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Sample records for central neuropathic pain

  1. 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.

  2. Neuropathic pain

    DEFF Research Database (Denmark)

    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...

  3. Neuropathic pain

    Directory of Open Access Journals (Sweden)

    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.

  4. Differential pain modulation properties in central neuropathic pain after spinal cord injury.

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    Gruener, Hila; Zeilig, Gabi; Laufer, Yocheved; Blumen, Nava; Defrin, Ruth

    2016-07-01

    It seems that central neuropathic pain (CNP) is associated with altered abilities to modulate pain; whereas dysfunction in descending pain inhibition is associated with the extent of chronic pain distribution, enhanced pain excitation is associated with the intensity of chronic pain. We investigated the hypothesis that CNP is associated with decreased descending pain inhibition along with increased neuronal excitability and that both traits are associated with spinothalamic tract (STT) damage. Chronic spinal cord injury subjects with CNP (n = 27) and without CNP (n = 23) and healthy controls (n = 20) underwent the measurement of pain adaptation, conditioned pain modulation (CPM), tonic suprathreshold pain (TSP), and spatial summation of pain above injury level. Central neuropathic pain subjects also underwent at and below-lesion STT evaluation and completed the questionnaires. Central neuropathic pain subjects showed decreased CPM and increased enhancement of TSP compared with controls. Among CNP subjects, the dysfunction of CPM and pain adaptation correlated positively with the number of painful body regions. The magnitude of TSP and spatial summation of pain correlated positively with CNP intensity. STT scores correlated with CNP intensity and with TSP, so that the more affected the STT below injury level, the greater the CNP and TSP magnitude. It seems that CNP is associated with altered abilities to modulate pain, whereas dysfunction in descending pain inhibition is associated with the extent of chronic pain distribution and enhanced pain excitation is associated with the intensity of chronic pain. Thus, top-down processes may determine the spread of CNP, whereas bottom-up processes may determine CNP intensity. It also seems that the mechanisms of CNP may involve STT-induced hyperexcitability. Future, longitudinal studies may investigate the timeline of this scenario.

  5. Neuropathic orofacial pain.

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    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.

  6. 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.

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

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    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.

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

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    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.

  9. Cannabinoids and centrak neuropathic pain. A review (Cannabinoidi e dolore neuropatico centrale. Una rassegna

    Directory of Open Access Journals (Sweden)

    Francesco Crestani

    2014-03-01

    Full Text Available Only recently, the medical community highlighted the pharmacological scientific bases of the effects of Cannabis. The most important active principle, Delta-9-tetrahydrocannabinol was identified in the second half of the last century, and receptors were subsequently identified and endogenous ligands, called endocannabinoids, were characterized. The effectiveness of the cannabinoids in the treatment of nausea and vomit due to anti-neoplastic chemotherapy and in the wasting-syndrome during AIDS is recognized. Moreover, the cannabinoids have shown analgesic properties, particularly interesting with regard to the central neuropathic pain. This article will review the current knowledge and will give practical guidance on how to proceed in prescribing cannabinoids.

  10. Effectiveness of low-dose pregabalin in three patients with Lewy body disease and central neuropathic pain.

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    Ukai, Katsuyuki; Fujishiro, Hiroshige; Ozaki, Norio

    2017-03-01

    Many patients with Lewy body disease complain of pain, and their pain may be associated with this disease. Recently, pain has become a focus of attention in Parkinson's disease, but there is little information regarding pain in patients who have dementia with Lewy bodies. We used pregabalin to treat three Lewy body disease patients with chronic pain that may have been related to degeneration of central neurons. All three patients responded well to pregabalin at 25-50 mg/day. To our knowledge, there have been no previous reports of pregabalin showing efficacy for central neuropathic pain in Parkinson's disease or Lewy body disease.

  11. 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.

  12. Meta-analysis of placebo responses in central neuropathic pain: impact of subject, study, and pain characteristics.

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    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.

  13. New therapy for neuropathic pain.

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    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.

  14. 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...

  15. 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...

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

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    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.

  17. The Discriminative validity of "nociceptive," "peripheral neuropathic," and "central sensitization" as mechanisms-based classifications of musculoskeletal pain.

    LENUS (Irish Health Repository)

    Smart, Keith M

    2012-02-01

    OBJECTIVES: Empirical evidence of discriminative validity is required to justify the use of mechanisms-based classifications of musculoskeletal pain in clinical practice. The purpose of this study was to evaluate the discriminative validity of mechanisms-based classifications of pain by identifying discriminatory clusters of clinical criteria predictive of "nociceptive," "peripheral neuropathic," and "central sensitization" pain in patients with low back (+\\/- leg) pain disorders. METHODS: This study was a cross-sectional, between-patients design using the extreme-groups method. Four hundred sixty-four patients with low back (+\\/- leg) pain were assessed using a standardized assessment protocol. After each assessment, patients\\' pain was assigned a mechanisms-based classification. Clinicians then completed a clinical criteria checklist indicating the presence\\/absence of various clinical criteria. RESULTS: Multivariate analyses using binary logistic regression with Bayesian model averaging identified a discriminative cluster of 7, 3, and 4 symptoms and signs predictive of a dominance of "nociceptive," "peripheral neuropathic," and "central sensitization" pain, respectively. Each cluster was found to have high levels of classification accuracy (sensitivity, specificity, positive\\/negative predictive values, positive\\/negative likelihood ratios). DISCUSSION: By identifying a discriminatory cluster of symptoms and signs predictive of "nociceptive," "peripheral neuropathic," and "central" pain, this study provides some preliminary discriminative validity evidence for mechanisms-based classifications of musculoskeletal pain. Classification system validation requires the accumulation of validity evidence before their use in clinical practice can be recommended. Further studies are required to evaluate the construct and criterion validity of mechanisms-based classifications of musculoskeletal pain.

  18. Neuropathic pain and pharmacological treatment.

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    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.

  19. 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 ...

  20. Role of central arginine vasopressin receptors in the analgesic effect of CDP-choline on acute and neuropathic pain.

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    Bagdas, Deniz; Yucel-Ozboluk, Hasret; Orhan, Fulya; Kanat, Ozkan; Isbil-Buyukcoskun, Naciye; Gurun, Mine S

    2013-12-04

    Recent studies have demonstrated that arginine vasopressin (AVP) plays a crucial role in pain modulation. In addition, our previous studies have proven that centrally administered cytidine-5'-diphosphate-choline (CDP-choline; citicoline) elicits an analgesic effect in different pain models in rats. Given that CDP-choline enhances central and peripheral vasopressin levels, the present study was designed to investigate the role of central AVP receptors in the analgesic effect of CDP-choline in acute and chronic constriction injury-induced neuropathic pain models. For this purpose, rats were pretreated intracerebroventricularly with the AVP V1 or AVP V2 receptor antagonist 15 min before intracerebroventricular injection of CDP-choline or saline, and pain threshold was determined using the Randall-Selitto test. AVP V1 and AVP V2 receptor antagonist blocked the CDP-choline-induced analgesic effect either in acute or neuropathic models of pain in rats. These results suggest, for the first time, that central AVP receptors are involved in the CDP-choline-elicited analgesic effect.

  1. MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain.

    Science.gov (United States)

    He, Shao-Qiu; Li, Zhe; Chu, Yu-Xia; Han, Liang; Xu, Qian; Li, Man; Yang, Fei; Liu, Qin; Tang, Zongxiang; Wang, Yun; Hin, Niyada; Tsukamoto, Takashi; Slusher, Barbara; Tiwari, Vinod; Shechter, Ronen; Wei, Feng; Raja, Srinivasa N; Dong, Xinzhong; Guan, Yun

    2014-03-01

    Chronic neuropathic pain is often refractory to current pharmacotherapies. The rodent Mas-related G-protein-coupled receptor subtype C (MrgC) shares substantial homogeneity with its human homologue, MrgX1, and is located specifically in small-diameter dorsal root ganglion neurons. However, evidence regarding the role of MrgC in chronic pain conditions has been disparate and inconsistent. Accordingly, the therapeutic value of MrgX1 as a target for pain treatment in humans remains uncertain. Here, we found that intrathecal injection of BAM8-22 (a 15-amino acid peptide MrgC agonist) and JHU58 (a novel dipeptide MrgC agonist) inhibited both mechanical and heat hypersensitivity in rats after an L5 spinal nerve ligation (SNL). Intrathecal JHU58-induced pain inhibition was dose dependent in SNL rats. Importantly, drug efficacy was lost in Mrg-cluster gene knockout (Mrg KO) mice and was blocked by gene silencing with intrathecal MrgC siRNA and by a selective MrgC receptor antagonist in SNL rats, suggesting that the drug action is MrgC dependent. Further, in a mouse model of trigeminal neuropathic pain, microinjection of JHU58 into ipsilateral subnucleus caudalis inhibited mechanical hypersensitivity in wild-type but not Mrg KO mice. Finally, JHU58 attenuated the miniature excitatory postsynaptic currents frequency both in medullary dorsal horn neurons of mice after trigeminal nerve injury and in lumbar spinal dorsal horn neurons of mice after SNL. We provide multiple lines of evidence that MrgC agonism at spinal but not peripheral sites may constitute a novel pain inhibitory mechanism that involves inhibition of peripheral excitatory inputs onto postsynaptic dorsal horn neurons in different rodent models of neuropathic pain.

