 60 mg/kg). By comparison, administration of melatonin alone was effective in reducing thermal hyperalgesia only at the highest dose (120 mg/kg, but not 30 or 60 mg/kg) tested in this experiment. Melatonin alone failed to reverse allodynia at all three tested doses (30, 60 and 120 mg/kg). However, the combined intraperitoneal administration of melatonin (30 mg/kg) and DM (15 mg/kg) effectively reversed both thermal hyperalgesia and mechanical allodynia although each individual dose alone did not reduce pain behaviors. These results suggest that a combination of melatonin with a clinically available NMDA receptor antagonist might be more effective than either drug alone for the treatment of neuropathic pain. PMID:19595681

  16. Ulcer piercing: cleansing of complicated diabetic neuropathic foot ulcers by positive pressure irrigation.

    Science.gov (United States)

    Cavallini, M

    2014-02-01

    To demonstrate the efficacy of the ulcer piercing procedure, which allows constant cleansing of the ulcer and facilitates a positive pressure irrigation of any pierced hidden tracts, in order to reduce the negative impact of stasis on wound healing. We designed a surgical procedure of ulcer piercing and drainage with a silastic tube, which allows positive pressure irrigation of any pierced tracts. This procedure was performed in a continuous series of 25 selected diabetic patients affected by a Wagner stage 3 ulcer of the toe (n=16), metatarsal midfoot (n=5) and plantar Charcot foot (n=4), and with adequate foot arterial blood supply. Within 6 months of the ulcer piercing procedure, 23/25 of ulcers had completely healed. In two further cases, the ulcer piercing ring was still in place after 3 and 5 months, progressively healing with no active signs of infection. Taking into consideration the advantages and the lack of side effects afforded by this procedure, ulcer piercing represents a small but effective step towards an easier and safer approach to treating complicated diabetic neuropathic foot ulcers with adequate arterial blood supply. There were no external sources of funding for this study. The author has no conflicts of interest to declare with regard to the manuscript or its content.

  17. Analgesic Effect of Harpagophytum procumbens on Postoperative and Neuropathic Pain in Rats

    Directory of Open Access Journals (Sweden)

    Dong Wook Lim

    2014-01-01

    Full Text Available Harpagophytum procumbens, also known as Devil’s Claw, has historically been used to treat a wide range of conditions, including pain and arthritis. The study was designed to investigate whether H. procumbens extracts exhibit analgesic effects in plantar incision and spared nerve injury (SNI rats. The whole procedure was performed on male SD rats. To evaluate pain-related behavior, we performed the mechanical withdrawal threshold (MWT test measured by von Frey filaments. Pain-related behavior was also determined through analysis of ultrasonic vocalization (USVs. The results of experiments showed MWT values of the group that was treated with 300 mg/kg H. procumbens extract increased significantly; on the contrary, the number of 22–27 kHz USVs of the treated group was reduced at 6 h and 24 h after plantar incision operation. After 21 days of continuous treatment with H. procumbens extracts at 300 mg/kg, the treated group showed significantly alleviated SNI-induced hypersensitivity responses by MWT, compared with the control group. These results suggest that H. procumbens extracts have potential analgesic effects in the case of acute postoperative pain and chronic neuropathic pain in rats.

  18. Neural mobilization reverses behavioral and cellular changes that characterize neuropathic pain in rats

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    Santos Fabio M

    2012-07-01

    Full Text Available Abstract Background The neural mobilization technique is a noninvasive method that has proved clinically effective in reducing pain sensitivity and consequently in improving quality of life after neuropathic pain. The present study examined the effects of neural mobilization (NM on pain sensitivity induced by chronic constriction injury (CCI in rats. The CCI was performed on adult male rats, submitted thereafter to 10 sessions of NM, each other day, starting 14 days after the CCI injury. Over the treatment period, animals were evaluated for nociception using behavioral tests, such as tests for allodynia and thermal and mechanical hyperalgesia. At the end of the sessions, the dorsal root ganglion (DRG and spinal cord were analyzed using immunohistochemistry and Western blot assays for neural growth factor (NGF and glial fibrillary acidic protein (GFAP. Results The NM treatment induced an early reduction (from the second session of the hyperalgesia and allodynia in CCI-injured rats, which persisted until the end of the treatment. On the other hand, only after the 4th session we observed a blockade of thermal sensitivity. Regarding cellular changes, we observed a decrease of GFAP and NGF expression after NM in the ipsilateral DRG (68% and 111%, respectively and the decrease of only GFAP expression after NM in the lumbar spinal cord (L3-L6 (108%. Conclusions These data provide evidence that NM treatment reverses pain symptoms in CCI-injured rats and suggest the involvement of glial cells and NGF in such an effect.

  19. Heme oxygenase-1 inhibits neuropathic pain in rats with diabetic mellitus

    Institute of Scientific and Technical Information of China (English)

    Qian Kong; Kang Liu; Lingxi Wu; Long Wang

    2012-01-01

    A diabetes mellitus model was established through single intraperitoneal injection of streptozotocin into rats.Seven days later,model rats were intraperitoneally administered zinc protoporphyrin,a heme oxygenase-1 inducer,and cobalt protoporphyrin,a heme oxygenase-1 inhibitor,once every two days,for 5 successive weeks.After administration,the paw withdrawal mechanical threshold of diabetic mellitus rats significantly decreased,the myelin sheath of the sciatic nerve thickened or showed vacuole defects,the number of spinal dorsal horn neurons reduced,some neurons degenerated and were necrotic,and heme oxygenase-1 was visible in the cytoplasm of spinal dorsal horn neurons.Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling demonstrated that the number of apoptotic neurons increased,which could be inhibited by cobalt protoporphyrin,however,zinc protoporphyrin led to an opposite effect.Our experimental findings indicate that heme oxygenase-1 attenuates neuropathic pain in diabetic mellitus rats through amelioration of peripheral neuropathy and inhibition of spinal dorsal horn neuron apoptosis.

  20. Celastrol Attenuates Inflammatory and Neuropathic Pain Mediated by Cannabinoid Receptor Type 2

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    Longhe Yang

    2014-08-01

    Full Text Available Celastrol, a major active ingredient of Chinese herb Tripterygium wilfordii Hook. f. (thunder god vine, has exhibited a broad spectrum of pharmacological activities, including anti-inflammation, anti-cancer and immunosuppression. In the present study, we used animal models of inflammatory pain and neuropathic pain, generated by carrageenan injection and spared nerve injury (SNI, respectively, to evaluate the effect of celastrol and to address the mechanisms underlying pain processing. Intraperitoneal (i.p. injection of celastrol produced a dose-dependent inhibition of carrageenan-induced edema and allodynia. Real-time PCR analysis showed that celastrol (0.3 mg/kg, i.p. significantly reduced mRNA expressions of inflammatory cytokines, TNF-α, IL-6, IL-1β, in carrageenan-injected mice. In SNI mice, pain behavior studies showed that celastrol (1 mg/kg, i.p. effectively prevented the hypersensitivity of mechanical nociceptive response on the third day post-surgery and the seventh day post-surgery. Furthermore, the anti-hyperalgesic effects of celastrol in carrageenan-injected mice and SNI mice were reversed by SR144528 (1 mg/kg, i.p., a specific cannabinoid receptor-2 (CB2 receptor antagonist, but not by SR141716 (1 mg/kg, i.p., a specific cannabinoid receptor-1 (CB1 receptor antagonist. Taken together, our results demonstrate the analgesia effects of celastrol through CB2 signaling and propose the potential of exploiting celastrol as a novel candidate for pain relief.

  1. Lysophosphatidic acid receptors (LPARs): Potential targets for the treatment of neuropathic pain.

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    Velasco, María; O'Sullivan, Catherine; Sheridan, Graham K

    2017-02-01

    Neuropathic pain can arise from lesions to peripheral or central nerve fibres leading to spontaneous action potential generation and a lowering of the nociceptive threshold. Clinically, neuropathic pain can manifest in many chronic disease states such as cancer, diabetes or multiple sclerosis (MS). The bioactive lipid, lysophosphatidic acid (LPA), via activation of its receptors (LPARs), is thought to play a central role in both triggering and maintaining neuropathic pain. In particular, following an acute nerve injury, the excitatory neurotransmitters glutamate and substance P are released from primary afferent neurons leading to upregulated synthesis of lysophosphatidylcholine (LPC), the precursor for LPA production. LPC is converted to LPA by autotaxin (ATX), which can then activate macrophages/microglia and modulate neuronal functioning. A ubiquitous feature of animal models of neuropathic pain is demyelination of damaged nerves. It is thought that LPA contributes to demyelination through several different mechanisms. Firstly, high levels of LPA are produced following macrophage/microglial activation that triggers a self-sustaining feed-forward loop of de novo LPA synthesis. Secondly, macrophage/microglial activation contributes to inflammation-mediated demyelination of axons, thus initiating neuropathic pain. Therefore, targeting LPA production and/or the family of LPA-activated G protein-coupled receptors (GPCRs) may prove to be fruitful clinical approaches to treating demyelination and the accompanying neuropathic pain. This review discusses our current understanding of the role of LPA/LPAR signalling in the initiation of neuropathic pain and suggests potential targeted strategies for its treatment. This article is part of the Special Issue entitled 'Lipid Sensing G Protein-Coupled Receptors in the CNS'. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. The prevalence of neuropathic pain is high following treatment for breast cancer: a systematic review.

    Science.gov (United States)

    Ilhan, Emre; Chee, Edwin; Hush, Julia; Moloney, Niamh

    2017-07-03

    Pain is common, but often poorly managed following breast cancer treatment. Screening questionnaires and the Neuropathic Pain Special Interest Group (NeuPSIG) criteria are two clinical approaches used to determine whether pain has neuropathic components, which may enable better pain management. The aims of this review were (1) to synthesise data from the literature on neuropathic pain prevalence in women following breast cancer treatment; (2) to investigate whether the prevalence of neuropathic pain differed between studies using screening questionnaires and the NeuPSIG criteria. We searched for studies that administered a validated neuropathic pain screening questionnaire and/or the NeuPSIG criteria to women treated for early-stage (I-III) breast cancer. Thirteen studies using screening questionnaires (N=3,792), and 3 studies using components of the NeuPSIG criteria (N=621) were included. Meta-analyses were conducted for questionnaire data but not NeuPSIG criteria data due to inadequate homogeneity. Among all participants treated for early-stage breast cancer, pooled prevalence estimates (95% confidence interval) ranged between 14.2% (8.3 to 21.4) to 27.2% (24.7 to 88.4) for studies using screening questionnaires; studies using NeuPSIG criteria reported prevalence rates from 24.1% to 31.3%. Among those who reported pain following treatment, the pooled prevalence estimate (95% confidence interval) of neuropathic pain from screening questionnaires ranged from 32.6% (24.2 to 41.6) to 58.2% (24.7 to 88.4); studies using NeuPSIG criteria reported prevalence rates from 29.5% to 57.1%. These prevalence estimates are higher than those reported for other types of cancer, and emphasise the need to assess the contribution of neuropathic pain following breast cancer treatment.

  3. Therapeutic potential for leukocyte elastase in chronic pain states harboring a neuropathic component.

    Science.gov (United States)

    Bali, Kiran Kumar; Kuner, Rohini

    2017-09-13

    Neuropathic pain is an integral component of several chronic pain conditions and poses a major health problem worldwide. Despite emerging understanding of mechanisms behind neuropathic pain, the available treatment options are still limited in efficacy or associated with side effects, therefore making it necessary to find viable alternatives. In a genetic screen, we recently identified SerpinA3N, a serine protease inhibitor secreted in response to nerve damage by the dorsal root ganglion neurons and we showed that SerpinA3N acts against induction of neuropathic pain by inhibiting the T-cell- and neutrophil-derived protease, leucocyte elastase (LE). In the current study, via detailed in vivo pharmacology combined with analyses of evoked- and spontaneous pain-related behaviors in mice, we report that on systemic delivery, a single dose of 3 independent LE inhibitors can block established nociceptive hypersensitivity in early and late phases in the spared nerve injury model of traumatic neuropathic pain in mice. We further report the strong efficacy of systemic LE inhibitors in reversing ongoing pain in 2 other clinically relevant mouse models-painful diabetic neuropathy and cancer pain. Detailed immunohistochemical analyses on the peripheral tissue samples revealed that both T-Lymphocytes and neutrophils are the sources of LE on peripheral nerve injury, whereas neutrophils are the primary source of LE in diabetic neuropathic conditions. In summary, our results provide compelling evidence for a strong therapeutic potential of generic LE inhibitors for the treatment of neuropathic pain and other chronic pain conditions harboring a neuropathic pain component.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission

  4. High Prevalence of Neuropathic Pain Features in Patients with Knee Osteoarthritis: A Cross-Sectional Study.

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    Oteo-Álvaro, Ángel; Ruiz-Ibán, Miguel A; Miguens, Xoan; Stern, Andrés; Villoria, Jesús; Sánchez-Magro, Isabel

    2015-09-01

    The present epidemiological research evaluated the prevalence of neuropathic pain characteristics in patients with painful knee osteoarthritis (OA) and the plausibility that such neuropathic features were specific of OA. Outpatients with chronic pain associated with knee OA who attended orthopedic surgery or rehabilitation clinics were systematically screened for neuropathic pain with the Douleur Neuropathique in 4 questions (DN4) questionnaire. Data from medical files and those obtained during a single structured clinical interview were correlated with the DN4 scores. Information on potential confounders of neuropathic-like qualities of knee pain was collected to evaluate as much as possible only the symptoms attributable to OA. Of 2,776 patients recruited, 2,167 patients provided valid data from 2,992 knees. The DN4 was scored positively (≥ 4) in 1,125 patients (51.9%) and 1,459 knees (48.8%). When patients with potential confounders were excluded, the respective prevalences were 33.3% and 29.4%. Patients who scored positively in the DN4 had more severe pain, greater structural damage, and more potential confounders of neuropathic pain. Three potential confounders conveyed much of the variability explained by regression analyses. However, latent class analyses revealed that the concourse of other factors is required to explain the neuropathic pain qualities. A relevant proportion of patients with chronic pain associated with knee OA featured neuropathic pain qualities that were not explained by other conditions. The present research has provided reasonable epidemiological grounds to attempt their definite diagnosis and classification. © 2014 World Institute of Pain.

  5. Economic burden of back and neck pain: effect of a neuropathic component.

    Science.gov (United States)

    Kleinman, Nathan; Patel, Aarti A; Benson, Carmela; Macario, Alex; Kim, Myoung; Biondi, David M

    2014-08-01

    This was a retrospective database analysis (2001-2009) of employees' medical, prescription drug, and absence costs and days from sick leave, short- and long-term disability, and workers' compensation. Employees with an ICD-9 diagnostic code for back or neck pain and an ICD-9 for a back- or neck-related neuropathic condition (eg, myelopathy, compression of the spinal cord, neuritis, radiculitis) or radiculopathy were considered to have nociceptive back or neck pain with a neuropathic component. Employees with an ICD-9 for back pain or neck pain and no ICD-9 for a back- or neck-related neuropathic condition or radiculopathy were defined to have nociceptive back or neck pain. Patients with nociceptive back or neck pain with a neuropathic component were classified as having or not having prior nociceptive pain. Annual costs (medical and prescription drug costs and absence costs) and days from sick leave, short- and long-term disability, and workers' compensation were evaluated. Mean annual total costs were highest ($8512) for nociceptive pain with a neuropathic component with prior nociceptive pain (n=9162 employees), $7126 for nociceptive pain with a neuropathic component with no prior nociceptive pain (n=5172), $5574 for nociceptive pain only (n=35,347), and $3017 for control employees with no back or neck pain diagnosis (n=226,683). Medical, short-term disability, and prescription drugs yielded the highest incremental costs compared to controls. Mean total absence days/year were 8.26, 7.86, 5.70, and 3.44, respectively. The economic burden of back pain or neck pain is increased when associated with a neuropathic component.

  6. Leptin is essential for microglial activation and neuropathic pain after preganglionic cervical root avulsion.

    Science.gov (United States)

    Chang, Kai-Ting; Lin, Yi-Lo; Lin, Chi-Te; Hong, Chen-Jei; Tsai, May-Jywan; Huang, Wen-Cheng; Shih, Yang-Hsin; Lee, Yi-Yen; Cheng, Henrich; Huang, Ming-Chao

    2017-10-15

    Preganglionic cervical root avulsion (PCRA) affects both the peripheral and central nervous systems and is often associated with neuropathic pain. Unlike peripheral nerve injuries (PNI), central lesions caused by disruption of cervical roots from the spinal cord following PCRA contribute to the generation of neuropathic pain. Leptin is involved in the development of neuropathic pain after PNI by affecting neurons. However, whether leptin is involved in microglial activation leading to neuropathic pain after PCRA is unknown. Preganglionic avulsion of the left 6(th)-8(th) cervical roots was performed in C57B/6J mice and leptin-deficient mice. A leptin antagonist or leptin was administered to C57B/6J mice and leptin-deficient mice after injury, respectively. The expression pattern of spinal and supraspinal microglia was examined by immunofluorescent staining. Von Frey filaments were used to test pain sensitivity. Leptin is essential for the development of neuropathic pain after PCRA. Allodynia was absent in the leptin-deficient mice and the mice administered the leptin antagonist. We also found that leptin deficiency or the administration of its antagonist inhibited the development of microgliosis in the dorsal horn and brainstem. Furthermore, increase in the expression of CD86 and iNOS, and Wallerian degeneration were noted in the spinal cord. The administration of exogenous leptin to leptin-deficient mice reversed these effects. We concluded that leptin is involved in the proliferation and activation of microglia, which in turn enhances the development of neuropathic pain. Blocking the effects of leptin might be a target for the treatment of neuropathic pain after PCRA. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Neuropathic pain in the orofacial region: The role of pain history. A retrospective study.