  2. Reduction of central neuropathic pain with ketamine infusion in a patient with Ehlers–Danlos syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Lo TC

    2016-09-01

    Full Text Available Tony Chung Tung Lo,1,* Stephen Tung Yeung,2,* Sujin Lee,1 Kira Skavinski,3 Solomon Liao,4 1Department of Physical Medicine and Rehabilitation, University of California Irvine, Orange, CA, 2Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, 3Department of Palliative Medicine, University of California San Diego, La Jolla, 4Department of Palliative Medicine, University of California Irvine, Orange, CA, USA *These authors contributed equally to this work Objective: Ehlers–Danlos syndrome frequently causes acute and chronic pain because of joint subluxations and dislocations secondary to hypermobility. Current treatments for pain related to Ehlers–Danlos syndrome and central pain syndrome are inadequate. This case report discusses the therapeutic use of ketamine intravenous infusion as an alternative. Case report: A 27-year-old Caucasian female with a history of Ehlers–Danlos syndrome and spinal cord ischemic myelopathy resulting in central pain syndrome, presented with severe generalized body pain refractory to multiple pharmacological interventions. After a 7-day course of ketamine intravenous infusion under controlled generalized sedation in the intensive care unit, the patient reported a dramatic reduction in pain levels from 7–8 out of 10 to 0–3 out of 10 on a numeric rating scale and had a significant functional improvement. The patient tolerated a reduction in her pain medication regimen, which originally included opioids, gabapentin, pregabalin, tricyclic antidepressants, and nonsteroidal anti-inflammatory drugs. Conclusion: Ketamine infusion treatment has been used in various pain syndromes, including central neuropathic pain, ischemic pain, and regional pain syndrome. Reports have suggested that ketamine modulates pain by the regression of N-methyl-D-aspartate receptor to a resting state. As such, propagation of nociceptive signal to brain is interrupted allowing for the restoration of

  3. Neuropathic pain in children.

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    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.

  4. Reduction of central neuropathic pain with ketamine infusion in a patient with Ehlers–Danlos syndrome: a case report

    Science.gov (United States)

    Lo, Tony Chung Tung; Yeung, Stephen Tung; Lee, Sujin; Skavinski, Kira; Liao, Solomon

    2016-01-01

    Objective Ehlers–Danlos syndrome frequently causes acute and chronic pain because of joint subluxations and dislocations secondary to hypermobility. Current treatments for pain related to Ehlers–Danlos syndrome and central pain syndrome are inadequate. This case report discusses the therapeutic use of ketamine intravenous infusion as an alternative. Case report A 27-year-old Caucasian female with a history of Ehlers–Danlos syndrome and spinal cord ischemic myelopathy resulting in central pain syndrome, presented with severe generalized body pain refractory to multiple pharmacological interventions. After a 7-day course of ketamine intravenous infusion under controlled generalized sedation in the intensive care unit, the patient reported a dramatic reduction in pain levels from 7–8 out of 10 to 0–3 out of 10 on a numeric rating scale and had a significant functional improvement. The patient tolerated a reduction in her pain medication regimen, which originally included opioids, gabapentin, pregabalin, tricyclic antidepressants, and nonsteroidal anti-inflammatory drugs. Conclusion Ketamine infusion treatment has been used in various pain syndromes, including central neuropathic pain, ischemic pain, and regional pain syndrome. Reports have suggested that ketamine modulates pain by the regression of N-methyl-D-aspartate receptor to a resting state. As such, propagation of nociceptive signal to brain is interrupted allowing for the restoration of physiological balance between pain inhibition and facilitation. The present report shows that this treatment option can be used in patients with refractory central pain syndrome in the setting of spinal cord myelopathy secondary to Ehlers–Danlos syndrome. In addition, as seen in this case, this protocol can potentially decrease the chronic use of pain medication, such as opioids.

  5. 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.

  6. Cytokines in Neuropathic Pain and Associated Depression.

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    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.

  7. Central pain.

    Science.gov (United States)

    Singh, Supreet

    2014-12-01

    Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. The topic addressed in this issue is central pain, a neuropathic pain syndrome caused by a lesion in the brain or spinal cord that sensitizes one's perception of pain. It is a debilitating condition caused by various diseases such as multiple sclerosis, strokes, spinal cord injuries, or brain tumors. Varied symptoms and the use of pharmacological medicines and nonpharmacological therapies will be addressed.

  8. 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

  9. Tetrahydrocannabinol (Delta 9-THC Treatment in Chronic Central Neuropathic Pain and Fibromyalgia Patients: Results of a Multicenter Survey

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    Janet Weber

    2009-01-01

    Full Text Available Central neuropathic pain is difficult to treat, but delta 9-Tetrahydrocannabinol (delta 9-THC may be a promising therapeutic agent. We administered in 172 patients on average 7.5 mg delta 9-THC over 7 months. Of these, 48 patients prematurely withdrew due to side effects, insufficient analgesia, or expense of therapy. Thus, 124 patients were assessed retrospectively in a multicenter telephone survey. Reported changes in pain intensity, recorded on a numeric rating scale (NRS, Pain Disability Index (PDI, Medical Outcomes Short-Form (SF-12, Quality of Life Impairment by Pain (QLIP, Hospital Anxiety Depression Scale (HADS, and amount of concomitant pain medication were recorded. Psychometric parameters (PDI, SF-12, QLIP, HADS and pain intensity improved significantly during delta 9-THC treatment. Opioid doses were reduced and patients perceived THC therapy as effective with tolerable side effects. About 25% of the patients, however, did not tolerate the treatment. Therapy success and tolerance can be assessed by a transient delta 9-THC titration and its maintained administration for several weeks. The present survey demonstrates its ameliorating potential for the treatment of chronic pain in central neuropathy and fibromyalgia. A supplemental delta 9-THC treatment as part of a broader pain management plan therefore may represent a promising coanalgesic therapeutic option.

  10. Use of Methadone for Neuropathic Pain

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    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...

  11. Neurotrophins and Neuropathic Pain: Role in Pathobiology

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    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.

  12. Use of Methadone for Neuropathic Pain

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    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.

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

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    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.

  14. Neuropathic pain and cytokines: current perspectives

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    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

  15. Importance of glial activation in neuropathic pain.

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    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

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

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    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.

  17. Antinociceptive effects of neurotropin in a rat model of central neuropathic pain: DSP-4 induced noradrenergic lesion.

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

    2011-09-26

    Neurotropin is a nonprotein extract isolated from inflamed skin of rabbits inoculated with vaccinia virus, and used for treatment of neuropathic pain. In the present study, we have determined whether neurotropin could exert antinociceptive action using the central neuropathic pain model that we recently established. Rats were randomly allocated to 3 groups: Sham group (n=20), DSP-4 [N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine] group (50mg/kg ip, n=18), and DSP-4+5,7-DHT [5,7-dihydroxytryptamine] group (ip DSP-4 50mg/kg+icv 5,7-DHT 200μg, n=18). In Sham, DSP-4 and DSP-4+5,7-DHT groups, the effects of ip neurotropin (100NU/Kg) on hot-plate latency in rats with no lesion, noradrenergic neuron depletion and both noradrenergic and serotonergic neuronal depletion were studied, respectively. Rats in each group were subdivided equally to 2 subgroups: saline and neurotropin. After completion of the hot-plate tests, each rat was decapitated, the cerebral cortex was dissected from its internal structure for measurement of norepinephrine contents. Hot-plate latency significantly decreased by ∼40% 10 days after ip DSP-4 or after ip DSP-4 and 5,7-DHT. Norepinephrine contents in DSP-4 treated rats (55.6±6.3ng/ng tissue) and DSP-4+5,7-DHT treated rats (35.3±6.3ng/ng tissue) were significantly lower than those in intact rats (131.6±5.7ng/ng tissue, p<0.01). Neurotropin significantly increased the area under the curve (AUC) of the hot-plate latency in the DSP-4 and DSP-4+5,7-DHT groups but not in the Sham group. There was a significant correlation between AUC and norepinephrine contents in saline subgroup (p<0.01, r=0.597) but not in neurotropin subgroup in DSP-4 group. Neurotropin exerted an antinociceptive effect in DSP-4 induced central neuropathic pain. The present data suggest neuronal pathways other than descending inhibitory noradrenergic and serotonergic systems may be involved in neurotropin mediated antinociception.

  18. Nurse’s knowledge of neuropathic pain

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    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.

  19. Diagnostic tools for neuropathic pain

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    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.

  20. Prevalence of Neuropathic Pain and the Need for Treatment

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    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...

  1. Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen.

    Science.gov (United States)

    Vranken, J H; Dijkgraaf, M G W; Kruis, M R; van der Vegt, M H; Hollmann, M W; Heesen, M

    2008-05-01

    The effective treatment of patients suffering from central neuropathic pain remains a clinical challenge, despite a standard pharmacological approach in combination with anticonvulsants and antidepressants. A randomized, double-blinded, placebo-controlled trial evaluated the effects of pregabalin on pain relief, tolerability, health status, and quality of life in patients with central neuropathic pain caused by brain or spinal cord injuries. At baseline and 4 weeks after the start of treatment subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analog scale, health status (Pain Disability Index and EQ-5D) and quality of life (SF-36). Forty patients received escalating doses of either pregabalin (150, 300, and 600mg/day) or matching placebo capsules. In both groups, patients started with 1 capsule per day (either 150mg of pregabalin or placebo). If pain relief was insufficient, patients were titrated to a higher dose. There was a statistically significant decrease in mean pain score at endpoint for pregabalin treatment, compared with placebo (P=0.016). Follow-up observation showed no significant difference in Pain Disability Index scores between the two groups. The pregabalin group, however, showed a statistically significant improvement for the EQ-5D. Pregabalin treatment led to a significant improvement in the bodily pain domain of the SF36. In the other domains, more favorable scores were reported without reaching statistical significance. Pregabalin, in a flexible-dose regime, produced clinically significant reductions in pain, as well as improvements in health status in patients suffering from severe central neuropathic pain.

  2. [Neuromodulation in severe neuropathic pain].

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    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.