    Science.gov (United States)

    Dieb, W; Moreau, N; Chemla, I; Descroix, V; Boucher, Y

    2017-06-01

    Orofacial neuropathic pain is often difficult to treat, mostly because of still unclear underlying mechanisms. The occurrence of such neuropathic pain varies depending on different factors, of which preexisting preoperative pain seems to be of high importance. The aim of this study was thus to test the hypothesis that prior history of pain could indeed be considered a risk factor for the development of orofacial neuropathic pain in the same region. The study was performed in the dental department of the Groupe Hospitalier Pitié-Salpêtrière (GHPS) in Paris, France. We investigated the presence of prior inflammatory pain before development of orofacial neuropathic pain in 56 patients. For each patient file, the following items were collected: age, gender; medical history; diagnosis; description of the pain (at time of consultation); presence or absence of prior dental treatment; date and type of dental treatment received. 41 patients (73%) of orofacial neuropathic pain patients had a history of pain compatible with an inflammatory condition; 4% (n=2) did not report any prior pain and 23% (n=13) could not remember. Among the patients with documented history of pain prior to neuropathy, 88% (n=36) received surgical treatment; 61%, (n=25) endodontic treatment and 22%, (n=9) restorative treatment. All eventually received endodontic treatment or tooth extraction. These dental treatments are compatible with the hypothesis of prior inflammatory pain in these patients. These results support the hypothesis that prior inflammatory pain could favor the development of orofacial neuropathic pain. Prevention and treatment of inflammatory trigeminal pain may therefore play a key role in preventing future neuropathic pain development. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Reflections on reducing insulin to lose weigh.

    Science.gov (United States)

    Wilson, Val

    Diabulimia is not a recognised medical condition, although it is thought to affect one-third of women with type 1 diabetes. Diabulimia involves deliberately omitting or reducing insulin dosages to lose weight. This article reports the reflections of women with long-duration type 1 diabetes who said that they had manipulated their insulin in the past to lose weight. Many were now dealing with serious heart and neuropathic complications, which they felt were a result of their diabulimia.

  9. Characterizing neuropathic pain profiles: enriching interpretation of painDETECT

    Directory of Open Access Journals (Sweden)

    Cappelleri JC

    2016-07-01

    Full Text Available Joseph C Cappelleri,1 Vijaya Koduru,2 E Jay Bienen,3 Alesia Sadosky4 1Pfizer Inc, Groton, CT, USA; 2Eliassen Group, New London, CT, USA; 3Outcomes Research Consultant, New York, NY, USA; 4Pfizer Inc, New York, NY, USA Purpose: To psychometrically evaluate painDETECT, a patient-reported screening questionnaire for neuropathic pain (NeP, for discriminating among sensory pain symptoms (burning, tingling/prickling, light touching, sudden pain attacks/electric shock-type pain, cold/heat, numbness, and slight pressure. Methods: The seven-item version of painDETECT provides an overall score that targets only sensory symptoms, while the nine-item version adds responses on two items to the overall score, covering pain course pattern and pain radiation. Both versions have relevance in terms of characterizing broad NeP. The nine- and seven-item versions of painDETECT were administered to subjects with confirmed NeP across six conditions identified during office visits to US community-based physicians. Responses on the sensory symptom items were dichotomized into “at least moderate” (ie, moderate, strongly, very strongly relative to the combined other responses (never, hardly noticed, slightly. Logistic regression of dichotomized variables on the total painDETECT score provided probabilities of experiencing each symptom across the range of painDETECT scores. Results: Both painDETECT versions discriminated among the symptoms with similar probabilities across the score ranges. Using these data, the probability of moderately experiencing each pain sensory item was estimated for a particular score, providing a pain profile. Additionally, the likelihood of experiencing each sensation was determined for a discrete increase in score, ie, the odds of at least a moderate sensation of burning (versus less than a moderate sensation was 1.29 for a 1-point increase, 3.52 for a 5-point increase, and 12.42 for every 10-point increase in the nine-item painDETECT score

  10. Efficacy of tramadol in combination with doxepin or venlafaxine in inhibition of nociceptive process in the rat model of neuropathic pain: an isobolographic analysis.

    Science.gov (United States)

    Wrzosek, A; Obara, I; Wordliczek, J; Przewlocka, B

    2009-12-01

    Neuropathic pain constitutes a serious therapeutic problem. In most cases polytherapy is necessary. Tramadol and antidepressants have common mechanisms of action and are frequently used together in clinical practice, thus interaction between them is very important. In the present study isobolographic analysis for equivalent doses of drugs was applied to examine the nature of interaction between tramadol and doxepin or venlafaxine in a neuropathic pain model in rats. Allodynia and hyperalgesia were assessed after intraperitoneal administration of each drug alone or in combination. Dose response curves were obtained and ED(50) doses were calculated. All drugs were effective in reducing thermal hyperalgesia and mechanical allodynia, however doxepin was more effective than venlafaxine. Combined administration of tramadol and doxepin demonstrated synergistic action in reducing thermal hyperalgesia and additive action in reducing mechanical allodynia. Combined administration of tramadol and venlafaxine showed additive action in reducing hyperalgesia and allodynia. Moreover, combined administration of tramadol and doxepin was more effective than combined administration of tramadol and venlafaxine. The experiments demonstrated that the nature of interaction between tramadol and doxepin is synergistic, which is not the case for tramadol and venlafaxine, what provides a valuable information referring to clinical practice, rationalizing administration of such drug combination.

  11. Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients.

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    Andreas Binder

    Full Text Available Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K was associated with the presence of paradoxical heat sensation (p = 0.03, and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V with cold hypoalgesia (p = 0.0035. Two main subgroups characterized by preserved (1 and impaired (2 sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and pG (rs222747, M315I to cold hypaesthesia (p = 0.002, but there was absence of associations in subgroup 2. In this study we found no evidence that genetic

  12. [Controlled release hydromorphone for visceral, somatic and neuropathic pain].

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    Alon, E; Cachin, C

    2010-03-03

    The aim of this multicentre, longitudinal investigation was to document the efficacy and tolerability profiles of controlled release hydromorphone in patients with heavy visceral, somatic or neuropathic pain under practical conditions. To this end, a prospective observational study was conducted in 57 centres in Switzerland, on a total of 196 patients. After an average of 43 days of treatment with controlled release hydromorphone, the intensity of momentary pain dropped by 46.5% and that of maximum pain dropped by 41.3%, with the efficacy of the treatment being most pronounced with visceral and somatic pain. At the same time, the prevalence of sleep disorders as a result of pain decreased from initially 86.7% to 21.0%. Controlled release hydromorphone was excellently tolerated in this group of elderly (average age 70.6 years), multimorbid pain patients receiving various medical treatments (average of 2.4 drugs in addition to pain medication), even in the voluntary long-term extension study of up to 96 days. No medical interactions were reported. Six and thirteen weeks after introducing the treatment, 89.8% and 85.2%, respectively, were still taking controlled release hydromorphone. Controlled release hydromorphone is a recommendable option for practical treatment of heavy and extremely heavy pain of various genesis.

  13. N-palmitoylethanolamide in the treatment of neuropathic pain associated with lumbosciatica.

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    Domínguez, C Morera; Martín, A Díaz; Ferrer, F Garibo; Puertas, Ma Ibáñez; Muro, A Leal; González, Jc Martí; Prieto, J Pombo; Taberna, I Rosselló

    2012-03-01

    SUMMARY  To investigate the effectiveness of N-palmitoylethanolamide (PEA) in the treatment of neuropathic pain due to lumbosciatica. Patients with neuropathic pain were assigned to standard treatment plus PEA (600 mg/day) or standard treatment for 30 days. Changes in visual analog scale, and score on Oswestry Disability Index and SF-12® Health Survey were assessed at baseline and follow-up. The mean age of the 118 patients evaluated was 48.4 years, and 47 (40.9%) were women. In the group comparison, significantly larger improvements were seen in the PEA group for visual analog scale and the physical component of the SF-12 Health Survey. The addition of PEA to standard treatment shows an improvement in pain relief in patients with neuropathic pain due to lumbosciatica. PEA was well tolerated. Future investigations of the role of PEA in the treatment of neuropathic pain might help to define novel therapeutic strategies for the treatment of this kind of neuropathic pain.

  14. Psychometric validation of the Portuguese version of the Neuropathic Pain Symptoms Inventory

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    de Andrade Daniel

    2011-11-01

    Full Text Available Abstract Backgroud It has been shown that different symptoms or symptom combinations of neuropathic pain (NeP may correspond to different mechanistic backgrounds and respond differently to treatment. The Neuropathic Pain Symptom Inventory (NPSI is able to detect distinct clusters of symptoms (i.e. dimensions with a putative common mechanistic background. The present study described the psychometric validation of the Portuguese version (PV of the NPSI. Methods Patients were seen in two consecutive visits, three to four weeks apart. They were asked to: (i rate their mean pain intensity in the last 24 hours on an 11-point (0-10 numerical scale; (ii complete the PV-NPSI; (iii provide the list of pain medications and doses currently in use. VAS and Global Impression of Change (GIC were filled out in the second visit. Results PV-NPSI underwent test-retest reliability, factor analysis, analysis of sensitivity to changes between both visits. The PV-NPSI was reliable in this setting, with a good intra-class correlation for all items. The factorial analysis showed that the PV-NPSI inventory assessed different components of neuropathic pain. Five different factors were found. The PV-NPSI was adequate to evaluate patients with neuropathic pain and to detect clusters of NeP symptoms. Conclusions The psychometric properties of the PV-NPSI rendered it adequate to evaluate patients with both central and peripheral neuropathic pain syndromes and to detect clusters of NeP symptoms.

  15. Validation of a New Arabic Version of the Neuropathic Pain Diagnostic Questionnaire (DN4).

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    Chatila, Nadwa; Pereira, Bruno; Maarrawi, Joseph; Dallel, Radhouane

    2017-01-01

    The "Douleur Neuropathique 4 (DN4) questionnaire" was developed for screening neuropathic pain. The purpose of this work was to validate the DN4 questionnaire in the standard Arabic language. First, the questionnaire was translated and semantically adapted to Arabic according to the international guidelines for cross-cultural adaptation. Second, a prospective observational study was performed to validate this questionnaire. A total of 195 patients with chronic pain (n = 99 with neuropathic pain and n = 96 without neuropathic pain) were enrolled in the study. The internal consistency Kuder-Richardson's Formula 20 for the whole DN4 questionnaire was 0.86 (P pain items. The sensitivity and specificity of the 7-item DN4 and 10-item DN4 were not influenced by either pain severity or educational level. In conclusion, this new Arabic version DN4 questionnaire is a simple, reliable, and valid tool for discriminating between neuropathic and non-neuropathic pain. It represents a useful tool in clinical setting and population-based studies. © 2016 World Institute of Pain.

  16. Targeting angiotensin II type 2 receptor pathways to treat neuropathic pain and inflammatory pain.

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    Smith, Maree T; Muralidharan, Arjun

    2015-01-01

    Neuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous 'pain targets' have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT2R) antagonist. Herein, angiotensin II/AT2R signaling-induced hyperexcitability and abnormal sprouting of cultured dorsal root ganglion neurons, together with radioligand binding, pharmacokinetics, analgesic efficacy and mode of action of small-molecule AT2R antagonists in rodent models of peripheral neuropathic and chronic inflammatory pain, are reviewed. The findings of a successful Phase IIa clinical trial of EMA401 in patients with neuropathic pain are presented in brief. The functional importance of angiotensin II/AT2R signaling has remained enigmatic for decades, and there are no clinically available medications that target the AT2R. However, on the basis of preclinical findings and recent clinical trial data showing that the peripherally restricted, small-molecule AT2R antagonist, EMA401, successfully alleviated neuropathic pain in a Phase II clinical trial, the AT2R is receiving considerable attention as a new therapeutic target with human validation for the relief of peripheral neuropathic and chronic inflammatory pain conditions.

  17. Intrathecal siRNA against GPNMB attenuates nociception in a rat model of neuropathic pain.

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    Hou, Lili; Zhang, Yanfeng; Yang, Yong; Xiang, Kai; Tan, Qindong; Guo, Qulian

    2015-02-01

    Neuropathic pain is characterized by hyperalgesia, allodynia, and spontaneous pain. Recent studies have shown that glycoprotein nonmetastatic melanoma B (GPNMB) plays a pivotal role in neuronal survival and neuroprotection. However, the role of GPNMB in neuropathic pain remains unknown. The aim of the present study was to assess the role of GPNMB in neuropathic pain. In cultured spinal cord neurons, we used two small interfering RNAs (siRNAs) targeting the complementary DNA (cDNA) sequence of rat GPNMB that had potent inhibitory effects on GPNMB, and siRNA1-GPNMB was selected for further in vivo study as it had the higher inhibitory effect. After sciatic nerve injury in rats, the endogenous level of GPNMB was increased in a time-dependent manner in the spinal cord. Furthermore, the intrathecal injection of siRNA1-GPNMB inhibited the expression of GPNMB and pro-inflammatory factors (TNF-α, IL-1β, and IL-6) and alleviated mechanical allodynia and thermal hyperalgesia in the chronic constriction injury (CCI) model of rats. Taken together, our findings suggest that siRNA against GPNMB can alleviate the chronic neuropathic pain caused by CCI, and this effect may be mediated by attenuated expression of TNF-α, IL-1β, and IL-6 in the spinal cord of CCI rats. Therefore, inhibition of GPNMB may provide a novel strategy for the treatment of neuropathic pain.

  18. What is the efficacy of physical therapeutics for treating neuropathic pain in spinal cord injury patients?

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    Fattal, C; Kong-A-Siou, D; Gilbert, C; Ventura, M; Albert, T

    2009-03-01

    Evaluate the place and level of proof of physical therapeutics for treating neuropathic pain in spinal cord injury (SCI) patients. Literature review from three databases: PubMed, Embase, Pascal. The following keywords were selected: chronic neuropathic pain/non-pharmacological treatment; transcutaneous electrical nerve stimulation, physiotherapy, acupuncture, physical therapy, transcranial magnetic stimulation, heat therapy, ice therapy, cold therapy, massage, ultrasound, alternative treatment, complementary treatment, occupational therapy. The articles were analyzed using the double-reading mode. Three techniques emerge from the literature: magnetic or electrical transcranial stimulation, transcutaneous electrical nerve stimulation and acupuncture. Even though the first method is not easily accessible on a daily basis it is the one that yields the most promising results validated by Grade B studies. Healthcare professionals remain faithful to pain-relieving transcutaneous neurostimulation for both segmental neuropathic pain and below-level central neuropathic pain. Acupuncture is advocated by Canadian teams and could offer some interesting options; however, to this day, it does not have the methodological support and framework required to validate its efficacy. All other physical therapies are used in a random way. Only below-level massages are advocated by the patients themselves. To this day, no study can validate the integration of physical therapy as part of the array of therapeutics used for treating neuropathic pain in SCI patients. In the future, it will require controlled and randomized therapeutic studies on homogenous groups of SCI patients, to control the various confusion factors.

  19. Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization.

    Science.gov (United States)

    Maher, Dermot P; Chen, Lucy; Mao, Jianren

    2017-02-01

    Intravenous ketamine infusions have been used extensively to treat often-intractable neuropathic pain conditions. Because there are many widely divergent ketamine infusion protocols described in the literature, the variation in these protocols presents a challenge for direct comparison of one protocol with another and in discerning an optimal protocol. Careful examination of the published literature suggests that ketamine infusions can be useful to treat neuropathic pain and that certain characteristics of ketamine infusions may be associated with better clinical outcomes. Increased duration of relief from neuropathic pain is associated with (1) higher total infused doses of ketamine; (2) prolonged infusion durations, although the rate of infusion does not appear to be a factor; and (3) coadministration of adjunct medications such as midazolam and/or clonidine that mitigate some of the unpleasant psychomimetic side effects. However, there are few studies designed to optimize ketamine infusion protocols by defining what an effective infusion protocol entails with regard to a respective neuropathic pain condition. Therefore, despite common clinical practice, the current state of the literature leaves the use of ketamine infusions without meaningful guidance from high-quality comparative evidence. The objectives of this topical review are to (1) analyze the available clinical evidence related to ketamine infusion protocols and (2) call for clinical studies to identify optimal ketamine infusion protocols tailored for individual neuropathic pain conditions. The Oxford Center for Evidence-Based Medicine classification for levels of evidence was used to stratify the grades of clinical recommendation for each infusion variable studied.

  20. From antidepressant drugs to beta-mimetics: preclinical insights on potential new treatments for neuropathic pain.

    Science.gov (United States)

    Barrot, Michel; Yalcin, Ipek; Choucair-Jaafar, Nada; Benbouzid, Malika; Freund-Mercier, Marie-José

    2009-11-01

    The market for pain treatment is a major segment of nervous system pathologies. Despite this dynamism, the management of some pain conditions remains a clinical challenge. Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. It is generally a chronic and disabling condition which is difficult to treat. Antidepressant drugs are recommended as one of the first line treatments, but they display noticeable side effects and are not effective on all patients. Using a murine model of neuropathy, we demonstrated that the stimulation of beta2-adrenergic receptors (beta2-AR) is not only necessary for antidepressant drugs to exert their antiallodynic action but that it is in fact sufficient to alleviate neuropathic allodynia. Chronic, but not acute, treatment with beta-mimetics such as terbutaline, salbutamol, fenoterol, salmeterol, ritodrine, isoprenaline (isoproterenol), metaproterenol (orciprenaline), procaterol, formoterol, clenbuterol or bambuterol, relieves allodynia. Agonists of beta2-ARs, and more generally any molecule stimulating beta2-ARs such as beta-mimetics, are thus proposed as potential new treatments for neuropathic pain. Clinical studies are now in preparation to confirm this potential in patients with neuropathic pain. This article reviews the findings leading to propose beta-mimetics for neuropathic pain treatment and other recent patents on the topic.