  3. Pharmacogenomics of neuropathic pain

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    Vandana Sharma

    2017-01-01

    Full Text Available Variation in pain sensitivity and analgesic drug response is well recognized among individuals. Pharmacogenomics hypothesis dictates that a patient′s response to a drug or development of adverse drug effects may depend on variation in genetic profile, in particular, the different alleles for the same gene that an individual carries. A review of the role of genetic variations in determining the receptor sensitivity and modulation of pain, response to analgesics drugs and their interactions are presented in this article. It is already known that genomic variations affect the pharmacokinetic and pharmacodynamic properties of various analgesic drugs. Genes related to the expression of mu-opioid receptor, ATP-binding cassette B1 (ABCB1, catechol-O-Methyl Transferase (COMT, Cytochrome P450 enzymes have been widely studied and show some promise in determining the drug response in individuals. Some recent studies on sodium channel mutations (SCN9A, SCN11A have been implicated in congenital insensitivity to pain. Voltage gated ion channels such as sodium, calcium and potassium channels are being targeted for development of novel analgesics. Based on the available research, the clinical implementation of pharmacogenomics for personalized pain medicine is still in its infancy, but is promising. These are opening further opportunities for development of newer analgesics targeting pain receptors and ion channels.

  4. PHARMACOTHERAPY IN ELDERLY NEUROPATHIC PAIN

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    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

  5. Chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala.

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    Li, Ming-Jia; Liu, Ling-Yu; Chen, Lin; Cai, Jie; Wan, You; Xing, Guo-Gang

    2017-04-01

    Exacerbation of pain by chronic stress and comorbidity of pain with stress-related psychiatric disorders, including anxiety and depression, represent significant clinical challenges. However, the underlying mechanisms still remain unclear. Here, we investigated whether chronic forced swim stress (CFSS)-induced exacerbation of neuropathic pain is mediated by the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala (CeA). We first demonstrated that CFSS indeed produces both depressive-like behaviors and exacerbation of spared nerve injury (SNI)-induced mechanical allodynia in rats. Moreover, we revealed that CFSS induces both sensitization of basolateral amygdala (BLA) neurons and augmentation of long-term potentiation (LTP) at the BLA-CeA synapse and meanwhile, exaggerates both SNI-induced sensitization of CeA neurons and LTP at the parabrachial (PB)-CeA synapse. In addition, we discovered that CFSS elevates SNI-induced functional up-regulation of GluN2B-containing NMDA (GluN2B-NMDA) receptors in the CeA, which is proved to be necessary for CFSS-induced augmentation of LTP at the PB-CeA synapse and exacerbation of pain hypersensitivity in SNI rats. Suppression of CFSS-elicited depressive-like behaviors by antidepressants imipramine or ifenprodil inhibits the CFSS-induced exacerbation of neuropathic pain. Collectively, our findings suggest that CFSS potentiates synaptic efficiency of the BLA-CeA pathway, leading to the activation of GluN2B-NMDA receptors and sensitization of CeA neurons, which subsequently facilitate pain-related synaptic plasticity of the PB-CeA pathway, thereby exacerbating SNI-induced neuropathic pain. We conclude that chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the CeA.

  6. Evidence-based pharmacological management of chronic neuropathic pain

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    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

  7. Neuropathic pain: is quantitative sensory testing helpful?

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    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.

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

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    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.

  9. Individualized pharmacological treatment of neuropathic pain.

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    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.

  10. The evidence for pharmacological treatment of neuropathic pain.

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    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.

  11. Molecular hydrogen attenuates neuropathic pain in mice.

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    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.

  12. Self-reported pain severity, quality of life, disability, anxiety and depression in patients classified with 'nociceptive', 'peripheral neuropathic' and 'central sensitisation' pain. The discriminant validity of mechanisms-based classifications of low back (±leg) pain.

    LENUS (Irish Health Repository)

    Smart, Keith M

    2012-04-01

    Evidence of validity is required to support the use of mechanisms-based classifications of pain clinically. The purpose of this study was to evaluate the discriminant validity of \\'nociceptive\\' (NP), \\'peripheral neuropathic\\' (PNP) and \\'central sensitisation\\' (CSP) as mechanisms-based classifications of pain in patients with low back (±leg) pain by evaluating the extent to which patients classified in this way differ from one another according to health measures associated with various dimensions of pain. This study employed a cross-sectional, between-subjects design. Four hundred and sixty-four patients with low back (±leg) pain were assessed using a standardised assessment protocol. Clinicians classified each patient\\'s pain using a mechanisms-based classification approach. Patients completed a number of self-report measures associated with pain severity, health-related quality of life, functional disability, anxiety and depression. Discriminant validity was evaluated using a multivariate analysis of variance. There was a statistically significant difference between pain classifications on the combined self-report measures, (p = .001; Pillai\\'s Trace = .33; partial eta squared = .16). Patients classified with CSP (n = 106) reported significantly more severe pain, poorer general health-related quality of life, and greater levels of back pain-related disability, depression and anxiety compared to those classified with PNP (n = 102) and NP (n = 256). A similar pattern was found in patients with PNP compared to NP. Mechanisms-based pain classifications may reflect meaningful differences in attributes underlying the multidimensionality of pain. Further studies are required to evaluate the construct and criterion validity of mechanisms-based classifications of musculoskeletal pain.

  13. 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.

  14. 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...

  15. 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.

  16. 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.

  17. Placebo manipulations reduce hyperalgesia in neuropathic pain.

    Science.gov (United States)

    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.

  18. Cerebral decreases in opioid receptor binding in patients with central neuropathic pain measured by [11C]diprenorphine binding and PET.

    Science.gov (United States)

    Jones, Anthony K P; Watabe, Hiroshi; Cunningham, Vin J; Jones, Terry

    2004-10-01

    Central neuropathic pain (CNP) is pain resulting from damage to the central nervous system. Up till now, it has not been possible to identify a common lesion or pharmacological deficit in these patients. This preliminary study in a group of patients with CNP with predominantly post-stroke pain, demonstrates that there is significantly less opioid receptor binding in a number of cortical and sub-cortical structures that are mostly, but not exclusively, within the medial pain system in patients compared to age-matched pain-free controls. The reductions in opioid receptor binding within the medial system were observed mainly in the dorsolateral (Brodman area 10) and anterior cingulate (Brodman area 24 with some extension into area 23) and insula cortices and the thalamus. There were also reductions in the lateral pain system within the inferior parietal cortex (Brodman area 40). These changes in binding could not be accounted for by the cerebral lesions shown by CT or MRI, which were outside the areas of reduced binding and the human pain system. To our knowledge this is the first systematic demonstration of a reduction in opioid receptor-binding capacity in neurones within the human nociceptive system in patients with CNP. This may be a key common factor resulting in undamped nociceptor activity within some of the structures that are predominantly within the medial nociceptive system. If confirmed, these findings may explain why certain patients with CNP require high doses of synthetic opiates to achieve optimum analgesia. The findings also raise the possibility of new pharmacological approaches to treatment.

  19. 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.

  20. 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.

  1. 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.

  2. Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats.

    Science.gov (United States)

    Gwak, Young S; Kang, Jonghoon; Unabia, Geda C; Hulsebosch, Claire E

    2012-04-01

    In the spinal cord, neuron and glial cells actively interact and contribute to neurofunction. Surprisingly, both cell types have similar receptors, transporters and ion channels and also produce similar neurotransmitters and cytokines. The neuroanatomical and neurochemical similarities work synergistically to maintain physiological homeostasis in the normal spinal cord. However, in trauma or disease states, spinal glia become activated, dorsal horn neurons become hyperexcitable contributing to sensitized neuronal-glial circuits. The maladaptive spinal circuits directly affect synaptic excitability, including activation of intracellular downstream cascades that result in enhanced evoked and spontaneous activity in dorsal horn neurons with the result that abnormal pain syndromes develop. Recent literature reported that spinal cord injury produces glial activation in the dorsal horn; however, the majority of glial activation studies after SCI have focused on transient and/or acute time points, from a few hours to 1 month, and peri-lesion sites, a few millimeters rostral and caudal to the lesion site. In addition, thoracic spinal cord injury produces activation of astrocytes and microglia that contributes to dorsal horn neuronal hyperexcitability and central neuropathic pain in above-level, at-level and below-level segments remote from the lesion in the spinal cord. The cellular and molecular events of glial activation are not simple events, rather they are the consequence of a combination of several neurochemical and neurophysiological changes following SCI. The ionic imbalances, neuroinflammation and alterations of cell cycle proteins after SCI are predominant components for neuroanatomical and neurochemical changes that result in glial activation. More importantly, SCI induced release of glutamate, proinflammatory cytokines, ATP, reactive oxygen species (ROS) and neurotrophic factors trigger activation of postsynaptic neuron and glial cells via their own receptors

  3. Basolateral amygdala lesion inhibits the development of pain chronicity in neuropathic pain rats.

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    Zheng Li

    Full Text Available BACKGROUND: Chronicity of pain is one of the most interesting questions in chronic pain study. Clinical and experimental data suggest that supraspinal areas responsible for negative emotions such as depression and anxiety contribute to the chronicity of pain. The amygdala is suspected to be a potential structure for the pain chronicity due to its critical role in processing negative emotions and pain information. OBJECTIVE: This study aimed to investigate whether amygdala or its subregions, the basolateral amygdala (BLA and the central medial amygdala (CeA, contributes to the pain chronicity in the spared nerve injury (SNI-induced neuropathic pain model of rats. METHODOLOGY/PRINCIPAL FINDINGS: (1 Before the establishment of the SNI-induced neuropathic pain model of rats, lesion of the amygdaloid complex with stereotaxic injection of ibotenic acid (IBO alleviated mechanical allodynia significantly at days 7 and 14, even no mechanical allodynia at day 28 after SNI; Lesion of the BLA, but not the CeA had similar effects; (2 however, 7 days after SNI when the neuropathic pain model was established, lesion of the amygdala complex or the BLA or the CeA, mechanical allodynia was not affected. CONCLUSION: These results suggest that BLA activities in the early stage after nerve injury might be crucial to the development of pain chronicity, and amygdala-related negative emotions and pain-related memories could promote pain chronicity.

  4. 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.

  5. 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.

  6. 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...

  7. 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

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    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

  10. EFNS guidelines on pharmacological treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Attal, Nadine; Cruccu, G; Haanpää, M

    2006-01-01

    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...... 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...

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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...

  1. 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

  2. Biochanin-A attenuates neuropathic pain in diabetic rats

    Directory of Open Access Journals (Sweden)

    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.

  3. 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.

  4. Psychometric validation of the Portuguese version of the Neuropathic Pain Symptoms Inventory

    Directory of Open Access Journals (Sweden)

    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.

  5. 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.

  6. 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?

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. [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.

  14. Self-reported somatosensory symptoms of neuropathic pain in fibromyalgia and chronic widespread pain correlate with tender point count and pressure-pain thresholds

    DEFF Research Database (Denmark)

    Amris, Kirstine; Jespersen, Anders; Bliddal, Henning

    2010-01-01

    Widespread pain and pain hypersensitivity are the hallmark of fibromyalgia, a complex pain condition linked to central sensitization. In this study the painDETECT questionnaire (PDQ), validated to identify neuropathic pain and based on pain quality items, was applied in a cross-sectional sample...... of patients with chronic widespread pain (CWP). The aims of the study were to assess the patient-reported sensory neuropathic symptoms by PDQ and to correlate these with tender point (TP) count and pressure-pain thresholds. Eighty-one patients (75 F, 6 M) with CWP (ACR-criteria) filled in the PDQ. Manual TP...... examination was conducted according to ACR guidelines. Computerized cuff pressure algometry was used for the assessment of pressure-pain detection thresholds (PDT, unit: kPa) and pressure-pain tolerance thresholds (PTT, unit: kPa). Mean TP count was 14.32 (range: 2-18), mean PDQ score 22.75 (range: 5...

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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...

  2. 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.

  3. Fear of pain in children and adolescents with neuropathic pain and complex regional pain syndrome.

    Science.gov (United States)

    Simons, Laura E

    2016-02-01

    A significant proportion of children and adolescents with chronic pain endorse elevated pain-related fear. Pain-related fear is associated with high levels of disability, depressive symptoms, and school impairment. Because of faulty nerve signaling, individuals with neuropathic pain and complex regional pain syndrome may be more prone to develop pain-related fear as they avoid use of and neglect the affected body area(s), resulting in exacerbated symptoms, muscle atrophy, maintenance of pain signaling, and ongoing pain-related disability. Not surprisingly, effective treatments for elevated pain-related fears involve exposure to previously avoided activities to downregulate incorrect pain signaling. In the context of intensive interdisciplinary pain treatment of youth with neuropathic pain, decreasing pain-related fear is associated with improved physical and psychological functioning, whereas high initial pain-related fear is a risk factor for less treatment responsiveness. An innovative approach to targeting pain-related fear and evidence of a neural response to treatment involving decoupling of the amygdala with key fear circuits in youth with complex regional pain syndrome suggest breakthroughs in our ability to ameliorate these issues.

  4. 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....

  5. 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.

  6. Pain relief with lidocaine 5% patch in localized peripheral neuropathic pain in relation to pain phenotype

    DEFF Research Database (Denmark)

    Demant, Dyveke T; Lund, Karen; Finnerup, Nanna B

    2015-01-01

    irritable nociceptor phenotype as defined by hypersensitivity and preserved small fibre function determined by quantitative sensory testing. Forty-six patients with neuropathic pain due to nerve injury or postherpetic neuralgia were randomised. The modified intention-to-treat population comprised 15...

  7. 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.

  8. [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.

  9. Recent evidence for activity-dependent initiation of sympathetic sprouting and neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    Jun-Ming ZHANG; Judith A. Strong

    2008-01-01

    Traumatic injury or inflammatory irritation of the peripheral nervous system often leads to persistent pathophysiological pain states. It has been well-documented that, after peripheral nerve injury or inflammation, functional and anatomical alterations sweep over the entire peripheral nervous system including the peripheral nerve endings, the injured or inflamed afferent fibers, the dorsal root ganglion (DRG), and the central afferent terminals in the spinal cord. Among all the changes, ectopic discharge or spontaneous activity of primary sensory neurons is of great clinical interest, as such discharges doubtless contribute to the develop-ment of pathological pain states such as neuropathic pain. Two key sources of abnormal spontaneous activity have been identified following peripheral nerve injury: the injured afferent fibers (neuroma) leading to the DRG, and the DRG somata. The purpose of this review is to provide a global account of the abnormal spontaneous activity in various animal models of pain. Particular attention is focused on the consequence of peripheral nerve injury and localized inflammation. Further, mechanisms involved in the generation of spontaneous activity are also reviewed; evidence of spontaneous activity in contributing to abnormal sympathetic sprouting in the axotomized DRG and to the initiation of neuropathic pain based on new findings from our research group are discussed. An improved understanding of the causes of spontaneous activity and the origins of neuropathic pain should facilitate the development of novel strategies for effective treatment of pathological pain.

  10. 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...

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

    Directory of Open Access Journals (Sweden)

    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.

  12. 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.

  13. 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,

  14. Neuropathic pain, back to the patient

    NARCIS (Netherlands)

    R. van Seventer (Robert)

    2011-01-01

    markdownabstract__Abstract__ Pain can be classified in several ways. The International Association for the Study of Pain (IASP) recommends describing pain according to five categories or axes, namely its anatomical location (neck, lower back, etc.), the body system involved (gastrointestinal, nervo

  15. 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...

  16. Pain severity and the economic burden of neuropathic pain in the United States: BEAT Neuropathic Pain Observational Study

    Directory of Open Access Journals (Sweden)

    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

  17. 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.

  18. 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

  19. The antihyperalgesic effect of cytidine-5'-diphosphate-choline in neuropathic and inflammatory pain models.

    Science.gov (United States)

    Bagdas, Deniz; Sonat, Fusun Ak; Hamurtekin, Emre; Sonal, Songul; Gurun, Mine Sibel

    2011-09-01

    This study was designed to test the effects of intracerebroventricularly (i.c.v.) administered CDP-choline (cytidine-5'-diphosphate-choline; citicoline) and its metabolites in rat models of inflammatory and neuropathic pain. The i.c.v. administration of CDP-choline (0.5, 1.0 and 2.0 µmol) produced a dose and time-dependent reversal of mechanical hyperalgesia in both carrageenan-induced inflammatory and chronic constriction injury-induced neuropathic pain models in rats. The antihyperalgesic effect of CDP-choline was similar to that observed with an equimolar dose of choline (1 µmol). The CDP-choline-induced antihyperalgesic effect was prevented by central administration of the neuronal high-affinity choline uptake inhibitor hemicholinium-3 (1 µg), the nonselective nicotinic receptor antagonist mecamylamine (50 µg), the α7-selective nicotinic ACh receptor antagonist, α-bungarotoxin (2 µg) and the γ-aminobutyric acid B receptor antagonist CGP-35348 (20 µg). In contrast, i.c.v. pretreatment with the nonselective opioid receptor antagonist naloxone (10 µg) only prevented the CDP-choline-induced antihyperalgesic effect in the neuropathic pain model while the nonselective muscarinic receptor antagonist atropine (10 µg) did not alter the antihyperalgesic effect in the two models. These results indicate that CDP-choline-elicited antihyperalgesic effect in different models of pain occurs through mechanisms that seem to involve an interaction with supraspinal α7-selective nicotinic ACh receptors, and γ-aminobutyric acid B receptors, whereas central opioid receptors have a role only in the neuropathic pain model.

  20. Fibromyalgia as a neuropathic pain syndrome

    Directory of Open Access Journals (Sweden)

    Manuel Martinez-Lavin

    2003-06-01

    Full Text Available This article discusses scientific evidence supporting the notion that all fibromyalgia (FM features can be explained on the basis of autonomic (sympathetic nervous system dysfunction. Also suggests that FM main features (widespread pain and tenderness at palpation on specific anatomic points are manifestations of painful neuropathy. On these bases, a holistic approach for FM treatment is proposed.

  1. 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.

  2. 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.

  3. 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.

  4. Central Pain Syndrome

    Science.gov (United States)

    ... or hands. Central pain syndrome often begins shortly after the causative injury or damage, but may be delayed by months or even years, especially if it is related to post-stroke pain. × Definition Central pain syndrome is a neurological ...

  5. Prevalence and associations of neuropathic pain in a cohort of multi-ethnic Asian low back pain patients.

    Science.gov (United States)

    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.

  6. 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...

  7. 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

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

    Science.gov (United States)

    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.

  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. Dor neuropática central após lesão medular traumática: capacidade funcional e aspectos sociais Dolor neuropático central después de lesión medular traumática: capacidad funcional y aspectos sociales Central neuropathic pain after traumatic spinal cord injury: functional capacity and social aspects

    Directory of Open Access Journals (Sweden)

    Janaina Vall

    2005-12-01

    Full Text Available Estudo de caso comparativo com o objetivo de avaliar a capacidade funcional e os aspectos sociais de dois pacientes, ambos com lesão medular traumática, sem e com dor neuropática central associada, respectivamente. Para avaliar a capacidade funcional, foi utilizado como instrumento o Functional Independence Measure ou Escala de Independência Funcional. E para avaliar os aspectos sociais foi construído o ecomapa de cada paciente, preconizado pelo modelo Calgary de avaliação de famílias. Ambos foram aplicados no domicílio do paciente. Os resultados mostraram que o paciente com dor neuropática central secundária à lesão medular possui baixa capacidade funcional e precária rede social de apoio, quando comparado com o paciente com as mesmas condições, porém sem dor associada.Estudio de caso comparativo con el objetivo de evaluar la capacidad funcional y los aspectos sociales de dos paciente, ambos con lesión medular traumática, sin y con el dolor neuropático central, respectivamente. Para evaluar la capacidad funcional, se usó como instrumento la Escala de Independencia Funcional. Y para evaluar los aspectos sociales, el ecomapa de cada paciente fue construido, preconizado por el modelo Calgary de evaluación de familias. Los dos furon aplicados en la casa del paciente. Los resultados mostraron que el paciente con dolor neuropatico central secundario a la lesión medular posee capacidad funcional baja y precaria red social de apoyo, cuando comparado con el paciente con las mismas condiciones, pero sin el dolor asociado.Comparative study of case with the aim of evaluating the functional capacity and social aspects of two patients, both with traumatic spinal cord injury, without and with central neuropathic pain associated, respectively. To evaluate the functional capacity it was used as instrument Functional Independence Measure. And to evaluate the social aspects the ecomap of each patient one it was built, extolled by the model

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with neuromyelitis optica.