  1. Treatment of localized neuropathic pain of different etiologies with the 5% lidocaine medicated plaster – a case series

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    Likar R

    2014-12-01

    Full Text Available Rudolf Likar,1 Susanne Demschar,1 Ingo Kager,1 Stefan Neuwersch,1 Wolfgang Pipam,1 Reinhard Sittl2 1Department of Anesthesiology and Intensive Care, Hospital Klagenfurt, Klagenfurt, Austria; 2Department of Anesthesiology, Interdisciplinary Pain Centre, University Hospital Erlangen, Erlangen, Germany Objective: To assess the efficacy and safety of the topical 5% lidocaine medicated plaster in the treatment of localized neuropathic pain. Study design: This was a case series at an Austrian pain clinic, using retrospective analysis. Patients and methods: Data of 27 patients treated for localized neuropathic pain with the 5% lidocaine medicated plaster were retrospectively analyzed. Assessment included changes in overall pain intensity, in intensity of different pain qualities, and of hyperalgesia and allodynia, and changes in sleep quality. Results: Patients (17 female, ten male; mean age 53.4±11.4 years presented mainly with dorsalgia (16 patients or postoperative/posttraumatic pain (seven patients; one patient suffered from both. The mean overall pain intensity prior to treatment with lidocaine medicated plaster was 8.4±1.2 on the 11-point Likert scale. In the majority of cases, the lidocaine plaster was applied concomitantly with preexisting pain medication (81.5% of the patients. During the 6-month observation period, overall mean pain intensity was reduced by almost 5 points (4.98 to 3.5±2.6. Substantial reductions were also observed for neuralgiform pain (5 points from 7.9±2.6 at baseline and burning pain (3 points from 5.2±4.1. Sleep quality improved from 4.6±2.6 at baseline to 5.5±1.8. Stratification by pain diagnosis showed marked improvements in overall pain intensity for patients with dorsalgia or postoperative/posttraumatic pain. The lidocaine plaster was well tolerated. Conclusion: Overall, topical treatment with the 5% lidocaine medicated plaster was associated with effective pain relief and was well tolerated. Keywords

  2. Prevalence of Neuropathic Pain in Patients with Traumatic Brachial Plexus Injury: A Multicenter Prospective Hospital-Based Study.

    Science.gov (United States)

    Ciaramitaro, Palma; Padua, Luca; Devigili, Grazia; Rota, Eugenia; Tamburin, Stefano; Eleopra, Roberto; Cruccu, Giorgio; Truini, Andrea

    2017-03-03

    Prevalence and clinical characteristics of neuropathic pain due to traumatic brachial plexus injury. Observational epidemiological study. Hospital-based multicenter study. One hundred seven prospectively enrolled patients with brachial plexus injury. All the patients underwent clinical examination and neurophysiological testing for a definitive diagnosis of the brachial plexus lesion. The DN4 questionnaire was used to identify neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to evaluate the different symptoms of neuropathic pain. The SF36 questionnaire and the Beck Depression Inventory (BDI) were used to assess quality of life and mood disturbances in patients with neuropathic pain. Of the 107 enrolled patients, 74 had pain (69%); neuropathic pain, as assessed by means of the DN4, was identified in 60 (56%) of these patients. According to the NPSI, the most frequent and severe pain type was the spontaneous burning pain. Clinical and neurophysiological findings showed that pain is unrelated to age but is associated with the severity of peripheral nerve damage. The SF36 questionnaire and BDI showed that neuropathic pain impairs quality of life and causes depression. Our study provides information on the prevalence, characteristics, and variables associated with neuropathic pain due to traumatic brachial plexus injuries that might provide a basis for improving the clinical management of this condition.

  3. Pharmacological correlation between the formalin test and the neuropathic pain behavior in different species with chronic constriction injury.

    NARCIS (Netherlands)

    Vissers, K.C.P.; Geenen, F.; Biermans, R.; Meert, T.F.

    2006-01-01

    Research on mechanisms of drug action, and preclinical screening of molecules with a potential activity on neuropathic pain requires extensive animal work. The chronic constriction injury model is one of the best-characterized models of neuropathic pain behavior in rats, but requires extensive time

  4. Alternative treatment strategies for neuropathic pain: Role of Indian medicinal plants and compounds of plant origin-A review.

    Science.gov (United States)

    Singh, Hasandeep; Bhushan, Sakshi; Arora, Rohit; Singh Buttar, Harpal; Arora, Saroj; Singh, Balbir

    2017-08-01

    Neuropathic pain is a complex, chronic pain state accompanied by tissue injury and nerve damage. This important health issue constitutes a challenge for the modern medicine worldwide. The management of neuropathic pain remains a major clinical challenge, pertaining to an inadequate understanding of pathophysiological mechanisms of neuropathic pain. Various classes of drugs have been reported effective for the management of neuropathic pain viz. opiates, tricyclic antidepressants, and antiepileptic agents. However, association of adverse effects with these drugs hinders their confident prescription in people with neuropathic pain. Recently, various medicinal plants have been reported effective for the management of neuropathic pain. So, it may be prudent to look beyond synthetic drugs pertaining to their unprecedented pharmacotherapeutic effects with lesser adverse effects. The extensive literature review has been carried out from databases such as Science direct, Scifinder, Wiley online library, PubMed, Research gate, Google scholar and Chemical Abstracts. The list of Traditional Indian Medicinal plants (TIMPs) and isolated compounds have been compiled which have been reported effective as an alternative therapy for the management of neuropathic pain. This helps the researchers to discover some novel therapeutic agents against neuropathic pain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. Combination of Tramadol with Minocycline Exerted Synergistic Effects on a Rat Model of Nerve Injury-Induced Neuropathic Pain

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    Xiao-Peng Mei

    2012-09-01

    Full Text Available Neuropathic pain is a refractory clinical problem. Certain drugs, such as tramadol, proved useful for the treatment of neuropathic pain by inhibiting the activity of nociceptive neurons. Moreover, studies indicated that suppression or modulation of glial activation could prevent or reverse neuropathic pain, for example with the microglia inhibitor minocycline. However, few present clinical therapeutics focused on both neuronal and glial participation when treating neuropathic pain. Therefore, the present study hypothesized that combination of tramadol with minocycline as neuronal and glial activation inhibitor may exert some synergistic effects on spinal nerve ligation (SNL-induced neuropathic pain. Intrathecal tramadol or minocycline relieved SNL-induced mechanical allodynia in a dose-dependent manner. SNL-induced spinal dorsal horn Fos or OX42 expression was downregulated by intrathecal tramadol or minocycline. Combination of tramadol with minocycline exerted powerful and synergistic effects on SNL-induced neuropathic pain also in a dose-dependent manner. Moreover, the drug combination enhanced the suppression effects on SNL-induced spinal dorsal horn Fos and OX42 expression, compared to either drug administered alone. These results indicated that combination of tramadol with minocycline could exert synergistic effects on peripheral nerve injury-induced neuropathic pain; thus, a new strategy for treating neuropathic pain by breaking the interaction between neurons and glia bilaterally was also proposed.

  6. Full inhibition of spinal FAAH leads to TRPV1-mediated analgesic effects in neuropathic rats and possible lipoxygenase-mediated remodeling of anandamide metabolism.

    Science.gov (United States)

    Starowicz, Katarzyna; Makuch, Wioletta; Korostynski, Michal; Malek, Natalia; Slezak, Michal; Zychowska, Magdalena; Petrosino, Stefania; De Petrocellis, Luciano; Cristino, Luigia; Przewlocka, Barbara; Di Marzo, Vincenzo

    2013-01-01

    Neuropathic pain elevates spinal anandamide (AEA) levels in a way further increased when URB597, an inhibitor of AEA hydrolysis by fatty acid amide hydrolase (FAAH), is injected intrathecally. Spinal AEA reduces neuropathic pain by acting at both cannabinoid CB1 receptors and transient receptor potential vanilloid-1 (TRPV1) channels. Yet, intrathecal URB597 is only partially effective at counteracting neuropathic pain. We investigated the effect of high doses of intrathecal URB597 on allodynia and hyperalgesia in rats with chronic constriction injury (CCI) of the sciatic nerve. Among those tested, the 200 µg/rat dose of URB597 was the only one that elevated the levels of the FAAH non-endocannabinoid and anti-inflammatory substrates, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and of the endocannabinoid FAAH substrate, 2-arachidonoylglycerol, and fully inhibited thermal and tactile nociception, although in a manner blocked almost uniquely by TRPV1 antagonism. Surprisingly, this dose of URB597 decreased spinal AEA levels. RT-qPCR and western blot analyses demonstrated altered spinal expression of lipoxygenases (LOX), and baicalein, an inhibitor of 12/15-LOX, significantly reduced URB597 analgesic effects, suggesting the occurrence of alternative pathways of AEA metabolism. Using immunofluorescence techniques, FAAH, 15-LOX and TRPV1 were found to co-localize in dorsal spinal horn neurons of CCI rats. Finally, 15-hydroxy-AEA, a 15-LOX derivative of AEA, potently and efficaciously activated the rat recombinant TRPV1 channel. We suggest that intrathecally injected URB597 at full analgesic efficacy unmasks a secondary route of AEA metabolism via 15-LOX with possible formation of 15-hydroxy-AEA, which, together with OEA and PEA, may contribute at producing TRPV1-mediated analgesia in CCI rats.

  7. Full inhibition of spinal FAAH leads to TRPV1-mediated analgesic effects in neuropathic rats and possible lipoxygenase-mediated remodeling of anandamide metabolism.

    Directory of Open Access Journals (Sweden)

    Katarzyna Starowicz

    Full Text Available Neuropathic pain elevates spinal anandamide (AEA levels in a way further increased when URB597, an inhibitor of AEA hydrolysis by fatty acid amide hydrolase (FAAH, is injected intrathecally. Spinal AEA reduces neuropathic pain by acting at both cannabinoid CB1 receptors and transient receptor potential vanilloid-1 (TRPV1 channels. Yet, intrathecal URB597 is only partially effective at counteracting neuropathic pain. We investigated the effect of high doses of intrathecal URB597 on allodynia and hyperalgesia in rats with chronic constriction injury (CCI of the sciatic nerve. Among those tested, the 200 µg/rat dose of URB597 was the only one that elevated the levels of the FAAH non-endocannabinoid and anti-inflammatory substrates, oleoylethanolamide (OEA and palmitoylethanolamide (PEA, and of the endocannabinoid FAAH substrate, 2-arachidonoylglycerol, and fully inhibited thermal and tactile nociception, although in a manner blocked almost uniquely by TRPV1 antagonism. Surprisingly, this dose of URB597 decreased spinal AEA levels. RT-qPCR and western blot analyses demonstrated altered spinal expression of lipoxygenases (LOX, and baicalein, an inhibitor of 12/15-LOX, significantly reduced URB597 analgesic effects, suggesting the occurrence of alternative pathways of AEA metabolism. Using immunofluorescence techniques, FAAH, 15-LOX and TRPV1 were found to co-localize in dorsal spinal horn neurons of CCI rats. Finally, 15-hydroxy-AEA, a 15-LOX derivative of AEA, potently and efficaciously activated the rat recombinant TRPV1 channel. We suggest that intrathecally injected URB597 at full analgesic efficacy unmasks a secondary route of AEA metabolism via 15-LOX with possible formation of 15-hydroxy-AEA, which, together with OEA and PEA, may contribute at producing TRPV1-mediated analgesia in CCI rats.

  8. Full Inhibition of Spinal FAAH Leads to TRPV1-Mediated Analgesic Effects in Neuropathic Rats and Possible Lipoxygenase-Mediated Remodeling of Anandamide Metabolism

    Science.gov (United States)

    Starowicz, Katarzyna; Makuch, Wioletta; Korostynski, Michal; Malek, Natalia; Slezak, Michal; Zychowska, Magdalena; Petrosino, Stefania; De Petrocellis, Luciano; Cristino, Luigia; Przewlocka, Barbara; Di Marzo, Vincenzo

    2013-01-01

    Neuropathic pain elevates spinal anandamide (AEA) levels in a way further increased when URB597, an inhibitor of AEA hydrolysis by fatty acid amide hydrolase (FAAH), is injected intrathecally. Spinal AEA reduces neuropathic pain by acting at both cannabinoid CB1 receptors and transient receptor potential vanilloid-1 (TRPV1) channels. Yet, intrathecal URB597 is only partially effective at counteracting neuropathic pain. We investigated the effect of high doses of intrathecal URB597 on allodynia and hyperalgesia in rats with chronic constriction injury (CCI) of the sciatic nerve. Among those tested, the 200 µg/rat dose of URB597 was the only one that elevated the levels of the FAAH non-endocannabinoid and anti-inflammatory substrates, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and of the endocannabinoid FAAH substrate, 2-arachidonoylglycerol, and fully inhibited thermal and tactile nociception, although in a manner blocked almost uniquely by TRPV1 antagonism. Surprisingly, this dose of URB597 decreased spinal AEA levels. RT-qPCR and western blot analyses demonstrated altered spinal expression of lipoxygenases (LOX), and baicalein, an inhibitor of 12/15-LOX, significantly reduced URB597 analgesic effects, suggesting the occurrence of alternative pathways of AEA metabolism. Using immunofluorescence techniques, FAAH, 15-LOX and TRPV1 were found to co-localize in dorsal spinal horn neurons of CCI rats. Finally, 15-hydroxy-AEA, a 15-LOX derivative of AEA, potently and efficaciously activated the rat recombinant TRPV1 channel. We suggest that intrathecally injected URB597 at full analgesic efficacy unmasks a secondary route of AEA metabolism via 15-LOX with possible formation of 15-hydroxy-AEA, which, together with OEA and PEA, may contribute at producing TRPV1-mediated analgesia in CCI rats. PMID:23573230

  9. Modulating the Delicate Glial-Neuronal Interactions in Neuropathic Pain: Promises and Potential Caveats

    Science.gov (United States)

    Tiwari, Vinod; Guan, Yun; Raja, Srinivasa N.

    2014-01-01

    During neuropathic pain, glial cells (mainly astrocytes and microglia) become activated and initiate a series of signaling cascades that modulate pain processing at both spinal and supraspinal levels. It has been generally accepted that glial cell activation contributes to neuropathic pain because glia release proinflammatory cytokines, chemokines, and factors such as calcitonin gene-related peptide, substance P, and glutamate, which are known to facilitate pain signaling. However, recent research has shown that activation of glia also leads to some beneficial outcomes. Glia release anti-inflammatory factors that protect against neurotoxicity and restore normal pain. Accordingly, use of glial inhibitors might compromise the protective functions of glia in addition to suppressing their detrimental effects. With a better understanding of how different conditions affect glial cell activation, we may be able to promote the protective function of glia and pave the way for future development of novel, safe, and effective treatments of neuropathic pain. PMID:24820245

  10. A Mangifera indica L. Extract Could Be Used to Treat Neuropathic Pain and Implication of Mangiferin

    Directory of Open Access Journals (Sweden)

    María del C. Rabí

    2010-12-01

    Full Text Available It has been accepted that neuroinflammation, oxidative stress and glial activation are involved in the central sensitization underlying neuropathic pain. Vimang is an aqueous extract of Mangifera indica L. traditionally used in Cuba for its analgesic, anti-inflammatory, antioxidant and immunomodulatory properties. Several formulations are available, and also for mangiferin, its major component. Preclinical studies demonstrated that these products prevented tumor necrosis factor α -induced IκB degradation and the binding of nuclear factor κB to DNA, which induces the transcription of genes implicated in the expression of some mediators and enzymes involved in inflammation, pain, oxidative stress and synaptic plasticity. In this paper we propose its potential utility in the neuropathic pain treatment. This hypothesis is supported in the cumulus of preclinical and clinical evidence around the extract and mangiferin, its major component, and speculates about the possible mechanism of action according to recent advances in the physiopathology of neuropathic pain.

  11. Neuropathic pain in patients with spinal cord injury: report of 213 patients

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    Manoel Jacobsen Teixeira

    2013-09-01

    Full Text Available Objective Management of neuropathic pain following spinal cord injury (SCI can be a frustrating experience for patients since it poses a therapeutic challenge. In this article the authors describe the clinical characteristics of a group of patients with pain after spinal cord injury. Methods In this retrospective study, 213 patients with SCI and neuropathic pain were assessed. We analyzed clinical characteristics, treatment options, and pain intensity for these patients. Results The main cause of SCI was spine trauma, which occurred in 169 patients, followed by tumors and infection. Complete lesions were verified in 144 patients. In our study, patients with traumatic SCI and partial lesions seem to be presented with more intense pain; however, this was not statistically significant. Conclusions Neuropathic pain is a common complaint in patients with SCI and presents a treatment challenge. Knowledge of the clinical characteristics of this group of patients may help determine the best approach to intervention.

  12. The impact of diabetes on neuropathic symptoms and receipt of chemotherapy among colorectal cancer patients

    DEFF Research Database (Denmark)

    Vissers, Pauline A J; Mols, Floortje; Thong, Melissa S Y;

    2015-01-01

    to clinical data from the population-based Eindhoven Cancer Registry. Diabetes status was self-reported and neuropathic symptoms were measured with the European Organization for Research and Treatment of Cancer quality of life questionnaire-chemotherapy-induced peripheral neuropathy 20 (EORTC QLQ-CIPN20......PURPOSE: This study assessed differences in neuropathic symptoms between colorectal cancer (CRC) patients with and without diabetes. Moreover, we aimed to explore whether neuropathic symptoms could be explained by the receipt of chemotherapy as it was previously shown that cancer patients...... with diabetes less often receive chemotherapy. METHODS: Data from a cross-sectional study among CRC patients (2-11 years after diagnosis) was used. Data were collected by the Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship (PROFILES) registry which is linked...