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    Hannah L Pellkofer

    Full Text Available Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO. While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST following the protocol of the German Research Network on Neuropathic Pain (DFNS. Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11 suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG. These data emphasize the high prevalence of neuropathic pain and hyperalgesia

  18. [Controlled release hydromorphone for visceral, somatic and neuropathic pain].

    Science.gov (United States)

    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.

  19. Pain-related psychological distress, self-rated health and significance of neuropathic pain in Danish soldiers injured in Afghanistan

    DEFF Research Database (Denmark)

    Duffy, J R; Warburg, Finn; Koelle, S-F T

    2015-01-01

    BACKGROUND: Pain and mental health concerns are prevalent among veterans. While the majority of research has focused on chronic pain as an entity, there has been little work directed towards investigating the role of neuropathic pain in relation to psychological comorbidity. As such, we hypothesi......BACKGROUND: Pain and mental health concerns are prevalent among veterans. While the majority of research has focused on chronic pain as an entity, there has been little work directed towards investigating the role of neuropathic pain in relation to psychological comorbidity. As such, we...... hypothesised that participants with signs of neuropathic pain would report higher levels of psychological distress and diminished self-rated health compared to those without a neuropathic component. METHODS: A retrospective review of standardised questionnaires (PainDETECT Questionnaire, Post-traumatic Stress...... Disorder Checklist-Civilian, the Hospital Anxiety and Depression Scale, and EuroQOL Visual Analogue Scale) administered to injured soldiers. The participants were classified into three groups according to the PainDETECT questionnaire: non-neuropathic pain, possible neuropathic pain and definite neuropathic...

  20. 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

  1. 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 .

  2. 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.

  3. 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.

  4. A Review of Select Centralized Pain Syndromes

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    David R. Spiegel

    2015-01-01

    Full Text Available Pain can be broadly divided into 3 classes, including nociceptive or inflammatory pain (protective, neuropathic (pathological, occurring after damage to the nervous system, or centralized (pathological, due to abnormal function but with no damage or inflammation to the nervous system. The latter has been posited to occur when descending analgesic pathways are attenuated and/or glutamatergic transmission is facilitated. Additionally, this “pain prone phenotype” can be associated with early life trauma and a suboptimal response to opiates. This article will review the relationships between centralized pain syndromes (ie, fibromyalgia, chronic low back pain, childhood sexual abuse, and opiate misuse. Finally, treatment implications, potentially effecting primary care physicians, will be discussed.

  5. 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

  6. Reaction to topical capsaicin in spinal cord injury patients with and without central pain

    DEFF Research Database (Denmark)

    Finnerup, Nanna Brix; Pedersen, Louise H.; Terkelsen, Astrid J.

    2007-01-01

    Central neuropathic pain is a debilitating and frequent complication to spinal cord injury (SCI). Excitatory input from hyperexcitable cells around the injured grey matter zone is suggested to play a role for central neuropathic pain felt below the level of a spinal cord injury. Direct evidence...... of a spinal cord injury which already is hyperexcitable, would cause enhanced responses in patients with central pain at the level of injury compared to patients without neuropathic pain and healthy controls. Touch, punctuate stimuli, cold stimuli and topical capsaicin was applied above, at, and below injury...... level in 10 SCI patients with central pain below a thoracic injury, in 10 SCI patients with a thoracic injury but without neuropathic pain, and in corresponding areas in 10 healthy control subjects. The study found increased responses to touch at injury level compared to controls (p = 0...

  7. 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.

  8. Effects of intrathecal and intracerebroventricular administration of luteolin in a rat neuropathic pain model.

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    Hara, Koji; Haranishi, Yasunori; Terada, Tadanori; Takahashi, Yoshihiro; Nakamura, Motohiro; Sata, Takeyoshi

    2014-10-01

    Luteolin, a major component of flavones, is known to have various physiological properties. Although luteolin reportedly has an antinociceptive effect on acute and inflammatory pain, little is known about its effect on neuropathic pain. The aim of the present study was to determine whether luteolin could ameliorate hyperalgesia in the central nervous system using a neuropathic pain model. Chronic constriction injury to the sciatic nerve was induced in male Sprague-Dawley rats. Luteolin (0.1-1.5 mg) was administered intrathecally or intracerebroventricularly to examine the central effects on mechanical, thermal, and cold hyperalgesia using the electronic von Frey test, plantar test, and cold plate test, respectively. A rotarod test was also performed to assess motor function in normal rats. Spinally applied luteolin dose-dependently attenuated mechanical and cold hyperalgesia, but it had no effect on thermal hyperalgesia. At the highest dose, luteolin affected motor performance. The spinal action of luteolin on mechanical hyperalgesia was inhibited by intrathecal pretreatment with the γ-aminobutyric acidA (GABAA) receptor antagonist bicuculline and μ-opioid receptor antagonist naloxone, but not by intrathecal pretreatment with either the benzodiazepine receptor antagonist flumazenil or glycine receptor antagonist strychnine. Supraspinal application of luteolin had no antihyperalgesic effects in any test. These findings suggest that luteolin ameliorates mechanical and cold hyperalgesia at least in part by activating GABAA receptors in a flumazenil-insensitive manner and μ-opioid receptors in the spinal cord, but that the supraspinal regions are unlikely to contribute to the antihyperalgesic action of luteolin. Luteolin could be a candidate therapeutic agent for neuropathic pain.

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

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    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.

  10. Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain

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    Salter Michael W

    2007-09-01

    Full Text Available Abstract Background Disinhibition of neurons in the superficial spinal dorsal horn, via microglia – neuron signaling leading to disruption of chloride homeostasis, is a potential cellular substrate for neuropathic pain. But, a central unresolved question is whether this disinhibition can transform the activity and responses of spinal nociceptive output neurons to account for the symptoms of neuropathic pain. Results Here we show that peripheral nerve injury, local spinal administration of ATP-stimulated microglia or pharmacological disruption of chloride transport change the phenotype of spinal lamina I output neurons, causing them to 1 increase the gain of nociceptive responsiveness, 2 relay innocuous mechanical input and 3 generate spontaneous bursts of activity. The changes in the electrophysiological phenotype of lamina I neurons may account for three principal components of neuropathic pain: hyperalgesia, mechanical allodynia and spontaneous pain, respectively. Conclusion The transformation of discharge activity and sensory specificity provides an aberrant signal in a primarily nociceptive ascending pathway that may serve as a basis for the symptoms of neuropathic pain.

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

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    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.

  12. 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

  13. Neuropathic pain-induced enhancement of spontaneous and pain-evoked neuronal activity in the periaqueductal gray that is attenuated by gabapentin.

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    Samineni, Vijay K; Premkumar, Louis S; Faingold, Carl L

    2017-03-21

    Neuropathic pain is a debilitating pathological condition that is poorly understood. Recent evidence suggests that abnormal central processing occurs during the development of neuropathic pain induced by the cancer chemotherapeutic agent, paclitaxel. Yet, it is unclear what role neurons in supraspinal pain network sites, such as the periaqueductal gray, play in altered behavioral sensitivity seen during chronic pain conditions. To elucidate these mechanisms, we studied the spontaneous and thermally evoked firing patterns of ventrolateral periaqueductal gray (vlPAG) neurons in awake-behaving rats treated with paclitaxel to induce neuropathic pain. In the present study, vlPAG neurons in naive rats exhibited either excitatory, inhibitory, or neutral responses to noxious thermal stimuli, as previously observed. However, after development of behavioral hypersensitivity induced by the chemotherapeutic agent, paclitaxel, vlPAG neurons displayed increased neuronal activity and changes in thermal pain-evoked neuronal activity. This involved elevated levels of spontaneous firing and heightened responsiveness to nonnoxious stimuli (allodynia) as well as noxious thermal stimuli (hyperalgesia) as compared with controls. Furthermore, after paclitaxel treatment, only excitatory neuronal responses were observed for both nonnoxious and noxious thermal stimuli. Systemic administration of gabapentin, a nonopioid analgesic, induced significant dose-dependent decreases in the elevated spontaneous and thermally evoked vlPAG neuronal firing to both nonnoxious and noxious thermal stimuli in rats exhibiting neuropathic pain, but not in naive rats. Thus, these results show a strong correlation between behavioral hypersensitivity to thermal stimuli and increased firing of vlPAG neurons in allodynia and hyperalgesia that occur in this neuropathic pain model.

  14. Duloxetine in the management of diabetic peripheral neuropathic pain

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    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

  15. 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.