  13. Chronobiology of chronic pain: focus on diurnal rhythmicity of neuropathic pain.

    Science.gov (United States)

    Gilron, Ian; Ghasemlou, Nader

    2014-12-01

    Although circadian rhythmicity has long been recognized in various nociceptive pain conditions such as arthritis, diurnal pain patterns in neuropathic conditions have only recently been described. The purpose of this article is to review emerging evidence and discuss future research to further understand this phenomenon. Secondary analyses of neuropathic pain clinical trials demonstrate that pain intensity fluctuations exhibit a distinct diurnal pattern that contrasts that of nociceptive pain conditions. Ongoing preclinical investigations support the phenomenon of circadian pain fluctuations and provide the opportunity to better describe pain chronobiology and to elucidate underlying mechanisms of circadian pain rhythmicity. The observation of clinically relevant diurnal pain variability in neuropathic conditions has important implications for future research and treatment of pain. This is an immature research field, and further investigation is needed to better characterize these patterns in more detail, investigate contributory mechanisms, and to develop therapeutic strategies that exploit this phenomenon.

  14. A Mangifera indica L. extract could be used to treat neuropathic pain and implication of mangiferin.

    Science.gov (United States)

    Garrido-Suárez, Bárbara B; Garrido, Gabino; Delgado, Rene; Bosch, Fe; del C Rabí, María

    2010-12-09

    It has been accepted that neuroinflammation, oxidative stress and glial activation are involved in the central sensitization underlying neuropathic pain. Vimang is an aqueous extract of Mangifera indica L. traditionally used in Cuba for its analgesic, anti-inflammatory, antioxidant and immunomodulatory properties. Several formulations are available, and also for mangiferin, its major component. Preclinical studies demonstrated that these products prevented tumor necrosis factor α -induced IκB degradation and the binding of nuclear factor κB to DNA, which induces the transcription of genes implicated in the expression of some mediators and enzymes involved in inflammation, pain, oxidative stress and synaptic plasticity. In this paper we propose its potential utility in the neuropathic pain treatment. This hypothesis is supported in the cumulus of preclinical and clinical evidence around the extract and mangiferin, its major component, and speculates about the possible mechanism of action according to recent advances in the physiopathology of neuropathic pain.

  15. Peripheral Neuropathic Pain: A mechanism-related organizing principle based on sensory profiles

    DEFF Research Database (Denmark)

    Baron, Ralf; Maier, Christoph; Attal, Nadine

    2017-01-01

    on Neuropathic Pain (DFNS), IMI-Europain, Neuropain).Standardized quantitative sensory testing (QST) was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping we performed a cluster analysis using 13 QST parameters.Three distinct...... with different sensory profiles might respond differently to treatment.The aim of the investigation was to identify subgroups in a large sample of neuropathic pain patients using hypothesis-free statistical methods on the database of three large multi-national research networks (German Research Network...... subgroups with characteristic sensory profiles were identified and replicated: Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination...

  16. Anti-hypernociceptive effect of mangiferin in persistent and neuropathic pain models in rats.

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    Garrido-Suárez, Bárbara B; Garrido, Gabino; Castro-Labrada, Marian; Merino, Nelson; Valdés, Odalys; Rodeiro, Idania; Hernández, Ivonnes; Godoy-Figueiredo, Jozi; Ferreira, Sergio H; Delgado-Hernández, René

    2014-09-01

    The present study examines the possible effect of the glucosylxanthone mangiferin (MG) on pain-related behaviors in a tonic acute pain model (formalin test at 5%) and in a chronic constriction injury (CCI) model to clarify the underlying transient and long-term mechanisms. Acute administration of MG (10-100mg/kg, i.p.) reduced licking/biting exclusivity in the tonic phase of formalin test in a naloxone and yohimbine-sensitive manner. This effect was enhanced by a nonselective nitric oxide synthase (NOS) inhibitor (NG-monomethyl-L-arginine) and by a non-competitive N-methyl-D-aspartate (NMDA) antagonist (ketamine), but it was reversed by the NOS substrate (L-arginine). Pre-treatment with intrathecal yohimbine prevented the anti-hypernociceptive effect of systemic MG. Pre-treatment during 4 days before surgical and 3 days after CCI with MG (50mg/kg, i.p.) reduced mechanical hypernociception and decreased the signs of Wallerian degeneration (WD) of the sciatic nerve. MG improved the PC-12 cellular viability exposure to glutamate-mediated neuronal death, also involved in neuropathic pain. The findings of this study suggest that MG shows ability to decrease tonic pain in the formalin test. A transient activity of this xanthone on nociceptive pathways mediated by α2 adrenergic receptors in cooperation with the opioid system could be involved, at least in part, in this effect. Its neuroprotective effect by preventing WD in mononeuropathic rats could be implicated in the mechano-antihypernociceptive long term mechanisms.

  17. Characterisation of a peripheral neuropathic component of the rat monoiodoacetate model of osteoarthritis.

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    Matthew Thakur

    Full Text Available Joint degeneration observed in the rat monoiodoacetate (MIA model of osteoarthritis shares many histological features with the clinical condition. The accompanying pain phenotype has seen the model widely used to investigate the pathophysiology of osteoarthritis pain, and for preclinical screening of analgesic compounds. We have investigated the pathophysiological sequellae of MIA used at low (1 mg or high (2 mg dose. Intra-articular 2 mg MIA induced expression of ATF-3, a sensitive marker for peripheral neuron stress/injury, in small and large diameter DRG cell profiles principally at levels L4 and 5 (levels predominated by neurones innervating the hindpaw rather than L3. At the 7 day timepoint, ATF-3 signal was significantly smaller in 1 mg MIA treated animals than in the 2 mg treated group. 2 mg, but not 1 mg, intra-articular MIA was also associated with a significant reduction in intra-epidermal nerve fibre density in plantar hindpaw skin, and produced spinal cord dorsal and ventral horn microgliosis. The 2 mg treatment evoked mechanical pain-related hypersensitivity of the hindpaw that was significantly greater than the 1 mg treatment. MIA treatment produced weight bearing asymmetry and cold hypersensitivity which was similar at both doses. Additionally, while pregabalin significantly reduced deep dorsal horn evoked neuronal responses in animals treated with 2 mg MIA, this effect was much reduced or absent in the 1 mg or sham treated groups. These data demonstrate that intra-articular 2 mg MIA not only produces joint degeneration, but also evokes significant axonal injury to DRG cells including those innervating targets outside of the knee joint such as hindpaw skin. This significant neuropathic component needs to be taken into account when interpreting studies using this model, particularly at doses greater than 1 mg MIA.

  18. The lidocaine metabolite N-ethylglycine has antinociceptive effects in experimental inflammatory and neuropathic pain.

    Science.gov (United States)

    Werdehausen, Robert; Mittnacht, Sebastian; Bee, Lucy A; Minett, Michael S; Armbruster, Anja; Bauer, Inge; Wood, John N; Hermanns, Henning; Eulenburg, Volker

    2015-09-01

    Glycine transporter 1 (GlyT1) plays a crucial role in regulating extracellular glycine concentrations and might thereby constitute a new drug target for the modulation of glycinergic inhibition in pain signaling. Consistent with this view, inhibition of GlyT1 has been found to induce antinociceptive effects in various animal pain models. We have shown previously that the lidocaine metabolite N-ethylglycine (EG) reduces GlyT1-dependent glycine uptake by functioning as an artificial substrate for this transporter. Here, we show that EG is specific for GlyT1 and that in rodent models of inflammatory and neuropathic pain, systemic treatment with EG results in an efficient amelioration of hyperalgesia and allodynia without affecting acute pain. There was no effect on motor coordination or the development of inflammatory edema. No adverse neurological effects were observed after repeated high-dose application of EG. EG concentrations both in blood and spinal fluid correlated with an increase of glycine concentration in spinal fluid. The time courses of the EG and glycine concentrations corresponded well with the antinociceptive effect. Additionally, we found that EG reduced the increase in neuronal firing of wide-dynamic-range neurons caused by inflammatory pain induction. These findings suggest that systemically applied lidocaine exerts antihyperalgesic effects through its metabolite EG in vivo, by enhancing spinal inhibition of pain processing through GlyT1 modulation and subsequent increase of glycine concentrations at glycinergic inhibitory synapses. EG and other substrates of GlyT1, therefore, may be a useful therapeutic agent in chronic pain states involving spinal disinhibition.

  19. Delta-opioid receptor analgesia is independent of microglial activation in a rat model of neuropathic pain.

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    Joanna Mika

    Full Text Available The analgesic effect of delta-opioid receptor (DOR ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p. over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t. administered morphine (10-20 µg, DAMGO (1-2 µg and U50,488H (25-50 µg were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10-20 µg, deltorphin II (1.5-15 µg and SNC80 (10-20 µg administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR and kappa-opioid receptors (KOR, further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain.

  20. Delta-opioid receptor analgesia is independent of microglial activation in a rat model of neuropathic pain.

    Science.gov (United States)

    Mika, Joanna; Popiolek-Barczyk, Katarzyna; Rojewska, Ewelina; Makuch, Wioletta; Starowicz, Katarzyna; Przewlocka, Barbara

    2014-01-01

    The analgesic effect of delta-opioid receptor (DOR) ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI) to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t.) administered morphine (10-20 µg), DAMGO (1-2 µg) and U50,488H (25-50 µg) were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10-20 µg), deltorphin II (1.5-15 µg) and SNC80 (10-20 µg) administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain.

  1. Delta-Opioid Receptor Analgesia Is Independent of Microglial Activation in a Rat Model of Neuropathic Pain

    Science.gov (United States)

    Rojewska, Ewelina; Makuch, Wioletta; Starowicz, Katarzyna; Przewlocka, Barbara

    2014-01-01

    The analgesic effect of delta-opioid receptor (DOR) ligands in neuropathic pain is not diminished in contrast to other opioid receptor ligands, which lose their effectiveness as analgesics. In this study, we examine whether this effect is related to nerve injury-induced microglial activation. We therefore investigated the influence of minocycline-induced inhibition of microglial activation on the analgesic effects of opioid receptor agonists: morphine, DAMGO, U50,488H, DPDPE, Deltorphin II and SNC80 after chronic constriction injury (CCI) to the sciatic nerve in rats. Pre-emptive and repeated administration of minocycline (30 mg/kg, i.p.) over 7 days significantly reduced allodynia and hyperalgesia as measured on day 7 after CCI. The antiallodynic and antihyperalgesic effects of intrathecally (i.t.) administered morphine (10–20 µg), DAMGO (1–2 µg) and U50,488H (25–50 µg) were significantly potentiated in rats after minocycline, but no such changes were observed after DPDPE (10–20 µg), deltorphin II (1.5–15 µg) and SNC80 (10–20 µg) administration. Additionally, nerve injury-induced down-regulation of all types of opioid receptors in the spinal cord and dorsal root ganglia was not influenced by minocycline, which indicates that the effects of opioid ligands are dependent on other changes, presumably neuroimmune interactions. Our study of rat primary microglial cell culture using qRT-PCR, Western blotting and immunocytochemistry confirmed the presence of mu-opioid receptors (MOR) and kappa-opioid receptors (KOR), further we provide the first evidence for the lack of DOR on microglial cells. In summary, DOR analgesia is different from analgesia induced by MOR and KOR receptors because it does not dependent on injury-induced microglial activation. DOR agonists appear to be the best candidates for new drugs to treat neuropathic pain. PMID:25105291

  2. Meta-analysis of placebo responses in central neuropathic pain: impact of subject, study, and pain characteristics.

    Science.gov (United States)

    Cragg, Jacquelyn J; Warner, Freda M; Finnerup, Nanna Brix; Jensen, Mark P; Mercier, Catherine; Richards, John Scott; Wrigley, Paul; Soler, Dolors; Kramer, John L K

    2016-03-01

    The placebo response is a complex construct related to psychobiological effects, as well as natural history and regression to the mean. Moreover, patient and study design characteristics have also been proposed as significantly affecting placebo responses. The aim of the current investigation was to identify factors that contribute to variable placebo responses in clinical trials involving individuals with central neuropathic pain. To this end, we performed a systematic review and meta-analysis of placebo-controlled trials examining pharmacological and noninvasive brain stimulation interventions for central neuropathic pain. Study design, subject characteristics, and pain ratings for the placebo group were extracted from each trial. Pooling of results and identification of moderating factors were carried out using random effects meta-analysis and meta-regression techniques. A total of 39 published trials met the inclusion criteria (spinal cord injury, n = 26; stroke, n = 6; multiple sclerosis, n = 7). No significant publication bias was detected. Overall, there was a significant effect for placebo to reduce central pain (-0.64, CI: -0.83 to -0.45). Smaller placebo responses were associated with crossover-design studies, longer pain duration, and greater between-subject baseline pain variability. There were no significant effects for neurological condition (stroke vs multiple sclerosis vs spinal cord injury) or the type of intervention (eg, pharmacological vs noninvasive brain stimulation). In a planned subanalysis, the severity of damage in the spinal cord also had no significant effect on the placebo response. Further study is warranted to identify factors that may explain the impact of pain duration on the placebo response at the individual subject level.

  3. Patients' Experience of therapeutic footwear whilst living at risk of neuropathic diabetic foot ulceration: an interpretative phenomenological analysis (IPA).

    Science.gov (United States)

    Paton, Joanne S; Roberts, Anne; Bruce, Graham K; Marsden, Jonathan

    2014-02-22

    Previous work has found that people with diabetes do not wear their therapeutic footwear as directed, but the thinking behind this behaviour is unclear. Adherence to therapeutic footwear advice must improve in order to reduce foot ulceration and amputation risk in people with diabetes and neuropathy. Therefore this study aimed to explore the psychological influences and personal experiences behind the daily footwear selection of individuals with diabetes and neuropathy. An interpretative phenomenological analysis (IPA) approach was used to explore the understanding and experience of therapeutic footwear use in people living at risk of diabetic neuropathic foot ulceration. This study benefited from the purposive selection of a small sample of four people and used in-depth semi structured interviews because it facilitated the deep and detailed examination of personal thoughts and feelings behind footwear selection. Four overlapping themes that interact to regulate footwear choice emerged from the analyses: a) Self-perception dilemma; resolving the balance of risk experienced by people with diabetes and neuropathy day to day, between choosing to wear footwear to look and feel normal and choosing footwear to protect their feet from foot ulceration; b) Reflective adaption; The modification and individualisation of a set of values about footwear usage created in the minds of people with diabetes and neuropathy; c) Adherence response; The realignment of footwear choice with personal values, to reinforce the decision not to change behaviour or bring about increased footwear adherence, with or without appearance management; d) Reality appraisal; A here and now appraisal of the personal benefit of footwear choice on emotional and physical wellbeing, with additional consideration to the preservation of therapeutic footwear. For some people living at risk of diabetic neuropathic foot ulceration, the decision whether or not to wear therapeutic footwear is driven by the

  4. Treatment of localized neuropathic pain of different etiologies with the 5% lidocaine medicated plaster - a case series.

    Science.gov (United States)

    Likar, Rudolf; Demschar, Susanne; Kager, Ingo; Neuwersch, Stefan; Pipam, Wolfgang; Sittl, Reinhard

    2015-01-01

    To assess the efficacy and safety of the topical 5% lidocaine medicated plaster in the treatment of localized neuropathic pain. This was a case series at an Austrian pain clinic, using retrospective analysis. Data of 27 patients treated for localized neuropathic pain with the 5% lidocaine medicated plaster were retrospectively analyzed. Assessment included changes in overall pain intensity, in intensity of different pain qualities, and of hyperalgesia and allodynia, and changes in sleep quality. Patients (17 female, ten male; mean age 53.4±11.4 years) presented mainly with dorsalgia (16 patients) or postoperative/posttraumatic pain (seven patients); one patient suffered from both. The mean overall pain intensity prior to treatment with lidocaine medicated plaster was 8.4±1.2 on the 11-point Likert scale. In the majority of cases, the lidocaine plaster was applied concomitantly with preexisting pain medication (81.5% of the patients). During the 6-month observation period, overall mean pain intensity was reduced by almost 5 points (4.98) to 3.5±2.6. Substantial reductions were also observed for neuralgiform pain (5 points from 7.9±2.6 at baseline) and burning pain (3 points from 5.2±4.1). Sleep quality improved from 4.6±2.6 at baseline to 5.5±1.8. Stratification by pain diagnosis showed marked improvements in overall pain intensity for patients with dorsalgia or postoperative/posttraumatic pain. The lidocaine plaster was well tolerated. Overall, topical treatment with the 5% lidocaine medicated plaster was associated with effective pain relief and was well tolerated.

  5. Treatment of localized neuropathic pain of different etiologies with the 5% lidocaine medicated plaster – a case series

    Science.gov (United States)

    Likar, Rudolf; Demschar, Susanne; Kager, Ingo; Neuwersch, Stefan; Pipam, Wolfgang; Sittl, Reinhard

    2015-01-01

    Objective To assess the efficacy and safety of the topical 5% lidocaine medicated plaster in the treatment of localized neuropathic pain. Study design This was a case series at an Austrian pain clinic, using retrospective analysis. Patients and methods Data of 27 patients treated for localized neuropathic pain with the 5% lidocaine medicated plaster were retrospectively analyzed. Assessment included changes in overall pain intensity, in intensity of different pain qualities, and of hyperalgesia and allodynia, and changes in sleep quality. Results Patients (17 female, ten male; mean age 53.4±11.4 years) presented mainly with dorsalgia (16 patients) or postoperative/posttraumatic pain (seven patients); one patient suffered from both. The mean overall pain intensity prior to treatment with lidocaine medicated plaster was 8.4±1.2 on the 11-point Likert scale. In the majority of cases, the lidocaine plaster was applied concomitantly with preexisting pain medication (81.5% of the patients). During the 6-month observation period, overall mean pain intensity was reduced by almost 5 points (4.98) to 3.5±2.6. Substantial reductions were also observed for neuralgiform pain (5 points from 7.9±2.6 at baseline) and burning pain (3 points from 5.2±4.1). Sleep quality improved from 4.6±2.6 at baseline to 5.5±1.8. Stratification by pain diagnosis showed marked improvements in overall pain intensity for patients with dorsalgia or postoperative/posttraumatic pain. The lidocaine plaster was well tolerated. Conclusion Overall, topical treatment with the 5% lidocaine medicated plaster was associated with effective pain relief and was well tolerated. PMID:25565882

  6. The astrocyte-targeted therapy by Bushi for the neuropathic pain in mice.

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    Keisuke Shibata

    Full Text Available BACKGROUND: There is accumulating evidence that the activation of spinal glial cells, especially microglia, is a key event in the pathogenesis of neuropathic pain. However, the inhibition of microglial activation is often ineffective, especially for long-lasting persistent neuropathic pain. So far, neuropathic pain remains largely intractable and a new therapeutic strategy for the pain is still required. METHODS/PRINCIPAL FINDINGS: Using Seltzer model mice, we investigated the temporal aspect of two types of neuropathic pain behaviors, i.e., thermal hyperalgesia and mechanical allodynia, as well as that of morphological changes in spinal microglia and astrocytes by immunohistochemical studies. Firstly, we analyzed the pattern of progression in the pain behaviors, and found that the pain consisted of an "early induction phase" and subsequent "late maintenance phase". We next analyzed the temporal changes in spinal glial cells, and found that the induction and the maintenance phase of pain were associated with the activation of microglia and astrocytes, respectively. When Bushi, a Japanese herbal medicine often used for several types of persistent pain, was administered chronically, it inhibited the maintenance phase of pain without affecting the induction phase, which was in accordance with the inhibition of astrocytic activation in the spinal cord. These analgesic effects and the inhibition of astrocytic activation by Bushi were mimicked by the intrathecal injection of fluorocitrate, an inhibitor of astrocytic activation. Finally, we tested the direct effect of Bushi on astrocytic activation, and found that Bushi suppressed the IL-1β- or IL-18-evoked ERK1/2-phosphorylation in cultured astrocytes but not the ATP-evoked p38- and ERK1/2-phosphorylation in microglia in vitro. CONCLUSIONS: Our results indicated that the activation of spinal astrocytes was responsible for the late maintenance phase of neuropathic pain in the Seltzer model mice and

  7. Neuropathic pain in ankylosing spondylitis: a psychophysics and brain imaging study.

    Science.gov (United States)

    Wu, Qi; Inman, Robert D; Davis, Karen D

    2013-06-01

    To determine whether there is a neuropathic component in ankylosing spondylitis (AS) back pain and to delineate gray matter brain abnormalities associated with AS. Seventeen patients with back pain secondary to AS who were not receiving biologic agents and 17 age- and sex-matched healthy controls consented to participate in the study and were assessed using the painDETECT instrument (scores of ≤12 indicating low probability of neuropathic pain) and the McGill Pain Questionnaire. Mechanical and thermal thresholds were determined in all subjects, and brain gray matter was assessed by 3T magnetic resonance imaging. Eleven of the 17 AS patients had painDETECT scores of >12. The patients had decreased mechanical and cold sensitivity on the dorsum of their feet but did not have altered pain thresholds. Compared to controls, the AS patients exhibited cortical thinning in the primary somatosensory, insular, anterior cingulate, and anterior mid-cingulate cortices and the supplemental motor area, and increased gray matter volume in the thalamus and putamen. Scores on the painDETECT in AS patients were correlated with decreased gray matter in the primary somatosensory cortex and with increased gray matter in the motor cortex, anterior cingulate cortex, prefrontal cortex, thalamus, and striatum. The present findings indicate that neuropathic pain occurs in AS. Furthermore, abnormal brain gray matter and neural correlates of neuropathic pain are concordant with the clinical picture of AS, which includes sensorimotor and mood deficits as well as neuropathic pain symptoms. These results suggest that back pain in AS is a mixed pain condition that includes a neuropathic pain component. Copyright © 2013 by the American College of Rheumatology.

  8. Pattern of neuropathic pain induced by topical capsaicin application in healthy subjects.

    Science.gov (United States)

    Lötsch, Jörn; Dimova, Violeta; Hermens, Hanneke; Zimmermann, Michael; Geisslinger, Gerd; Oertel, Bruno G; Ultsch, Alfred

    2015-03-01

    Human experimental pain models are widely used to study drug effects under controlled conditions, but they require further optimization to better reflect clinical pain conditions. To this end, we measured experimentally induced pain in 110 (46 men) healthy volunteers. The quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain) was applied on untreated ("control") and topical capsaicin-hypersensitized ("test") skin. Z-transformed QST-parameter values obtained at the test site were compared with corresponding values published from 1236 patients with neuropathic pain using Bayesian statistics. Subjects were clustered for the resemblance of their QST pattern to neuropathic pain. Although QST parameter values from the untreated site agreed with reference values, several QST parameters acquired at the test site treated with topical capsaicin deviated from normal. These deviations resembled in 0 to 7 parameters of the QST pattern observed in patients with neuropathic pain. Higher degrees (50%-60%) of resemblance to neuropathic QST pattern were obtained in 18% of the subjects. Inclusion in the respective clusters was predictable at a cross-validated accuracy of 86.9% by a classification and regression tree comprising 3 QST parameters (mechanical pain sensitivity, wind-up ratio, and z-transformed thermal sensory limen) from the control sites. Thus, we found that topical capsaicin partly induced the desired clinical pattern of neuropathic pain in a preselectable subgroup of healthy subjects to a degree that fuels expectations that experimental pain models can be optimized toward mimicking clinical pain. The subjects, therefore, qualify for enrollment in analgesic drug studies that use highly selected cohorts to enhance predictivity for clinical analgesia.

  9. Towards a definition of refractory neuropathic pain for epidemiological research. An international Delphi survey of experts

    Science.gov (United States)

    2012-01-01

    Background Best current estimates of neuropathic pain (NeuP) prevalence come from studies using various screening detecting pain with probable neuropathic features; the proportion experiencing significant, long-term NeuP, and the proportion not responding to standard treatment are unknown. These “refractory” cases are the most clinically important to detect, being the most severe, requiring specialist treatment. Methods We report an international Delphi survey of experts in NeuP, aiming for consensus on the features required to define, for epidemiological research: (1) neuropathic pain; and (2) when NeuP is “refractory”. A web-based questionnaire was developed and data collected from three rounds of questionnaires from nineteen experts. Results There was good consensus on essential inclusion of six items to identify NeuP (“prickling, tingling, pins & needles”, “pain evoked by light touch”, “electric shocks or shooting pain”, “hot or burning” pain, “brush allodynia on self-examination”, and “relevant history”) and on some items that were non-essential. Consensus was also reached on components of a “refractory NeuP” definition: minimum duration (one year); number of trials of drugs of known effectiveness (four); adequate duration of these trials (three months / maximum tolerated); outcomes of treatment (pain severity, quality of life). Further work needs to validate these proposed criteria in general population research. Conclusions This paper presents an international consensus on measuring the epidemiology of refractory neuropathic pain. This will be valuable in reaching an agreed estimate of the prevalence of neuropathic pain, and the first estimate of refractory neuropathic pain prevalence. PMID:22640002

  10. Exploring acute-to-chronic neuropathic pain in rats after contusion spinal cord injury.

    Science.gov (United States)

    Gaudet, Andrew D; Ayala, Monica T; Schleicher, Wolfgang E; Smith, Elana J; Bateman, Emily M; Maier, Steven F; Watkins, Linda R

    2017-09-01

    Spinal cord injury (SCI) causes chronic pain in 65% of individuals. Unfortunately, current pain management is inadequate for many SCI patients. Rodent models could help identify how SCI pain develops, explore new treatment strategies, and reveal whether acute post-SCI morphine worsens chronic pain. However, few studies explore or compare SCI-elicited neuropathic pain in rats. Here, we sought to determine how different clinically relevant contusion SCIs in male and female rats affect neuropathic pain, and whether acute morphine worsens later chronic SCI pain. First, female rats received sham surgery, or 150kDyn or 200kDyn midline T9 contusion SCI. These rats displayed modest mechanical allodynia and long-lasting thermal hyperalgesia. Next, a 150kDyn (1s dwell) midline contusion SCI was performed in male and female rats. Interestingly, males, but not females showed SCI-elicited mechanical allodynia; rats of both sexes had thermal hyperalgesia. In this model, acute morphine treatment had no significant effect on chronic neuropathic pain symptoms. Unilateral SCIs can also elicit neuropathic pain that could be exacerbated by morphine, so male rats received unilateral T13 contusion SCI (100kDyn). These rats exhibited significant, transient mechanical allodynia, but not thermal hyperalgesia. Acute morphine did not exacerbate chronic pain. Our data show that specific rat contusion SCI models cause neuropathic pain. Further, chronic neuropathic pain elicited by these contusion SCIs was not amplified by our course of early post-trauma morphine. Using clinically relevant rat models of SCI could help identify novel pain management strategies. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Moringa oleifera Leaves Extract Attenuates Neuropathic Pain Induced by Chronic Constriction Injury

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    Jurairat Khongrum

    2012-01-01

    Full Text Available Problem statement: Neuropathic pain, a challenge of this decade, has been reported to be associated with the diversity conditions including diabetes. At present, there are no conventional analgesics that can effectively treat neuropathic pain with a satisfactory outcome. Due to the limitation of therapeutic efficacy, the searching for novel effective remedies in the management of neuropathic pain is required. Approach: Male Wistar rats, weighing 180-220 g were induced diabetes mellitus by Streptozotocin (STZ (single injection, 65 mg kg-1 BW, i.p. Diabetic rats were induced neuropathic pain by Constricting the right sciatic nerve (CCI at permanently. Then, all rats were administered the extract of M. oleifera leaves at doses of 100, 200 and 300 mg kg-1 BW once daily in a period of 21 days. The analgesic effect of the plant extract was evaluated using Von Frey filament and hot plate tests every 3 days after CCI throughout 21-day experimental period. In addition, at the end of the experiment, the alteration of oxidative damage markers including MDA level and the activities of SOD, CAT and GSH-PX in the injured sciatic nerve were also evaluated. Results: The current results showed that rats subjected to M.oleifera leaves extract at doses of 100 and 200 mg kg-1 BW significantly reversed the decreased withdrawal threshold intensity and withdrawal latency in Von Frey filament and hot plate tests respectively. In addition, rats subjected to the medium dose extract also reversed the decreased activities of SOD and GSH-Px and the elevation of MDA level in the injured nerve. Taken all together, our data suggest that M. oleifera leaves extract can attenuate neuropathic pain in diabetic condition. The possible underlying mechanism may occur partly via the decreased oxidative stress. However, other mechanisms may also involve. Conclusion: Our results suggest that M. oleifera leaves may be the potential novel adjuvant therapy for neuropathic pain management.

  12. Learning and memory in mice with neuropathic pain: impact of old age and progranulin deficiency

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    Boris eAlbuquerque

    2013-11-01

    Full Text Available Persistent neuropathic pain is a frequent consequence of peripheral nerve injuries, particularly in the elderly. Using the IntelliCage we studied if a sciatic nerve injury obstructed learning and memory in young and aged mice, each in wild type and progranulin deficient mice, which develop premature signs of brain aging and are more susceptible to nerve injury evoked nociceptive hypersensitivity and hence allow to assess a potential mutual aggravation of pain and old age. Both young and aged mice developed long-term nerve injury-evoked hyperalgesia and allodynia but, in both genotypes, only aged mice with neuropathic pain showed high error rates in place avoidance acquisition tasks. Once learnt however, aged mice with neuropathic pain maintained the aversive memory longer, i.e. the extinction was significantly slowed. In addition, nerve injury in progranulin deficient mice impaired the learning of spatial sequences of awarded places, particularly in aged mice, whereas easy place preference learning was not affected by nerve injury or progranulin deficiency. The sequencing task required a discrimination of clockwise and anti-clockwise sequences and spatial flexibility to re-learn a novel sequence. The loss of spatial flexibility did not occur in sham operated mice, i.e. was a consequence of nerve injury and suggests that neuropathic pain accelerates manifestations of old age and progranulin deficiency. Neuropathic pain at old age, irrespective of the genotype, resulted in a long maintenance of aversive memory suggesting a negative alliance and possibly mutual aggravation of chronic neuropathic pain and aversive memory at old age.

  13. Effect of Botulinum Toxin on Disabling Neuropathic Pain: A Case Presentation Suggesting a New Therapeutic Strategy.

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    Buonocore, Michelangelo; Demartini, Laura; Mandrini, Silvia; Dall'Angelo, Anna; Dalla Toffola, Elena

    2017-02-01

    This case presentation describes a 47-year-old woman who developed complex regional pain syndrome type II with severe neuropathic pain following iatrogenic transection of the tibial nerve at the ankle. The pain and disability progressively worsened over time, markedly impaired ambulation, and were not relieved despite various analgesic treatments. After injection of botulinum toxin (abobotulinumtoxinA, BoNT-A) in the leg muscles the tendons of which pass through the tarsal tunnel (together with the tibial nerve), her pain decreased and her walking capacity improved. This case suggests a new therapeutic role for botulin toxin in treating peripheral neuropathic pain caused by movement-evoked ectopic potentials.

  14. Individual differences in the sensitivity of cold allodynia to phentolamine in neuropathic rats.

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    Kim, Sun Kwang; Min, Byung-Il; Kim, Ji Hoon; Hwang, Byung Gil; Yoo, Gi Yong; Park, Dong Suk; Na, Heung Sik

    2005-10-31

    In neuropathic rats sensitive to phentolamine (alpha-adrenoreceptor antagonist, 2 mg/kg, i.p.), prazosin (alpha1-adrenoreceptor antagonist, 0.5 mg/kg, i.p.) significantly attenuated cold allodynia whereas yohimbine (alpha2-adrenoreceptor antagonist, 0.5 mg/kg, i.p.) had no significant effect. In neuropathic rats insensitive to phentolamine, yohimbine significantly exacerbated cold allodynia whereas prazosin had no significant effect. These results suggest that the individual differences in the sensitivity of cold allodynia to phentolamine may be due to the difference in the alpha-adrenoreceptor subtype predominantly involved in cold allodynia.

  15. Reduction of follistatin-like 1 in primary afferent neurons contributes to neuropathic pain hypersensitivity

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    Kai-Cheng Li; Feng Wang; Yan-Qing Zhong; Ying-Jin Lu; Qiong Wang; Fang-Xiong Zhang; Hua-Sheng Xiao; Lan Bao; Xu Zhang

    2011-01-01

    @@ Dear Editor, Nerve injury-induced neuropathic pain is difficult to treat in clinic.Lack of comprehensive understanding of the mechanism underlying such chronic pain hypersensitivity delays the development of more effective therapy.Accumulated evidence shows that peripheral nerve injury alters the expression of many neurotransmitters, receptors, ion channels and signaling molecules in the dorsal root ganglion (DRG) and the dorsal horn of spinal cord [1].Some of these molecular changes in the pain pathway are correlated with the current therapy for neuropathic pain.

  16. [Pregabalin--profile of efficacy and tolerability in neuropathic pain].

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    Stump, Patrick

    2009-10-01

    Pregabalin (PGB), like its predecessor gabapentin, is a structural analogue (but not functional) of the gammaaminobutyric acid (GABA). PGB has analgesic, antoconvulsivant, and ansiolytic activities. Neuropathic pain (NP) initial recommended dose is 150 mg per day. Depending on the patient response or bodily resistance to the drug the initial dose can be increased up to 300 mg per day (divided in 2-3 daily doses) during a one-week period. PGB is quickly absorbed in the digestive system with high oral biodisponibility. The drug is eliminated almost exclusively by renal excretion (98%). PGB efficacy was evaluated by several studies by means of visual analog scales (VAS) in several NP conditions such as post-herpetic neuropathy (PHN) or painful diabetic neuropathy (PDN). When compared with placebo, PGB provided significant benefit with 150 mg doses in the treatment of PHN pain. In studies developed in patients with PDN, the significant difference between placebo and treatment group only was achieved in individuals with daily doses of 300 mg/day, and the response was clearly dose-dependent. Tolerability information obtained from a number of studies has shown that the drug has a very good safety and tolerability profile. Side effects were mild to moderate and dose-dependent. Based on controlled studies, the main adverse effects observed with PGB are dizziness (23.1%), drowsiness (14.6%), and peripheral aedema (10.4%). As these side effects are dosedependent, they can be easily managed by a simple dose reduction, with no need to discontinue the therapy. Thus, according to efficacy and tolerability data, PGB is an important therapeutic option in NP treatment.

  17. Identification of therapeutic targets in a model of neuropathic pain

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    Hemalatha B Raju

    2014-05-01

    Full Text Available Neuropathic pain (NP is caused by damage to the nervous system, resulting in dysfunction and aberrant pain. The cellular functions (e.g. peripheral neuron spinal cord innervation, neuronal excitability associated with NP often develop over time and are likely associated with gene expression changes. Gene expression studies on the cells involved in NP (e.g. sensory dorsal root ganglion neurons are publically available; the mining of these studies may enable the identification of novel targets and the subsequent development of therapies that are essential for improving quality of life for the millions of individuals suffering with NP. Here we analyzed a publically available microarray dataset (GSE30165 in order to identify new RNAs (e.g. messenger RNA isoforms and non-coding RNAs underlying NP. GSE30165 profiled gene expression in dorsal root ganglion neurons (DRG and in sciatic nerve (SN after resection, a NP model. Gene ontological analysis shows enrichment for sensory and neuronal processes. Protein network analysis demonstrates DRG upregulated genes typical to an injury and NP response. Of the top changing genes, 34% and 36% are associated with more than one protein coding isoform in the dorsal root ganglia (DRG and sciatic nerve (SN respectively. The majority of genes are receptor and enzymes. We identified fifteen long non-coding RNAs (lncRNAs targeting these genes in LNCipedia.org, an online comprehensive lncRNA database. These RNAs represent new therapeutic targets for preventing NP development and this approach demonstrates the feasibility of data reanalysis for their identification.