  16. Antihyperalgesic Effect of Hesperidin Improves with Diosmin in Experimental Neuropathic Pain.

    Science.gov (United States)

    Carballo-Villalobos, Azucena I; González-Trujano, María-Eva; Pellicer, Francisco; López-Muñoz, Francisco J

    Neuropathic pain is caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system. In this study, we investigated the hesperidin antihyperalgesic effects alone or combined with diosmin in a model of neuropathic pain to corroborate a possible synergistic antinociceptive activity. Mechanical and thermal hyperalgesia were assessed in the aesthesiometer and plantar tests, respectively, after chronic constriction injury (CCI) model in rats receiving hesperidin (HS, 5 doses from 10 to 1000 mg/kg) alone or combined with diosmin (DS, 10 and 100 mg/kg) in comparison to gabapentin (31.6 mg/kg). UHPLC-MS analysis of cerebral samples was used to recognize the central concentrations of these flavonoids. Participation of different receptors was also investigated in the presence of haloperidol, bicuculline, and naloxone antagonists. Acute hesperidin administration significantly decreased mechanical and thermal hyperalgesia in CCI rats. Antihyperalgesic response of hesperidin, improved by a combination with diosmin (DS10/HS100) in both stimuli, was blockaded by haloperidol, bicuculline, and naloxone, but not WAY100635, antagonists. Both flavonoids were detected in brain samples. In conclusion, hesperidin alone and combined with diosmin produces antihyperalgesic response in the CCI model in rats. Antihyperalgesic effect of DS10/HS100 combination involves central activity partially modulated by D2, GABAA, and opioids, but not by 5-HT1A, receptors.

  17. Antihyperalgesic Effect of Hesperidin Improves with Diosmin in Experimental Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Azucena I. Carballo-Villalobos

    2016-01-01

    Full Text Available Neuropathic pain is caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system. In this study, we investigated the hesperidin antihyperalgesic effects alone or combined with diosmin in a model of neuropathic pain to corroborate a possible synergistic antinociceptive activity. Mechanical and thermal hyperalgesia were assessed in the aesthesiometer and plantar tests, respectively, after chronic constriction injury (CCI model in rats receiving hesperidin (HS, 5 doses from 10 to 1000 mg/kg alone or combined with diosmin (DS, 10 and 100 mg/kg in comparison to gabapentin (31.6 mg/kg. UHPLC-MS analysis of cerebral samples was used to recognize the central concentrations of these flavonoids. Participation of different receptors was also investigated in the presence of haloperidol, bicuculline, and naloxone antagonists. Acute hesperidin administration significantly decreased mechanical and thermal hyperalgesia in CCI rats. Antihyperalgesic response of hesperidin, improved by a combination with diosmin (DS10/HS100 in both stimuli, was blockaded by haloperidol, bicuculline, and naloxone, but not WAY100635, antagonists. Both flavonoids were detected in brain samples. In conclusion, hesperidin alone and combined with diosmin produces antihyperalgesic response in the CCI model in rats. Antihyperalgesic effect of DS10/HS100 combination involves central activity partially modulated by D2, GABAA, and opioids, but not by 5-HT1A, receptors.

  18. Antihyperalgesic Effect of Hesperidin Improves with Diosmin in Experimental Neuropathic Pain

    Science.gov (United States)

    Pellicer, Francisco; López-Muñoz, Francisco J.

    2016-01-01

    Neuropathic pain is caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system. In this study, we investigated the hesperidin antihyperalgesic effects alone or combined with diosmin in a model of neuropathic pain to corroborate a possible synergistic antinociceptive activity. Mechanical and thermal hyperalgesia were assessed in the aesthesiometer and plantar tests, respectively, after chronic constriction injury (CCI) model in rats receiving hesperidin (HS, 5 doses from 10 to 1000 mg/kg) alone or combined with diosmin (DS, 10 and 100 mg/kg) in comparison to gabapentin (31.6 mg/kg). UHPLC-MS analysis of cerebral samples was used to recognize the central concentrations of these flavonoids. Participation of different receptors was also investigated in the presence of haloperidol, bicuculline, and naloxone antagonists. Acute hesperidin administration significantly decreased mechanical and thermal hyperalgesia in CCI rats. Antihyperalgesic response of hesperidin, improved by a combination with diosmin (DS10/HS100) in both stimuli, was blockaded by haloperidol, bicuculline, and naloxone, but not WAY100635, antagonists. Both flavonoids were detected in brain samples. In conclusion, hesperidin alone and combined with diosmin produces antihyperalgesic response in the CCI model in rats. Antihyperalgesic effect of DS10/HS100 combination involves central activity partially modulated by D2, GABAA, and opioids, but not by 5-HT1A, receptors. PMID:27672659

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  1. TMEM16F Regulates Spinal Microglial Function in Neuropathic Pain States

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    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.

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

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    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.

  3. A comparison of coping strategies in patients with fibromyalgia, chronic neuropathic pain, and pain-free controls

    DEFF Research Database (Denmark)

    Baastrup, Sidsel; Schultz, Rikke; Moore, Rod;

    2016-01-01

    different groups of chronic pain patients and a group of healthy controls. Thirty neuropathic pain (NP) patients, 28 fibromyalgia (FM) patients, and 26 pain-free healthy controls completed the Coping Strategy Questionnaire (CSQ-48/27) and rated their daily pain. The results showed that FM and NP patients...

  4. Imaging central pain syndromes.

    Science.gov (United States)

    Veldhuijzen, Dieuwke S; Greenspan, Joel D; Kim, Jong H; Coghill, Robert C; Treede, Rolf-Detlef; Ohara, Shinji; Lenz, Frederick A

    2007-06-01

    Anatomic, functional, and neurochemical imaging studies have provided new investigative tools in the study of central pain. High-resolution imaging studies allow for precise determination of lesion location, whereas functional neuroimaging studies measure pathophysiologic consequences of injury to the central nervous system. Additionally, magnetic resonance spectroscopy evaluates lesion-induced neurochemical changes in specific brain regions that may be related to central pain. The small number of studies to date precludes definitive conclusions, but the recent findings provide information that either supports or refutes current hypotheses and can serve to generate new ideas.

  5. pain2: A neuropathic pain QTL identified on rat chromosome 2.

    Science.gov (United States)

    Nissenbaum, Jonathan; Shpigler, Hagai; Pisanté, Anne; DelCanho, Sonia; Minert, Anne; Seltzer, Ze'ev; Devor, Marshall; Darvasi, Ariel

    2008-03-01

    We aimed to locate a chronic pain-associated QTL in the rat (Rattus norvegicus) based on previous findings of a QTL (pain1) on chromosome 15 of the mouse (Mus musculus). The work was based on rat selection lines HA (high autotomy) and LA (low autotomy) which show a contrasting pain phenotype in response to nerve injury in the neuroma model of neuropathic pain. An F(2) segregating population was generated from HA and LA animals. Phenotyped F(2) rats were genotyped on chromosome 7 and chromosome 2, regions that share a partial homology with mouse chromosome 15. Our interval mapping analysis revealed a LOD score value of 3.63 (corresponding to p=0.005 after correcting for multiple testing using permutations) on rat chromosome 2, which is suggestive of the presence of a QTL affecting the predisposition to neuropathic pain. This QTL was mapped to the 14-26cM interval of chromosome 2. Interestingly, this region is syntenic to mouse chromosome 13, rather than to the region of mouse chromosome 15 that contains pain1. This chromosomal position indicates that it is possibly a new QTL, and hence we name it pain2. Further work is needed to replicate and to uncover the underlying gene(s) in both species.

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

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    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.

  7. 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...

  8. Effect of Botulinum Toxin on Disabling Neuropathic Pain: A Case Presentation Suggesting a New Therapeutic Strategy.

    Science.gov (United States)

    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.

  9. Central pain: definition, phisiopathology and therapy

    Directory of Open Access Journals (Sweden)

    Vincenzo Moschini

    2012-12-01

    Full Text Available Central pain is the expression of an injury and/or a primary or secondary dysfunction of the central nervous system.1 It is based on total or partial damage along the spinal-thalamic-cortical pathways and it may have cerebral or spinal origin. It has variable incidence according to its etiology: 8-10% in stroke patients, 30% in multiple sclerosis patients, 30-60% in paraplegic patients.2-3 At the spinal level, the most frequent causes are: traumatic injuries, cancer, plaques from multiple sclerosis, syringomyelia. In this review, we examine the main symptoms that contribute to confirm the diagnosis of central pain, neuropathic or thalamic. The presence of nerve injury, evaluated by neuroimaging and neurophysiological tests, allows us to complete the diagnostic picture.

  10. [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.

  11. 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...

  12. 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

  13. Nerve Regenerative Effects of GABA-B Ligands in a Model of Neuropathic Pain

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    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.

  14. Effects of fisetin on oxaliplatin-induced neuropathic pain in mice

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    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.

  15. 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.

  16. 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

  17. Is the pain in chronic pancreatitis of neuropathic origin? Support from EEG studies during experimental pain

    Institute of Scientific and Technical Information of China (English)

    Asbjφrn M Drewes; Maciej Gratkowski; Saber AK Sami; Georg Dimcevski; Peter Funch-Jensen; Lars Arendt-Nielsen

    2008-01-01

    AIM: To prove the hypothesis that patients with chronic pancreatitis would show increased theta activity during painful visceral stimulation.METHODS: Eight patients and 12 healthy controls underwent an experiment where the esophagus was electrically stimulated at the pain threshold using a nasal endoscope. The electroencephalogram (EEG) was recorded from 64 surface electrodes and "topographic matching pursuit" was used to extract the EEG information in the early brain activation after stimulation.RESULTS: A major difference between controls and patients were seen in delta and theta bands, whereas there were only minor differences in other frequency bands. In the theta band, the patients showed higher activity than controls persisting throughout the 450 ms of analysis with synchronous brain activation between the channels. The main theta components oscillated with 4.4Hz in the patients and 5.5Hz in the controls. The energy in the delta (0.5-3.5Hz) band was higher in the controls, whereas the patients only showed scattered activity in this band.CONCLUSION: The differences in the theta band indicate that neuropathic pain mechanisms are involved in chronic pancreatitis. This has important implications for the understanding and treatment of pain in these patients, which should be directed against drugs with effects on neuropathic pain disorders.

  18. 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

  19. [Pregabalin--profile of efficacy and tolerability in neuropathic pain].

    Science.gov (United States)

    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.

  20. 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.

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

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    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.

  2. Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain?

    Science.gov (United States)

    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.