  18. Blockade of P2X4 Receptors Inhibits Neuropathic Pain-Related Behavior by Preventing MMP-9 Activation and, Consequently, Pronociceptive Interleukin Release in a Rat Model

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    Jurga, Agnieszka M.; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2017-01-01

    Neuropathic pain is still an extremely important problem in today’s medicine because opioids, which are commonly used to reduce pain, have limited efficacy in this type of pathology. Therefore, complementary therapy is needed. Our experiments were performed in rats to evaluate the contribution of the purinergic system, especially P2X4 receptor (P2X4R), in the modulation of glia activation and, consequently, the levels of nociceptive interleukins after chronic constriction injury (CCI) of the right sciatic nerve, a rat model of neuropathic pain. Moreover, we studied how intrathecal (ith.) injection of a P2X4R antagonist Tricarbonyldichlororuthenium (II) dimer (CORM-2) modulates nociceptive transmission and opioid effectiveness in the CCI model. Our results demonstrate that repeated ith. administration of CORM-2 once daily (20 μg/5 μl, 16 and 1 h before CCI and then daily) for eight consecutive days significantly reduced pain-related behavior and activation of both spinal microglia and/or astroglia induced by CCI. Moreover, even a single administration of CORM-2 on day 7 after CCI attenuated mechanical and thermal hypersensitivity as efficiently as morphine and buprenorphine. In addition, using Western blot, we have shown that repeated ith. administration of CORM-2 lowers the CCI-elevated level of MMP-9 and pronociceptive interleukins (IL-1β, IL-18, IL-6) in the dorsal L4-L6 spinal cord and/or DRG. Furthermore, in parallel, CORM-2 upregulates spinal IL-1Ra; however, it does not influence other antinociceptive factors, IL-10 and IL-18BP. Additionally, based on our biochemical results, we hypothesize that p38MAPK, ERK1/2 and PI3K/Akt but not the NLRP3/Caspase-1 pathway are partly involved in the CORM-2 analgesic effects in rat neuropathic pain. Our data provide new evidence that P2X4R may indeed play a significant role in neuropathic pain development by modulating neuroimmune interactions in the spinal cord and DRG, suggesting that its blockade may have potential

  19. Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and tactile allodynia in a rodent model of neuropathic pain.

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    Shigeo Hasegawa

    Full Text Available BACKGROUND: Neuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A(2 (cPLA(2 in injured dorsal root ganglion (DRG neurons that contribute to tactile allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA(2 activation to produce tactile allodynia remain to be determined. PRINCIPAL FINDINGS: Here we provide evidence that platelet-activating factor (PAF is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs reduced the development and expression of tactile allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced tactile allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor alpha (TNFalpha and interleukin-1beta (IL-1beta expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of naïve rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFalpha and IL-1beta, both of which were inhibited by pretreatment with a PAFR antagonist. CONCLUSIONS: Our results indicate that the PAF/PAFR system has an important role in production of TNFalpha and IL-1beta in the DRG and tactile allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.

  20. Gene transfer of GLT-1, a glial glutamate transporter, into the spinal cord by recombinant adenovirus attenuates inflammatory and neuropathic pain in rats

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    Nakagawa Takayuki

    2008-12-01

    Full Text Available Abstract Background The glial glutamate transporter GLT-1 is abundantly expressed in astrocytes and is crucial for glutamate removal from the synaptic cleft. Decreases in glutamate uptake activity and expression of spinal glutamate transporters are reported in animal models of pathological pain. However, the lack of available specific inhibitors and/or activators for GLT-1 makes it difficult to determine the roles of spinal GLT-1 in inflammatory and neuropathic pain. In this study, we examined the effect of gene transfer of GLT-1 into the spinal cord with recombinant adenoviruses on the inflammatory and neuropathic pain in rats. Results Intraspinal infusion of adenoviral vectors expressing the GLT-1 gene increased GLT-1 expression in the spinal cord 2–21 days after the infusion. Transgene expression was primarily localized to astrocytes. The spinal GLT-1 gene transfer had no effect on acute mechanical and thermal nociceptive responses in naive rats, whereas it significantly reduced the inflammatory mechanical hyperalgesia induced by hindlimb intraplantar injection of carrageenan/kaolin. Spinal GLT-1 gene transfer 7 days before partial sciatic nerve ligation recovered the extent of the spinal GLT-1 expression in the membrane fraction that was decreased following the nerve ligation, and prevented the induction of tactile allodynia. However, the partial sciatic nerve ligation-induced allodynia was not reversed when the adenoviruses were infused 7 or 14 days after the nerve ligation. Conclusion These results suggest that overexpression of GLT-1 on astrocytes in the spinal cord by recombinant adenoviruses attenuates the induction, but not maintenance, of inflammatory and neuropathic pain, probably by preventing the induction of central sensitization, without affecting acute pain sensation. Upregulation or functional enhancement of spinal GLT-1 could be a novel strategy for the prevention of pathological pain.

  1. Pain severity and the economic burden of neuropathic pain in the United States: BEAT Neuropathic Pain Observational Study

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    Schaefer C

    2014-10-01

    Full Text Available Caroline Schaefer,1 Alesia Sadosky,2 Rachael Mann,3 Shoshana Daniel,4 Bruce Parsons,2 Michael Tuchman,5 Alan Anschel,6 Brett R Stacey,7 Srinivas Nalamachu,8 Edward Nieshoff9 1Covance Market Access Services Inc., Gaithersburg, MD, 2Pfizer, Inc., New York, NY, 3Covance Market Access Services Inc., San Diego, CA, 4Covance Market Access Services Inc., Conshohocken, PA, 5Palm Beach Neurological Center, Palm Beach Gardens, FL, 6Rehabilitation Institute of Chicago, Chicago, IL, 7Oregon Health and Science University, Portland, OR, 8International Clinical Research Institute, Overland Park, KS, 9Rehabilitation Institute of Michigan/Wayne State University, Detroit, MI, USABackground: As with many chronic conditions, patients with neuropathic pain (NeP are high consumers of health care resources. However, limited literature exists on the economic burden of NeP, including its impact on productivity. The aim of this study was to characterize health care resource utilization, productivity, and costs associated with NeP by pain severity level in US adults.Methods: Subjects (n=624 with painful diabetic peripheral neuropathy, human immunodeficiency virus-related peripheral NeP, post-trauma/post-surgical NeP, spinal cord injury with NeP, chronic low back pain with NeP, and small fiber neuropathy were recruited during routine office visits to US community-based general practitioners and specialists. Clinicians captured clinical characteristics, NeP-related medications, and health care resource utilization based on 6-month retrospective medical chart review. Subjects completed questionnaires on demographics, pain/symptoms, costs, and productivity. Brief Pain Inventory pain severity scores were used to classify subjects by mild, moderate, or severe pain. Annualized NeP-related costs (adjusted for covariates were estimated, and differences across pain severity groups were evaluated.Results: In total, 624 subjects were recruited (mean age 55.5±13.7 years; 55.4% male

  2. Schwann cell autophagy counteracts the onset and chronification of neuropathic pain.

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    Marinelli, Sara; Nazio, Francesca; Tinari, Antonella; Ciarlo, Laura; D'Amelio, Marcello; Pieroni, Luisa; Vacca, Valentina; Urbani, Andrea; Cecconi, Francesco; Malorni, Walter; Pavone, Flaminia

    2014-01-01

    Axonal degeneration in peripheral nerves after injury is accompanied by myelin degradation initiated by Schwann cells (SCs). These cells activate autophagy, a ubiquitous cytoprotective process essential for degradation and recycling of cellular constituents. Concomitantly to nerve insult and axonal degeneration, neuropathic pain (NeP) arises. The role of SC autophagy in the mechanisms underlying NeP is still unknown. In this study, we examined the role of the autophagy during the early phase of Wallerian degeneration in NeP induction and chronification by using a murine model of peripheral nerve lesion (chronic constriction injury). We demonstrate that the autophagy inducer rapamycin, administered in the first week after nerve damage, induces long-lasting analgesic and antiinflammatory effects, facilitates nerve regeneration, and prevents pain chronification. Conversely, when autophagy is altered, by means of autophagic inhibitor 3-methyladenine administration or as occurs in activating molecule in Beclin-1-regulated autophagy transgenic mice (Ambra1(+/gt)), NeP is dramatically enhanced and prolonged. Immunohistochemical and ultrastructural evaluations show that rapamycin is able to increase autophagic flux in SCs, to accelerate myelin compaction, and to reduce inflammatory and immune reaction. Proteomic analysis combined with bioinformatic analysis suggests that a redox-sensitive mechanism could be responsible for SC autophagy activation. These data suggest that a deficiency of autophagic activity in SCs can be an early event in the origin of NeP chronification and that autophagy modulation may represent a powerful pharmacological approach to prevent the onset and chronification of NeP in the clinical setting.

  3. Prevalence and associations of neuropathic pain in a cohort of multi-ethnic Asian low back pain patients.

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    Kew, Yueting; Tan, Cheng-Yin; Ng, Chong-Jing; Thang, Sue-Sien; Tan, Leong-Hooi; Khoo, Yvonne Khaii; Lim, Jun-Ni; Ng, Jia-Hui; Chan, Chris Yin-Wei; Kwan, Mun-Keong; Goh, Khean-Jin

    2017-04-01

    The prevalence of neuropathic low back pain differs in different ethnic populations. The aims of the study are to determine its frequency and associations in a multi-ethnic cohort of Asian low back pain patients. This was a cross-sectional study of low back patients seen at the University of Malaya Medical Centre, Kuala Lumpur, Malaysia. Neuropathic low back pain patients were identified using the painDETECT questionnaire and compared with non-neuropathic (unclear or nociceptive) low back pain patients, in terms of socio-demographic and clinical factors, pain severity (numerical pain rating scale, NPRS), disability (Roland Morris Disability Questionnaire, RMDQ), as well as anxiety and depression (Hospital Anxiety and Depression Scale, HADS). Of 210 patients, 26 (12.4%) have neuropathic low back pain. Neuropathic pain is associated with non-Chinese ethnicity, higher body mass index and pain radiation below the knee. Patients with neuropathic pain have significantly higher NPRS and RMDQ scores, and there are more subjects with anxiety on HADS. However, there are no differences between the groups in age, gender, pain duration or underlying diagnosis of low back pain. The prevalence of neuropathic low back pain in a multi-ethnic Malaysian cohort is lower than previously reported in other populations with possible differences between ethnic groups. It is associated with greater pain severity, disability and anxiety.

  4. Medial plantar nerve ligation as a novel model of neuropathic pain in mice: pharmacological and molecular characterization

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    Sant’Anna, Morena B.; Kusuda, Ricardo; Bozzo, Tiago A.; Bassi, Gabriel S.; Alves-Filho, José C.; Cunha, Fernando Q.; Ferreira, Sergio H.; Souza, Guilherme R.; Cunha, Thiago M.

    2016-01-01

    Peripheral neuropathic pain is a consequence of an injury/disease of the peripheral nerves. The mechanisms involved in its pathophysiology are not entirely understood. To better understand the mechanisms involved in the development of peripheral nerve injury-induced neuropathic pain, more experimental models are required. Here, we developed a novel peripheral neuropathic pain model in mice by using a minimally invasive surgery and medial plantar nerve ligation (MPNL). After MPNL, mechanical allodynia was established, and mice quickly recovered from the surgery without any significant motor impairment. MPNL causes an increased expression of ATF-3 in the sensory neurons. At 14 days after surgery, gabapentin was capable of reversing the mechanical allodynia, whereas anti-inflammatory drugs and opioids were ineffective. MPNL-induced neuropathic pain was mediated by glial cells activation and the production of TNF-α and IL-6 in the spinal cord. These results indicate MPNL as a reasonable animal model for the study of peripheral neuropathic pain, presenting analgesic pharmacological predictivity to clinically used drugs. The results also showed molecular phenotypic changes similar to other peripheral neuropathic pain models, with the advantage of a lack of motor impairment. These features indicate that MPNL might be more appropriate for the study of neuropathic pain than classical models. PMID:27230787

  5. Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats.

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    Liu, Su; Liu, Yue-Peng; Huang, Zhi-Jiang; Zhang, Yan-Kai; Song, Angela A; Ma, Ping-Chuan; Song, Xue-Jun

    2015-12-01

    Treating neuropathic pain continues to be a major clinical challenge and underlying mechanisms of neuropathic pain remain elusive. We have recently demonstrated that Wnt signaling, which is important in developmental processes of the nervous systems, plays critical roles in the development of neuropathic pain through the β-catenin-dependent pathway in the spinal cord and the β-catenin-independent pathway in primary sensory neurons after nerve injury. Here, we report that Wnt signaling may contribute to neuropathic pain through the atypical Wnt/Ryk signaling pathway in rats. Sciatic nerve injury causes a rapid-onset and long-lasting expression of Wnt3a, Wnt5b, and Ryk receptors in primary sensory neurons, and dorsal horn neurons and astrocytes. Spinal blocking of the Wnt/Ryk receptor signaling inhibits the induction and persistence of neuropathic pain without affecting normal pain sensitivity and locomotor activity. Blocking activation of the Ryk receptor with anti-Ryk antibody, in vivo or in vitro, greatly suppresses nerve injury-induced increased intracellular Ca and hyperexcitability of the sensory neurons, and also the enhanced plasticity of synapses between afferent C-fibers and the dorsal horn neurons, and activation of the NR2B receptor and the subsequent Ca-dependent signals CaMKII, Src, ERK, PKCγ, and CREB in sensory neurons and the spinal cord. These findings indicate a critical mechanism underlying the pathogenesis of neuropathic pain and suggest that targeting the Wnt/Ryk signaling may be an effective approach for treating neuropathic pain.

  6. Endogenous CBS-H2S Pathway Contributes to the Development of CCI-Induced Neuropathic Pain.

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    Gui, Yulong; Li, Aiyuan; Qiu, Bihui; Chen, Feng; Chen, Liang; Liu, Daming; Chen, Shuxian; Zhou, Wei; Zhou, Hong

    2016-06-01

    Studies showed a complex relationship between hydrogen sulfide (H2S) and neuropathic pain. In this study, the relationship between endogenous CBS-H2S pathway in L4-6 spinal cord and neuropathic pain was explored. A total of 163 adult Kunming mice were used in this study. CBS expression and H2S formation in L4-6 spinal cord were detected in the development of neuropathic pain firstly. Then, effect of AOAA, an CBS inhibitor, on treatment of neuropathic pain by chronic construction injury surgery (CCI) was detected. Pain thresholds and activation of NF-κB(p65), ERK1/2 and CREB were measured as biomarks of neuropathic pain. Results showed that CCI surgery significantly upregulated protein expression of CBS and H2S formation. Correlation analysis showed pain thresholds had negative relationships with protein expression of CBS and H2S formation. Treatment with AOAA, a CBS inhibitor, inhibited CCI-induced upregulation of CBS expression and H2S formation (P H2S pathway promoted the development of neuropathic pain. CBS-H2S pathway could be a promising target for treatment of neuropathic pain.

  7. Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain?

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    Truini, A; Biasiotta, A; Di Stefano, G; Leone, C; La Cesa, S; Galosi, E; Piroso, S; Pepe, A; Giordano, C; Cruccu, G

    2014-04-01

    The different neuropathic pain types (e.g., ongoing burning pain and allodynia) are frequent and disabling complaints in patients with peripheral neuropathies. Although the reference standard technique for diagnosing painful small-fibre neuropathies is nerve fibre density assessment by skin biopsy, the relationship between the epidermal nerve fibre (ENF) density and neuropathic pain is still unclear. In a clinical and skin biopsy study designed to investigate whether changes in ENF density are directly related to pain, we enrolled 139 consecutive patients with distal symmetric peripheral neuropathy. All patients underwent clinical examination. The Neuropathic Pain Symptom Inventory was used to distinguish the different neuropathic pain types. A skin biopsy was conducted, and ENFs were immunostained with the antiprotein gene product 9.5, and their linear density was quantified with bright-field microscopy. No difference was found in ENF density between patients with and without neuropathic pain, nor between patients with and without ongoing burning pain. Conversely, ENF density was higher in patients with provoked pains (including mechanical dynamic allodynia) than in those without. The variable association between ENF density and symptoms of neuropathic pain supports the idea that neuropathic pain symptoms arise through distinct underlying mechanisms. The lack of relationship between ongoing burning pain and ENF density suggests that this type of pain reflects factors other than loss of nociceptive afferents. The association between ENF density and provoked pain (including mechanical dynamic allodynia) suggests that this type of pain might be mediated by spared and sensitised nociceptive afferents.

  8. The Effect of Intrathecal Administration of Muscimol on Modulation of Neuropathic Pain Symptoms Resulting from Spinal Cord Injury; an Experimental Study

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    Marjan Hosseini

    2014-09-01

    Full Text Available Introduction: Neuropathic pain can be very difficult to treat and it is one of the important medical challenging about pain treatments. Muscimol as a new agonist of gamma-Aminobutyric acid receptor type A (GABAA have been introduced for pain management. Thus, the present study was performed to evaluate the pain alleviating effect of intrathecal injection of different doses of muscimol as GABAA receptor agonist in spinal cord injury (SCI model of neuropathic pain. Methods: In the present experimental study male Wistar rats were treated by muscimol 0.01, 0.1 or 1 µg/10ul, intrathecally (i.t. three weeks after induction of spinal cord injury using compression injury model. Neuropathic pain symptoms were assessed at before treatment, 15 minutes, one hour and three hours after muscimol administration. The time of peak effect and optimum dosage was assessed by repeated measures analysis of variance and analysis of covariance, respectively. Results: Muscimol with the dose of 0.01 µg in 15 minutes caused to improve the thermal hyperalgesia (df: 24, 5; F= 6.6; p<0.001, mechanical hyperalgesia (df: 24, 5; F= 7.8; p<0.001, cold allodynia (df: 24, 5; F= 6.96; p<0.001, and mechanical allodynia (df: 24, 5; F= 15.7; p<0.001. The effect of doses of 0.1 µg and 1 µg were also significant. In addition, the efficacy of different doses of muscimol didn't have difference on thermal hyperalgesia (df: 24, 5; F= 1.52; p= 0.24, mechanical hyperalgesia (df: 24, 5; F= 0.3; p= -0.75, cold allodynia (df: 24, 5; F= 0.8; p= -0.56, and mechanical allodynia (df: 24, 5; F= 1.75; p= 0.86. Conclusion: The finding of the present study revealed that using muscimol with doses of 0.01µg, 0.1µg, and 1 µg reduces the symptoms of neuropathic pain. Also the effect of GABAA agonist is short term and its effectiveness gradually decreases by time.

  9. Evaluation of the safety and efficacy of pregabalin in older patients with neuropathic pain: results from a pooled analysis of 11 clinical studies

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    Zlateva Gergana

    2010-11-01

    Full Text Available Abstract Background Older patients are typically underrepresented in clinical trials of medications for chronic pain. A post hoc analysis of multiple clinical studies of pregabalin in patients with painful diabetic peripheral neuropathy (DPN or postherpetic neuralgia (PHN was conducted to evaluate the efficacy and safety of pregabalin in older patients. Methods Data from 11 double-blind, randomized, placebo-controlled clinical studies of pregabalin in patients with DPN or PHN were pooled. Efficacy outcomes included change in Daily Pain Rating Scale score, ≥30% and ≥50% responders, and endpoint pain score ≤3. Safety was based on adverse events (AEs. Primary efficacy was analyzed by analysis of covariance with terms for treatment, age category, protocol, baseline pain, and treatment-by-age category interaction. Results 2516 patients (white, n = 2344 [93.2%]; men, n = 1347 [53.5%]; PHN, n = 1003 [39.9%]; pregabalin, n = 1595 were included in the analysis. Patients were grouped by age: 18 to 64 years (n = 1236, 65 to 74 years (n = 766, and ≥75 years (n = 514. Baseline mean pain and sleep interference scores were comparable across treatment and age groups. Significant improvements in endpoint mean pain were observed for all pregabalin dosages versus placebo in all age groups (p ≤ 0.0009, except for the lowest dosage (150 mg/day in the youngest age group. Clinically meaningful pain relief, defined as ≥30% and ≥50% pain response, was observed in all age groups. The most common AEs were dizziness, somnolence, peripheral edema, asthenia, dry mouth, weight gain, and infections. The relative risks for these AEs increased with pregabalin dose, but did not appear related to older age or type of neuropathic pain. Conclusions Pregabalin (150-600 mg/day significantly reduced pain in older patients (age ≥65 years with neuropathic pain and improvements in pain were comparable to those observed in younger patients. Titration of pregabalin to the

  10. High Prevalence of Chronic Pain With Neuropathic Characteristics After Open Reduction and Internal Fixation of Ankle Fractures.

    Science.gov (United States)

    Rbia, Nadia; van der Vlies, Cornelis H; Cleffken, Berry I; Selles, Ruud W; Hovius, Steven E R; Nijhuis, Tim H J

    2017-09-01

    Unstable ankle fractures require treatment with open reduction and internal fixation (ORIF). Long-term functional outcome is satisfying in most patients; however, a number of patients have persistent complaints. Superficial nerve complications following ankle surgery may be the cause of chronic pain and disability. In this observational retrospective survey, a cohort of 527 women and men, who underwent ORIF in the period from January 2007 to January 2014, were invited to an online questionnaire. Pain symptoms were assessed using the McGill Pain Questionnaire (MPQ) and the Douleur Neuropathic en 4 Questions (DN4) Questionnaire. Descriptive statistics were used to present patient characteristics; a logistic regression model was used to analyze prognostic factors of neuropathic pain. A total of 271 patients completed the questionnaire. Mean follow-up period was 5.8 years (±1.9). Persistent neuropathic pain symptoms were present in 61 of all patients, and 51 of these patients reported an impaired quality of life caused by their symptoms. In univariate analysis, the following parameters were associated with neuropathic pain: age, hypertension, a thyroid disorder, lower back pain, fracture dislocations, and late complications such as nonunion, posttraumatic arthritis, or osteochondral injury. In multivariate analysis, an age between 40 and 60 years was found to be a significant predictor of neuropathic pain. Hypertension, dislocation, and late complications were significant predictors of persistent pain without neuropathic characteristics. The present study demonstrated a prevalence of persistent neuropathic pain symptoms after ORIF for ankle fractures in 23% of the respondents, which caused an impaired health-related quality of life. We identified 4 significant predictors of chronic and neuropathic pain after ORIF. This knowledge may aid the treating surgeon to identify patients who are at increased risk of persistent postoperative neuropathic pain and may affect the

  11. α2δ Modulators for management of compression neuropathic pain: A review of three case series

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    Tariq A Tramboo

    2009-01-01

    Conclusion: These results indicate the effectiveness of a2d modulators for management of neuropathic pain secondary to compression radiculopathy. The results also suggest a possible therapeutic superiority of LYRICA over locally available generic brands of pregabalin and gabapentin. These findings need to be further examined in randomized, controlled trials.

  12. Exploring the potential effect of Ocimum sanctum in vincristine-induced neuropathic pain in rats

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    Jaggi Amteshwar

    2010-01-01

    Full Text Available Abstract The present study was designed to investigate the ameliorative potential of Ocimum sanctum and its saponin rich fraction in vincristine-induced peripheral neuropathic pain in rats. Peripheral neuropathy was induced in rats by administration of vincristine sulfate (50 μg/kg i.p. for 10 consecutive days. The mechanical hyperalgesia, cold allodynia, paw heat hyperalgesia and cold tail hyperalgesia were assessed by performing the pinprick, acetone, hot plate and cold tail immersion tests, respectively. Biochemically, the tissue thio-barbituric acid reactive species (TBARS, super-oxide anion content (markers of oxidative stress and total calcium levels were measured. Vincristine administration was associated with the development of mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia. Furthermore, vincristine administration was also associated with an increase in oxidative stress and calcium levels. However, administration of Ocimum sanctum (100 and 200 mg/kg p.o. and its saponin rich fraction (100 and 200 mg/kg p.o. for 14 days significantly attenuated vincristine-induced neuropathic pain along with decrease in oxidative stress and calcium levels. It may be concluded that Ocimum sanctum has ameliorative potential in attenuating chemotherapy induced-painful neuropathic state, which may be attributed to decrease in oxidative stress and calcium levels. Furthermore, saponin rich fraction of Ocimum sanctum may be responsible for its noted beneficial effect in neuropathic pain in rats.

  13. Acupuncture for neuropathic pain due to bortezomib in a patient with multiple myeloma.

    Science.gov (United States)

    Mandıroğlu, Sibel; Cevik, Cemal; Aylı, Meltem

    2014-04-01

    Multiple myeloma (MM) is characterised by an increase in plasma cells, particularly in the bone marrow but also in other organs and systems, and with the abnormal production of immunoglobulin. Bortezomib, a current treatment option, inhibits angiogenesis by proteasome inhibition and is known to be effective in the treatment of MM. Peripheral neuropathy (PN) is a common dose-related side effect of bortezomib in patients with MM. We describe a case of PN due to bortezomib treatment which responded dramatically to acupuncture treatment, enabling his bortezomib treatment to continue. The patient was a 74-year-old man with pain, numbness, tingling and weakness in his hands and feet after 22 days of bortezomib treatment given by the haematology clinic. His neuropathic pain score was 8/10. There were no autonomic symptoms. Electroneurophysiological testing confirmed sensorimotor PN. Acupuncture treatment was planned as his neuropathic pain continued. Acupuncture was administered bilaterally to ST36, SP6 and LI4 15 times (every other day in the first five sessions and then twice a week). The numbness, tingling and pain symptoms substantially decreased after the first two treatments. After the 15th session acupuncture treatment was continued once a month. At the end of the sixth month the neuropathic pain assessment score was 0/10. There was no side effect of acupuncture treatment. Acupuncture seems promising as a complementary medical treatment for neuropathic pain from bortezomib-induced PN. Clinical studies involving more cases and electrophysiological studies are necessary to investigate the effectiveness of acupuncture.

  14. Characterization of two Runx1-dependent nociceptor differentiation programs necessary for inflammatory versus neuropathic pain

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    Arber Silvia

    2010-07-01

    Full Text Available Abstract Background The cellular and molecular programs that control specific types of pain are poorly understood. We reported previously that the runt domain transcription factor Runx1 is initially expressed in most nociceptors and controls sensory neuron phenotypes necessary for inflammatory and neuropathic pain. Results Here we show that expression of Runx1-dependent ion channels and receptors is distributed into two nociceptor populations that are distinguished by persistent or transient Runx1 expression. Conditional mutation of Runx1 at perinatal stages leads to preferential impairment of Runx1-persistent nociceptors and a selective defect in inflammatory pain. Conversely, constitutive Runx1 expression in Runx1-transient nociceptors leads to an impairment of Runx1-transient nociceptors and a selective deficit in neuropathic pain. Notably, the subdivision of Runx1-persistent and Runx1-transient nociceptors does not follow the classical nociceptor subdivision into IB4+ nonpeptidergic and IB4- peptidergic populations. Conclusion Altogether, we have uncovered two distinct Runx1-dependent nociceptor differentiation programs that are permissive for inflammatory versus neuropathic pain. These studies lend support to a transcription factor-based distinction of neuronal classes necessary for inflammatory versus neuropathic pain.

  15. Decompression with the aid of insoles in the treatment of diabetic neuropathic ulcers

    DEFF Research Database (Denmark)

    Holstein, P; Larsen, K; Sager, P

    1976-01-01

    Thirty-seven out of 38 neuropathic ulcers in 21 diabetic patients healed during relief of external pressure obtained by properly fitted interchangeable insoles. The time required for healing was 1 to 12 months (mean 3.6 months). The presence of mild occlussive arterial disease did not influence...

  16. Peroxisome Proliferator-Activated Receptor Agonists Modulate Neuropathic Pain: a Link to Chemokines?

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    Caroline eFreitag

    2014-08-01

    Full Text Available Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1α, fractalkine, SDF-1 among others have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between PPAR agonists' pain ameliorating effects and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide, shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain.

  17. Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine.

    Science.gov (United States)

    Pilat, Dominika; Piotrowska, Anna; Rojewska, Ewelina; Jurga, Agnieszka; Ślusarczyk, Joanna; Makuch, Wioletta; Basta-Kaim, Agnieszka; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Currently, the low efficacy of antinociceptive drugs for the treatment of neuropathic pain is a major therapeutic problem. Here, we show the potential role of interleukin (IL)-18 signaling in this phenomenon. IL-18 is an important molecule that performs various crucial functions, including the alteration of nociceptive transmission in response to neuropathic pain. We have studied the changes in the mRNA and protein levels (qRT-PCR and Western blot analysis, respectively) of IL-18, IL-18-binding protein (IL-18BP) and the IL-18 receptor (IL-18R) over time in rats following chronic constriction injury (CCI) of the sciatic nerve. Our study demonstrated that the spinal levels of IL-18BP were slightly downregulated at days 7 and 14 in the rats subjected to CCI. In contrast, the IL-18 and IL-18R mRNA expression and protein levels were elevated in the ipsilateral spinal cord on days 2, 7 and 14. Moreover, in rats exposed to a single intrathecal administration of IL-18BP (50 and 100 ng) 7 or 14 days following CCI, symptoms of neuropathic pain were attenuated, and the analgesia pursuant to morphine and buprenorphine (0.5 and 2.5 μg) was enhanced. In summary, the restoration of the analgesic activity of morphine and buprenorphine via the blockade of IL-18 signaling suggests that increased IL-18 pathway may account for the decreased analgesic efficacy of opioids for neuropathic pain.

  18. Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system.

    Science.gov (United States)

    Zhao, Xin; Wang, Chuang; Cui, Wu-Geng; Ma, Qing; Zhou, Wen-Hua

    2015-03-12

    Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain.

  19. Quantifying allodynia in patients suffering from unilateral neuropathic pain using Von Frey monofilaments

    NARCIS (Netherlands)

    Keizer, D.; van Wijhe, M.; Post, W.J.; Wierda, J.M.K.H.

    Objectives: The aim of this study is to investigate whether quantitative sensory testing with Von Frey monofilaments (VFMs) can be used for the quantification of allodynia in patients with chronic neuropathic pain, and how the pain threshold of affected skin differs from healthy skin. Methods: Using

  20. Quantifying allodynia in patients suffering from unilateral neuropathic pain using Von Frey monofilaments

    NARCIS (Netherlands)

    Keizer, D.; van Wijhe, M.; Post, W.J.; Wierda, J.M.K.H.

    2007-01-01

    Objectives: The aim of this study is to investigate whether quantitative sensory testing with Von Frey monofilaments (VFMs) can be used for the quantification of allodynia in patients with chronic neuropathic pain, and how the pain threshold of affected skin differs from healthy skin. Methods: Using

  1. Upregulation of glutamatergic transmission in anterior cingulate cortex in the diabetic rats with neuropathic pain.

    Science.gov (United States)

    Li, Weifang; Wang, Peng; Li, Hua

    2014-05-07

    Peripheral neuropathic pain is a common complication in the diabetic patients, and the underlying central mechanism remains unclear. Forebrain anterior cingulate cortex (ACC) is critically involved in the supraspinal perception of physical and affective components of noxious stimulus and pain modulation. Excitatory glutamatergic transmission in the ACC extensively contributed to the maintenance of negative affective component of chronic pain. The present study examined the adaptation of glutamatergic transmission in the ACC in rats with diabetic neuropathic pain. Injection with streptozotocin (STZ) induced hyperglycemia, thermal hyperalgesia and mechanical allodynia in the rats. In these rats, significant enhanced basal glutamatergic transmission was observed in the ACC neurons. The increased presynaptic glutamate release and enhanced conductance of postsynaptic glutamate receptors were also observed in the ACC neurons of these modeled rats. Increased phosphorylation of PKMζ, but not the expression of total PKMζ, was also observed in the ACC. Microinjection of PKMζ inhibitor ZIP into ACC attenuated the upregulation of glutamate transmission and painful behaviors in STZ-injected rats. These results revealed a substantial central sensitization in the ACC neurons in the rodents with diabetic neuropathic pain, which may partially underlie the negative affective components of patients with diabetic neuropathic pain.

  2. Prevalence, Causes, and Treatment of Neuropathic Pain in Dutch Nursing Home Residents : A Retrospective Chart Review

    NARCIS (Netherlands)

    van Kollenburg, Esther G. P.; Lavrijsen, Jan C. M.; Verhagen, Stans C.; Zuidema, Sytse U.; Schalkwijk, Annelies; Vissers, Kris C. P.

    Objectives To identify the prevalence and causes of neuropathic pain in Dutch nursing home residents; to establish the prevalence of painful and nonpainful diabetic polyneuropathy in a subsample of individuals with diabetes mellitus and central poststroke pain (CPSP) in a subsample of individuals

  3. Only half of the chronic pain after thoracic surgery shows a neuropathic component.

    NARCIS (Netherlands)

    Steegers, M.A.H.; Snik, D.M.; Verhagen, A.F.T.M.; Drift, M.A. van der; Wilder-Smith, O.H.G.

    2008-01-01

    Chronic pain is a common complication after thoracic surgery. The cause of chronic post-thoracotomy pain is often suggested to be intercostal nerve damage. Thus chronic pain after thoracic surgery should have an important neuropathic component. The present study investigated the prevalence of the

  4. Dynamics of Circadian Thalamocortical Flow of Information during a Peripheral Neuropathic Pain Condition.

    Science.gov (United States)

    Cardoso-Cruz, Helder; Sameshima, Koichi; Lima, Deolinda; Galhardo, Vasco

    2011-01-01

    It is known that the thalamocortical loop plays a crucial role in the encoding of sensory-discriminative features of painful stimuli. However, only a few studies have addressed the changes in thalamocortical dynamics that may occur after the onset of chronic pain. Our goal was to evaluate how the induction of chronic neuropathic pain affected the flow of information within the thalamocortical loop throughout the brain states of the sleep-wake cycle. To address this issue we recorded local field potentials (LFPs) - both before and after the establishment of neuropathic pain in awake freely moving adult rats chronically implanted with arrays of multielectrodes in the lateral thalamus and primary somatosensory cortex. Our results show that the neuropathic injury induced changes in the number of wake and slow-wave-sleep (SWS) state episodes, and especially in the total number of transitions between brain states. Moreover, partial directed coherence - analysis revealed that the amount of information flow between cortex and thalamus in neuropathic animals decreased significantly, indicating that the overall thalamic activity had less weight over the cortical activity. However, thalamocortical LFPs displayed higher phase-locking during awake and SWS episodes after the nerve lesion, suggesting faster transmission of relevant information along the thalamocortical loop. The observed changes are in agreement with the hypothesis of thalamic dysfunction after the onset of chronic pain, and may result from diminished inhibitory effect of the primary somatosensory cortex over the lateral thalamus.

  5. Neuropathic pain and its treatment with ARA 290 and ketamine : overlapping pathways

    NARCIS (Netherlands)

    Swartjes, Maarten

    2014-01-01

    Neuropathic pain is a disabling disease with a mechanism consisting of several pathways that ultimately converge in the development and persistence tactile and cold allodynia. Pharmacological treatment is often inadequate and coincides with intolerable side effects. The spared nerve injury animal mo

  6. Dynamics of circadian thalamocortical flow of information during a peripheral neuropathic pain condition

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    Helder eCardoso-Cruz

    2011-08-01

    Full Text Available It is known that the thalamocortical loop plays a crucial role in the encoding of sensory-discriminative features of painful stimuli. However, only a few studies have addressed the changes in thalamocortical dynamics that may occur after the onset of chronic pain. Our goal was to evaluate how the induction of chronic neuropathic pain affected the flow of information within the thalamocortical loop throughout the brain states of the sleep-wake cycle. To address this issue we recorded local field potentials – LFPs – both before and after the establishment of neuropathic pain in awake freely moving adult rats chronically implanted with arrays of multielectrodes in the lateral thalamus and primary somatosensory cortex. Our results show that the neuropathic injury induced changes in the number of wake and slow-wave-sleep state episodes, and especially in the total number of transitions between brain states. Moreover, partial directed coherence – PDC – analysis revealed that the amount of information flow between cortex and thalamus in neuropathic animals decreased significantly, indicating that the overall thalamic activity had less weight over the cortical activity. However, thalamocortical LFPs displayed higher phase-locking during awake and slow-wave-sleep episodes after the nerve lesion, suggesting faster transmission of relevant information along the thalamocortical loop. The observed changes are in agreement with the hypothesis of thalamic dysfunction after the onset of chronic pain, and may result from diminished inhibitory effect of the primary somatosensory cortex over the lateral thalamus.