  3. Reduction of follistatin-like 1 in primary afferent neurons contributes to neuropathic pain hypersensitivity

    Institute of Scientific and Technical Information of China (English)

    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.

  4. 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

  5. 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.

  6. R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

    Science.gov (United States)

    Marian, Claudiu; Häussler, Annett; Wijnvoord, Nina; Ziebell, Simone; Metzner, Julia; Koch, Marco; Myrczek, Thekla; Bechmann, Ingo; Kuner, Rohini; Costigan, Michael; Dehghani, Faramarz; Geisslinger, Gerd; Tegeder, Irmgard

    2010-01-01

    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 PPARγ 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. PMID:20498712

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Central sensitization in chronic low back pain: A narrative review.

    Science.gov (United States)

    Sanzarello, Ilaria; Merlini, Luciano; Rosa, Michele Attilio; Perrone, Mariada; Frugiuele, Jacopo; Borghi, Raffaele; Faldini, Cesare

    2016-11-21

    Low back pain is one of the four most common disorders in all regions, and the greatest contributor to disability worldwide, adding 10.7% of total years lost due to this health state. The etiology of chronic low back pain is, in most of the cases (up to 85%), unknown or nonspecific, while the specific causes (specific spinal pathology and neuropathic/radicular disorders) are uncommon. Central sensitization has been recently recognized as a potential pathophysiological mechanism underlying a group of chronic pain conditions, and may be a contributory factor for a sub-group of patients with chronic low back pain. The purposes of this narrative review are twofold. First, to describe central sensitization and its symptoms and signs in patients with chronic pain disorders in order to allow its recognition in patients with nonspecific low back pain. Second, to provide general treatment principles of chronic low back pain with particular emphasis on pharmacotherapy targeting central sensitization.

  9. Intrathecal siRNA against GPNMB attenuates nociception in a rat model of neuropathic pain.

    Science.gov (United States)

    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.

  10. 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.

  11. 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...

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. Participation of neuronal nitric oxide synthase in experimental neuropathic pain induced by sciatic nerve transection

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    M. Chacur

    2010-04-01

    Full Text Available Nerve injury leads to a neuropathic pain state that results from central sensitization. This phenomenom is mediated by NMDA receptors and may involve the production of nitric oxide (NO. In this study, we investigated the expression of the neuronal isoform of NO synthase (nNOS in the spinal cord of 3-month-old male, Wistar rats after sciatic nerve transection (SNT. Our attention was focused on the dorsal part of L3-L5 segments receiving sensory inputs from the sciatic nerve. SNT resulted in the development of neuropathic pain symptoms confirmed by evaluating mechanical hyperalgesia (Randall and Selitto test and allodynia (von Frey hair test. Control animals did not present any alteration (sham-animals. The selective inhibitor of nNOS, 7-nitroindazole (0.2 and 2 µg in 50 µL, blocked hyperalgesia and allodynia induced by SNT. Immunohistochemical analysis showed that nNOS was increased (48% by day 30 in the lumbar spinal cord after SNT. This increase was observed near the central canal (Rexed’s lamina X and also in lamina I-IV of the dorsal horn. Real-time PCR results indicated an increase of nNOS mRNA detected from 1 to 30 days after SNT, with the highest increase observed 1 day after injury (1469%. Immunoblotting confirmed the increase of nNOS in the spinal cord between 1 and 15 days post-lesion (20%, reaching the greatest increase (60% 30 days after surgery. The present findings demonstrate an increase of nNOS after peripheral nerve injury that may contribute to the increase of NO production observed after peripheral neuropathy.

  19. Prevalence of neuropathic features of back pain in clinical populations: implications for the diagnostic triage paradigm.

    Science.gov (United States)

    Hush, Julia M; Marcuzzi, Anna

    2012-07-01

    SUMMARY Contemporary clinical assessment of back pain is based on the diagnostic triage paradigm. The most common diagnostic classification is nonspecific back pain, considered to be of nociceptive etiology. A small proportion are diagnosed with radicular pain, of neuropathic origin. In this study we review the body of literature on the prevalence of neuropathic features of back pain, revealing that the point prevalence is 17% in primary care, 34% in mixed clinical settings and 53% in tertiary care. There is evidence that neuropathic features of back pain are not restricted to typical clinical radicular pain phenotypes and may be under-recognized, particularly in primary care. The consequence of this is that in the clinic, diagnostic triage may erroneously classify patients with nonspecific back pain or radicular pain. A promising alternative is the development of mechanism-based pain phenotyping in patients with back pain. Timely identification of contributory pain mechanisms may enable greater opportunity to select appropriate therapeutic targets and improve patient outcomes.

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

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    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

  1. Nociceptive transmission and modulation via P2X receptors in central pain syndrome.

    Science.gov (United States)

    Kuan, Yung-Hui; Shyu, Bai-Chuang

    2016-05-26

    Painful sensations are some of the most frequent complaints of patients who are admitted to local medical clinics. Persistent pain varies according to its causes, often resulting from local tissue damage or inflammation. Central somatosensory pathway lesions that are not adequately relieved can consequently cause central pain syndrome or central neuropathic pain. Research on the molecular mechanisms that underlie this pathogenesis is important for treating such pain. To date, evidence suggests the involvement of ion channels, including adenosine triphosphate (ATP)-gated cation channel P2X receptors, in central nervous system pain transmission and persistent modulation upon and following the occurrence of neuropathic pain. Several P2X receptor subtypes, including P2X2, P2X3, P2X4, and P2X7, have been shown to play diverse roles in the pathogenesis of central pain including the mediation of fast transmission in the peripheral nervous system and modulation of neuronal activity in the central nervous system. This review article highlights the role of the P2X family of ATP receptors in the pathogenesis of central neuropathic pain and pain transmission. We discuss basic research that may be translated to clinical application, suggesting that P2X receptors may be treatment targets for central pain syndrome.

  2. 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...... in the analysis assessed tricyclic antidepressants (TCAs) and antiepileptic drugs (AEDs). RESULTS: TCAs had the lowest NNT followed by opioids and AEDs, such as gabapentin and pregabalin. The nature of the retrospective calculation of the NNT and NNH involves obvious limitations because of the pooling of studies...

  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. 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.

  5. Orofacial pain--Part I: Assessment and management of musculoskeletal and neuropathic causes.

    Science.gov (United States)

    Sarlani, Eleni; Balciunas, Birute A; Grace, Edward G

    2005-01-01

    Orofacial pain is a common complaint, affecting the lives of millions of people around the world. Chronic orofacial pain often constitutes a challenging diagnostic problem that can be complicated by psychosocial factors and typically requires multidisciplinary treatment approaches. The fundamental prerequisite for successful management of orofacial pain is an accurate diagnosis. Generating a differential diagnosis, which will ultimately lead to a definite diagnosis, requires thorough knowledge of the diagnostic range of orofacial pain. There is a vast array of orofacial pain categories including: (1) musculoskeletal, (2) neuropathic, (3) vascular, (4) neurovascular, (5) idiopathic, (6) pain caused by local, distant, or systemic pathology, and (7) psychogenic. This article presents the salient clinical features and the therapeutic approaches for the various subtypes of musculoskeletal and neuropathic pain. Musculoskeletal pain is the most prevalent orofacial pain, with temporomandibular disorders and tension-type headache being the main examples. Neuropathic pain develops secondary to neural injury and/or irritation and can be distinguished into episodic, including trigeminal neuralgia and glossopharyngeal neuralgia, as well as continuous, such as herpetic and postherpetic neuralgia, traumatic neuralgia, and Eagle's syndrome.

  6. Calcium-permeable AMPA receptors in the nucleus accumbens regulate depression-like behaviors in the chronic neuropathic pain state.

    Science.gov (United States)

    Goffer, Yossef; Xu, Duo; Eberle, Sarah E; D'amour, James; Lee, Michelle; Tukey, David; Froemke, Robert C; Ziff, Edward B; Wang, Jing

    2013-11-27

    Depression is a salient emotional feature of chronic pain. Depression alters the pain threshold and impairs functional recovery. To date, however, there has been limited understanding of synaptic or circuit mechanisms that regulate depression in the pain state. Here, we demonstrate that depression-like behaviors are induced in a rat model of chronic neuropathic pain. Using this model, we show that chronic pain selectively increases the level of GluA1 subunits of AMPA-type glutamate receptors at the synapses of the nucleus accumbens (NAc), a key component of the brain reward system. We find, in addition, that this increase in GluA1 levels leads to the formation of calcium-permeable AMPA receptors (CPARs). Surprisingly, pharmacologic blockade of these CPARs in the NAc increases depression-like behaviors associated with pain. Consistent with these findings, an AMPA receptor potentiator delivered into the NAc decreases pain-induced depression. These results show that transmission through CPARs in the NAc represents a novel molecular mechanism modulating the depressive symptoms of pain, and thus CPARs may be a promising therapeutic target for the treatment of pain-induced depression. More generally, these findings highlight the role of central glutamate signaling in pain states and define the brain reward system as an important region for the regulation of depressive symptoms of pain.

  7. Moringa oleifera Leaves Extract Attenuates Neuropathic Pain Induced by Chronic Constriction Injury

    Directory of Open Access Journals (Sweden)

    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.