  7. Type 2 Gaucher Disease (Acute Infantile Gaucher Disease or Neuropathic Type

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    Mohammad Mehdi TAGHDIRI

    2012-12-01

    Full Text Available How to Cite this Article: Taghdiri MM. Type 2 Gaucher Disease (Acute Infantile Gaucher Disease or Neuropathic Type. Iran J Child Neurol Autumn 2012; 6:4 (suppl. 1:12. Pls see PDF. 

  8. Identification of patients with neuropathic pain using electronic primary care records

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    Camille Gajria

    2011-05-01

    Conclusion Computerised health records offer an excellent opportunity to improve the identification of patients for clinical research in complex conditions like chronic neuropathic pain. To make full use of data from these records, standardisation of clinical coding and consensus on diagnostic criteria are needed.

  9. Antinociceptive effect of matrine on vincristine-induced neuropathic pain model in mice.

    Science.gov (United States)

    Linglu, Dun; Yuxiang, Li; Yaqiong, Xu; Ru, Zhou; Lin, Ma; Shaoju, Jin; Juan, Du; Tao, Sun; Jianqiang, Yu

    2014-06-01

    Chemotherapy drugs treatment causes neuropathic pain, hyperalgesia and allodynia are common components of neuropathic pain, so effectively therapeutic strategy is required. In this study, we evaluated the antinociceptive effects of matrine on vincristine-induced neuropathic pain in mice. Vincristine (100 μg/kg i.p.) was administered once per day for 7 days (day 0-6) in mice. Matrine (15, 30, 60 mg/kg, i.p.) was repeated administration in early phase (day 0-6) or late phase (day 7-13). Hyperalgesia and allodynia were evaluated by withdrawal response using von Frey filaments, plantar and cold-plate on 7, 14 and 21 day. Injection of vincristine produced mechanical hyperalgesia and cold allodynia. Matrine was found to produce a protective role in both von Frey filaments and cold-plate test. The analysis of the effect supports the hypothesis that matrine is useful in therapy of vincristine-induced neuropathic pain. In conclusion, this study demonstrates that administration of matrine is associated with antinociceptive effect on mechanical and cold stimuli in a mice model of vincristine-induced neuropathy pain.

  10. Recent Advances in Urinary Tract Reconstruction for Neuropathic Bladder in Children [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Roberto I. Lopes

    2016-02-01

    Full Text Available Neuropathic bladder usually causes several limitations to patients’ quality of life, including urinary incontinence, recurrent urinary tract infections, and upper urinary tract damage. Its management has significantly changed over the last few years. The aim of our paper is to address some salient features of recent literature dealing with reconstructive procedures in pediatric and adolescent patients with lower urinary tract dysfunction.

  11. Dynamics of Circadian Thalamocortical Flow of Information during a Peripheral Neuropathic Pain Condition

    Science.gov (United States)

    Cardoso-Cruz, Helder; Sameshima, Koichi; Lima, Deolinda; Galhardo, Vasco

    2011-01-01

    It is known that the thalamocortical loop plays a crucial role in the encoding of sensory–discriminative features of painful stimuli. However, only a few studies have addressed the changes in thalamocortical dynamics that may occur after the onset of chronic pain. Our goal was to evaluate how the induction of chronic neuropathic pain affected the flow of information within the thalamocortical loop throughout the brain states of the sleep–wake cycle. To address this issue we recorded local field potentials (LFPs) – both before and after the establishment of neuropathic pain in awake freely moving adult rats chronically implanted with arrays of multielectrodes in the lateral thalamus and primary somatosensory cortex. Our results show that the neuropathic injury induced changes in the number of wake and slow-wave-sleep (SWS) state episodes, and especially in the total number of transitions between brain states. Moreover, partial directed coherence – analysis revealed that the amount of information flow between cortex and thalamus in neuropathic animals decreased significantly, indicating that the overall thalamic activity had less weight over the cortical activity. However, thalamocortical LFPs displayed higher phase-locking during awake and SWS episodes after the nerve lesion, suggesting faster transmission of relevant information along the thalamocortical loop. The observed changes are in agreement with the hypothesis of thalamic dysfunction after the onset of chronic pain, and may result from diminished inhibitory effect of the primary somatosensory cortex over the lateral thalamus. PMID:22007162

  12. Decompression with the aid of insoles in the treatment of diabetic neuropathic ulcers

    DEFF Research Database (Denmark)

    Holstein, P; Larsen, K; Sager, P

    1976-01-01

    Thirty-seven out of 38 neuropathic ulcers in 21 diabetic patients healed during relief of external pressure obtained by properly fitted interchangeable insoles. The time required for healing was 1 to 12 months (mean 3.6 months). The presence of mild occlussive arterial disease did not influence...

  13. Neuropathic pain: an updated grading system for research and clinical practice

    DEFF Research Database (Denmark)

    Finnerup, Nanna B; Haroutounian, Simon; Kamerman, Peter;

    2016-01-01

    for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014...

  14. Traumatic peripheral nerve injuries: epidemiological findings, neuropathic pain and quality of life in 158 patients.

    Science.gov (United States)

    Ciaramitaro, Palma; Mondelli, Mauro; Logullo, Francesco; Grimaldi, Serena; Battiston, Bruno; Sard, Arman; Scarinzi, Cecilia; Migliaretti, Giuseppe; Faccani, Giuliano; Cocito, Dario

    2010-06-01

    The objectives of this study were (1) epidemiological analysis of traumatic peripheral nerve injuries; (2) assessment of neuropathic pain and quality of life in patients affected by traumatic neuropathies. All consecutive patients with a diagnosis of traumatic neuropathies from four Italian centres were enrolled. Electromyography confirmed clinical level and site diagnosis of peripheral nerve injury. All patients were evaluated by disability scales, pain screening tools, and quality of life tests. 158 consecutive patients for a total of 211 traumatic neuropathies were analysed. The brachial plexus was a frequent site of traumatic injury (36%) and the radial, ulnar, and peroneal were the most commonly involved nerves with 15% of iatrogenic injuries. Seventy-two percent of the traumatic neuropathies were painful. Pain was present in 66% and neuropathic pain in 50% of all patients. Patients had worse quality of life scores than did the healthy Italian population. Moreover, there was a strong correlation between the quality of life and the severity of the pain, particularly neuropathic pain (Short Form-36 [SF-36] p < 0.005; Beck Depression Inventory [BDI] p < 0.0001). Traumatic neuropathies were more frequent in young males after road accidents, mainly in the upper limbs. Severe neuropathic pain and not only disability contributed to worsening the quality of life in patients with traumatic neuropathies.

  15. Paeoniflorin and Albiflorin Attenuate Neuropathic Pain via MAPK Pathway in Chronic Constriction Injury Rats

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    Jianyu Zhou

    2016-01-01

    Full Text Available Neuropathic pain remains as the most frequent cause of suffering and disability around the world. The isomers paeoniflorin (PF and albiflorin (AF are major constituents extracted from the roots of Paeonia (P. lactiflora Pall. Neuroprotective effect of PF has been demonstrated in animal models of neuropathologies. However, only a few studies are related to the biological activities of AF and no report has been published on analgesic properties of AF about neuropathic pain to date. The aim of this study was to compare the effects of AF and PF against CCI-induced neuropathic pain in rat and explore the underlying mechanism. We had found that both PF and AF could inhibit the activation of p38 mitogen-activated protein kinase (p38 MAPK pathway in spinal microglia and subsequent upregulated proinflammatory cytokines (interleukin-1β (IL-1β and tumor necrosis factor-α (TNF-α. AF further displayed remarkable effects on inhibiting the activation of astrocytes, suppressing the overelevated expression of phosphorylation of c-Jun N-terminal kinases (p-JNK in astrocytes, and decreasing the content of chemokine CXCL1 in the spinal cord. These results suggest that both PF and AF are potential therapeutic agents for neuropathic pain, which merit further investigation.

  16. Ultrasound-Guided Nerve Block with Botulinum Toxin Type A for Intractable Neuropathic Pain

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    Young Eun Moon

    2016-01-01

    Full Text Available Neuropathic pain includes postherpetic neuralgia (PHN, painful diabetic neuropathy (PDN, and trigeminal neuralgia, and so on. Although various drugs have been tried to treat neuropathic pain, the effectiveness of the drugs sometimes may be limited for chronic intractable neuropathic pain, especially when they cannot be used at an adequate dose, due to undesirable severe side effects and the underlying disease itself. Botulinum toxin type A (BoNT-A has been known for its analgesic effect in various pain conditions. Nevertheless, there are no data of nerve block in PHN and PDN. Here, we report two patients successfully treated with ultrasound-guided peripheral nerve block using BoNT-A for intractable PHN and PDN. One patient had PHN on the left upper extremity and the other patient had PDN on a lower extremity. Due to side effects of drugs, escalation of the drug dose could not be made. We injected 50 Botox units (BOTOX®, Allergan Inc., Irvine, CA, USA into brachial plexus and lumbar plexus, respectively, under ultrasound. Their pain was significantly decreased for about 4–5 months. Ultrasound-guided nerve block with BoNT-A may be an effective analgesic modality in a chronic intractable neuropathic pain especially when conventional treatment failed to achieve adequate pain relief.

  17. Use of Lidocaine Patches for Neuropathic Pain in a Comprehensive Cancer Centre

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    Julia Ann Fleming

    2009-01-01

    Full Text Available BACKGROUND: There are few reports of the use of the lidocaine 5% patch (L5%P for neuropathic pain (NP in the cancer patient. Within a comprehensive cancer centre, L5%P has been prescribed by the Pain and Palliative Care Service (Peter McCallum Cancer Centre, East Melbourne, Victoria, Australia for selected patients with NP since 2001.

  18. Endocannabinoid regulation of spinal nociceptive processing in a model of neuropathic pain.

    Science.gov (United States)

    Sagar, Devi Rani; Jhaveri, Maulik D; Richardson, Denise; Gray, Roy A; de Lago, Eva; Fernández-Ruiz, Javier; Barrett, David A; Kendall, David A; Chapman, Victoria

    2010-04-01

    Models of neuropathic pain are associated with elevated spinal levels of endocannabinoids (ECs) and altered expression of cannabinoid receptors on primary sensory afferents and post-synaptic cells in the spinal cord. We investigated the impact of these changes on the spinal processing of sensory inputs in a model of neuropathic pain. Extracellular single-unit recordings of spinal neurones were made in anaesthetized neuropathic and sham-operated rats. The effects of spinal administration of the cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) and the cannabinoid receptor type 2 (CB(2)) receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicycloheptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) on mechanically-evoked responses of spinal neurones were determined. The effects of spinal administration of (5Z,8Z11Z,14Z)-N-(3-furanylmethyl)-5,8,11,14-eicosatetraenamide (UCM707), which binds to CB(2) receptors and alters transport of ECs, on evoked responses of spinal neurones and spinal levels of ECs were also determined. The cannabinoid CB(1) receptor antagonist AM251, but not the CB(2) receptor antagonist, significantly facilitated 10-g-evoked responses of spinal neurones in neuropathic, but not sham-operated, rats. Spinal administration of UCM707 did not alter spinal levels of ECs but did significantly inhibit mechanically-evoked responses of neurones in neuropathic, but not sham-operated, rats. Pharmacological studies indicated that the selective inhibitory effects of spinal UCM707 in neuropathic rats were mediated by activation of spinal CB(2) receptors, as well as a contribution from transient receptor potential vanilloid 1 (TRPV1) channels. This work demonstrates that changes in the EC receptor system in the spinal cord of neuropathic rats influence the processing of sensory inputs, in particular low-weight inputs that drive allodynia

  19. Low doses of dextromethorphan have a beneficial effect in the treatment of neuropathic pain.

    Science.gov (United States)

    Morel, Véronique; Pickering, Gisèle; Etienne, Monique; Dupuis, Amandine; Privat, Anne-Marie; Chalus, Maryse; Eschalier, Alain; Daulhac, Laurence

    2014-12-01

    N-methyl-D-aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y-maze tests and molecular events by Western blot analysis. Spinal nerve-ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr(1336)NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr(1336)NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life.

  20. Increased efficacy of early spinal cord stimulation in an animal model of neuropathic pain.

    Science.gov (United States)

    Truin, Michiel; van Kleef, Maarten; Linderoth, Bengt; Smits, Helwin; Janssen, Sofie P M; Joosten, Elbert A J

    2011-02-01

    Although spinal cord stimulation (SCS) is an established treatment for chronic neuropathic pain, pain relief is still not successful in a large group of patients. We suggest that the success of SCS may be related to the timing of SCS during the development of chronic neuropathic pain. We therefore compared the effect of SCS applied after 24h of neuropathic pain (early SCS) and after 16days of neuropathic pain (late SCS). For early SCS, male Sprague-Dawley rats (n=13) were implanted with an SCS device, followed by a partial ligation of the sciatic nerve. Using von Frey monofilaments, tactile allodynia was assessed 24h after ligation. Animals with tactile allodynia received 30min of SCS. Withdrawal thresholds were assessed just before SCS, during SCS and until the return to pre-stimulation withdrawal threshold. Results were compared with the data from late SCS (n=29). Out of the 13 allodynic animals that received early SCS, 10 (77%) responded to SCS with significantly increased withdrawal thresholds, compared to 38% in the late SCS group. The increase of the withdrawal threshold in the early SCS group could still be noticed 90min after termination of SCS. In more than half of these animals, pre-stimulation withdrawal thresholds were reached only the next day. Early SCS resulted in an increased number of responders to SCS and furthermore an increased duration of the effect of SCS as compared to late SCS. Early SCS treatment of neuropathic rats is more effective as compared to the late SCS treatment. Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

  1. Chronic nerve injury-induced Mas receptor expression in dorsal root ganglion neurons alleviates neuropathic pain.

    Science.gov (United States)

    Zhao, Yuanting; Qin, Yue; Liu, Tuanjiang; Hao, Dingjun

    2015-12-01

    Neuropathic pain, which is characterized by hyperalgesia, allodynia and spontaneous pain, is one of the most painful symptoms that can be experienced in the clinic. It often occurs as a result of injury to the peripheral nerves, dorsal root ganglion (DRG), spinal cord or brain. The renin-angiotensin system (RAS) plays an important role in nociception. As an essential component of the RAS, the angiotensin (Ang)-(1-7)/Mas axis may be involved in antinociception. The aim of the present study was to explore the expression pattern of Mas in DRG neurons following chronic nerve injury and examine the effects of Mas inhibition and activation on neuropathic pain in a chronic constriction injury (CCI) rat model. The results showed, that compared with the sham group, CCI caused a time-dependent induction of Mas expression at both the mRNA and the protein levels in DRG neurons. Consistent with the results, isolated DRG neurons showed a time-dependent increase in Ang-(1-7) binding on the cell membrane following the CCI surgery, but not the sham surgery. Compared with the sham control groups, CCI significantly decreased the paw withdrawal latency and threshold, and this was markedly improved and aggravated by intrathecal injection of the selective Mas agonist Ang-(1-7) and the selective Mas inhibitor D-Pro7-Ang-(1-7), respectively. In conclusion, this study has provided the first evidence, to the best of our knowledge, that the Mas expression in DRG neurons is time-dependently induced by chronic nerve injury and that the intrathecal activation and inhibition of Mas can improve and aggravate CCI-induced neuropathic pain, respectively. This study has provided novel insights into the pathophysiological process of neuropathic pain and suggests that the Ang-(1-7)/Mas axis could be an effective therapeutic target for neuropathic pain, warranting further study.

  2. Neuropathic cancer pain: What we are dealing with? How to manage it?

    Science.gov (United States)

    Esin, Ece; Yalcin, Suayib

    2014-01-01

    Cancer pain is a serious health problem, and imposes a great burden on the lives of patients and their families. Pain can be associated with delay in treatment, denial of treatment, or failure of treatment. If the pain is not treated properly it may impair the quality of life. Neuropathic cancer pain (NCP) is one of the most complex phenomena among cancer pain syndromes. NCP may result from direct damage to nerves due to acute diagnostic/therapeutic interventions. Chronic NCP is the result of treatment complications or malignancy itself. Although the reason for pain is different in NCP and noncancer neuropathic pain, the pathophysiologic mechanisms are similar. Data regarding neuropathic pain are primarily obtained from neuropathic pain studies. Evidence pertaining to NCP is limited. NCP due to chemotherapeutic toxicity is a major problem for physicians. In the past two decades, there have been efforts to standardize NCP treatment in order to provide better medical service. Opioids are the mainstay of cancer pain treatment; however, a new group of therapeutics called coanalgesic drugs has been introduced to pain treatment. These coanalgesics include gabapentinoids (gabapentin, pregabalin), antidepressants (tricyclic antidepressants, duloxetine, and venlafaxine), corticosteroids, bisphosphonates, N-methyl-D-aspartate antagonists, and cannabinoids. Pain can be encountered throughout every step of cancer treatment, and thus all practicing oncologists must be capable of assessing pain, know the possible underlying pathophysiology, and manage it appropriately. The purpose of this review is to discuss neuropathic pain and NCP in detail, the relevance of this topic, clinical features, possible pathology, and treatments of NCP.

  3. Long-term treatment of neuropathic pain with a 5% lidocaine medicated plaster.

    Science.gov (United States)

    Wilhelm, Ilca Ricarda; Tzabazis, Alexander; Likar, Rudolf; Sittl, Reinhard; Griessinger, Norbert

    2010-02-01

    The 5% lidocaine medicated plaster is a topical treatment for peripheral neuropathic pain symptoms (e.g. burning, shooting and stabbing pain) and is registered for the treatment of postherpetic neuralgia. This study examined the efficacy and tolerability of lon