  8. Combining ketamine with astrocytic inhibitor as a potential analgesic strategy for neuropathic pain. ketamine, astrocytic inhibitor and pain

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    Mei Xiao-Peng

    2010-09-01

    Full Text Available Abstract Background Neuropathic pain is an intractable clinical problem. Intrathecal ketamine, a noncompetitive N--methyl-D-aspartate receptor (NMDAR antagonist, is reported to be useful for treating neuropathic pain in clinic by inhibiting the activity of spinal neurons. Nevertheless, emerging studies have disclosed that spinal astrocytes played a critical role in the initiation and maintenance of neuropathic pain. However, the present clinical therapeutics is still just concerning about neuronal participation. Therefore, the present study is to validate the coadministration effects of a neuronal noncompetitive N-methyl-D-aspartate receptor (NMDAR antagonist ketamine and astrocytic cytotoxin L-α-aminoadipate (LAA on spinal nerve ligation (SNL-induced neuropathic pain. Results Intrathecal ketamine (10, 100, 1000 μg/kg or LAA (10, 50, 100 nmol alleviated SNL-induced mechanical allodynia in a dose-dependent manner respectively. Phosphorylated NR1 (pNR1 or glial fibrillary acidic protein (GFAP expression was down-regulated by intrathecal ketamine (100, 1000 μg/kg or LAA (50, 100 nmol respectively. The combination of ketamine (100 μg/kg with LAA (50 nmol showed superadditive effects on neuropathic pain compared with that of intrathecal administration of either ketamine or LAA alone. Combined administration obviously relieved mechanical allodynia in a quick and stable manner. Moreover, down-regulation of pNR1 and GFAP expression were also enhanced by drugs coadministration. Conclusions These results suggest that combining NMDAR antagonist ketamine with an astrocytic inhibitor or cytotoxin, which is suitable for clinical use once synthesized, might be a potential strategy for clinical management of neuropathic pain.

  9. Acupuncture for neuropathic pain due to bortezomib in a patient with multiple myeloma.

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    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.

  10. HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter.

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    Keltner, John R; Fennema-Notestine, Christine; Vaida, Florin; Wang, Dongzhe; Franklin, Donald R; Dworkin, Robert H; Sanders, Chelsea; McCutchan, J Allen; Archibald, Sarah L; Miller, David J; Kesidis, George; Cushman, Clint; Kim, Sung Min; Abramson, Ian; Taylor, Michael J; Theilmann, Rebecca J; Julaton, Michelle D; Notestine, Randy J; Corkran, Stephanie; Cherner, Mariana; Duarte, Nichole A; Alexander, Terry; Robinson-Papp, Jessica; Gelman, Benjamin B; Simpson, David M; Collier, Ann C; Marra, Christina M; Morgello, Susan; Brown, Greg; Grant, Igor; Atkinson, J Hampton; Jernigan, Terry L; Ellis, Ronald J

    2014-06-01

    Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.

  11. HIV-Associated Distal Neuropathic Pain is Associated with Smaller Total Cerebral Cortical Gray Matter

    Science.gov (United States)

    Keltner, John R.; Fennema-Notestine, Christine; Vaida, Florin; Wang, Dongzhe; Franklin, Donald R.; Dworkin, Robert H.; Sanders, Chelsea; McCutchan, J. Allen; Archibald, Sarah L.; Miller, David J.; Kesidis, George; Cushman, Clint; Kim, Sung Min; Abramson, Ian; Taylor, Michael J.; Theilmann, Rebecca J.; Julaton, Michelle D.; Notestine, Randy J.; Corkran, Stephanie; Cherner, Mariana; Duarte, Nichole A.; Alexander, Terry; Robinson-Papp, Jessica; Gelman, Benjamin B.; Simpson, David M.; Collier, Ann C.; Marra, Christina M.; Morgello, Susan; Brown, Greg; Grant, Igor; Atkinson, J. Hampton; Jernigan, Terry L.; Ellis, Ronald J.

    2014-01-01

    Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50% of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging (MRI) volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (R = −0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance. PMID:24549970

  12. Heritability of nociception IV: neuropathic pain assays are genetically distinct across methods of peripheral nerve injury.

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    Young, Erin E; Costigan, Michael; Herbert, Teri A; Lariviere, William R

    2014-05-01

    Prior genetic correlation analysis of 22 heritable behavioral measures of nociception and hypersensitivity in the mouse identified 5 genetically distinct pain types. In the present study, we reanalyzed that dataset and included the results of an additional 9 assays of nociception and hypersensitivity, with the following goals: to replicate the previously identified 5 pain types; to test whether any of the newly added pain assays represent novel genetically distinct pain types; and to test the level of genetic relatedness among 9 commonly used neuropathic pain assays. Multivariate analysis of pairwise correlations between assays shows that the newly added zymosan-induced heat hypersensitivity assay does not conform to the 2 previously identified groups of heat hypersensitivity assays and cyclophosphamide-induced cystitis, the first organ-specific visceral pain model examined, is genetically distinct from other inflammatory assays. The 4 included mechanical hypersensitivity assays are genetically distinct and do not comprise a single pain type as previously reported. Among the 9 neuropathic pain assays including autotomy, chemotherapy, nerve ligation and spared nerve injury assays, at least 4 genetically distinct types of neuropathic sensory abnormalities were identified, corresponding to differences in nerve injury method. In addition, 2 itch assays and Comt genotype were compared to the expanded set of nociception and hypersensitivity assays. Comt genotype was strongly related only to spontaneous inflammatory nociception assays. These results indicate the priority for continued investigation of genetic mechanisms in several assays newly identified to represent genetically distinct pain types.

  13. Expectations and positive emotional feelings accompany reductions in ongoing and evoked neuropathic pain following placebo interventions.

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    Petersen, Gitte L; Finnerup, Nanna B; Grosen, Kasper; Pilegaard, Hans K; Tracey, Irene; Benedetti, Fabrizio; Price, Donald D; Jensen, Troels S; Vase, Lene

    2014-12-01

    Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain-relieving (lidocaine) or pain-inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M-VAS). They also reported their emotional feelings via a quantitative/qualitative experiential method. Subsequently, patients rated their ongoing pain levels on the M-VAS and underwent quantitative sensory testing of evoked pain (brush, pinprick, area of hyperalgesia, wind-up-like pain). There was a significant placebo effect on both ongoing (P=.009 to .019) and evoked neuropathic pain (P=.0005 to .053). Expected pain levels accounted for significant amounts of the variance in ongoing (53.4%) and evoked pain (up to 34.5%) after the open lidocaine administration. Furthermore, patients reported high levels of positive and low levels of negative emotional feelings in the placebo condition compared with the nocebo condition (P⩽.001). Pain increases during nocebo were nonsignificant (P=.394 to 1.000). To our knowledge, this is the first study to demonstrate placebo effects in ongoing neuropathic pain. It provides further evidence for placebo-induced reduction in hyperalgesia and suggests that patients' expectations coexist with emotional feelings about treatments.

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

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    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.

  15. Endogenous CBS-H2S Pathway Contributes to the Development of CCI-Induced Neuropathic Pain.

    Science.gov (United States)

    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.

  16. [Neuropathic pain associated with Nav1.7 mutations: clinical picture and treatment].

    Science.gov (United States)

    Doppler, K; Sommer, C

    2013-12-01

    Voltage-gated sodium channels are essential for electrogenesis in excitable cells. The isoform Nav1.7 is primarily expressed in nociceptors. Mutations of the SCN9A gene, which codes for the α-subunit of Nav1.7, are the cause of primary erythromelalgia and paroxysmal extreme pain disorder, two rare neuropathic pain conditions. Recent studies have shown that mutations in the SCN9A gene are the cause of a subgroup of idiopathic small fiber neuropathies and that polymorphisms of SCN9A are associated with an increase in susceptibility to pain. These findings not only contribute to the understanding of the pathophysiology of neuropathic pain but also offer targets for a more specific pain therapy.

  17. Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in diabetic neuropathic pain

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    Migliorati Filippo

    2009-01-01

    Full Text Available Abstract Background In this paper we explored thalamocortical functional connectivity in a group of eight patients suffering from peripheral neuropathic pain (diabetic pain, and compared it with that of a group of healthy subjects. We hypothesized that functional interconnections between the thalamus and cortex can be altered after years of ongoing chronic neuropathic pain. Results Functional connectivity was studied through a resting state functional magnetic resonance imaging (fMRI paradigm: temporal correlations between predefined regions of interest (primary somatosensory cortex, ventral posterior lateral thalamic nucleus, medial dorsal thalamic nucleus and the rest of the brain were systematically investigated. The patient group showed decreased resting state functional connectivity between the thalamus and the cortex. Conclusion This supports the idea that chronic pain can alter thalamocortical connections causing a disruption of thalamic feedback, and the view of chronic pain as a thalamocortical dysrhythmia.

  18. Antinociceptive effect of matrine on vincristine-induced neuropathic pain model in mice.

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    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.

  19. Dynamics of Circadian Thalamocortical Flow of Information during a Peripheral Neuropathic Pain Condition.

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    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.

  20. 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.

  1. 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

  2. Cytidine 5′-diphosphocholine administration prevents peripheral neuropathic pain after sciatic nerve crush injury in rats

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    Emril, Dessy R; Wibowo, Samekto; Meliala, Lucas; Susilowati, Rina

    2016-01-01

    Background Cytidine 5′-diphosphocholine (citicoline) has been shown to have beneficial effects in central nervous system injury as well as in motoric functional recovery after peripheral nerve injury. This study aimed to examine the effect of citicoline on prevention of neuropathic pain in a rat model of sciatic nerve crush injury. Methods Forty experimental rats were divided into four groups. In three groups, the right sciatic nerves were crushed in the mid-thigh region, and a gelatin sponge moistened with 0.4 or 0.8 mL of 100 µmol/L citicoline, or saline 0.4 mL in the control group, was applied. The fourth group of rats was sham-operated, ie the sciatic nerve was exposed with no crush. Functional assessments were performed 4 weeks after crush injury. von Frey filaments (100 g threshold) were used to assess neuropathic pain. In addition, the sciatic functional index and extensor postural thrust (EPT) tests were used to assess motoric function. Results The crush/citicoline 0.4 mL group had a lower percentage of pain (23.53%, n=17) compared with the crush/saline group (53.33%, n=15, Pciticoline 0.4 mL group also showed better motoric recovery, as seen in stronger EPT results (Pciticoline 0.8 mL group showed a higher percentage of pain (66.67%, n=18) and less EPT recovery. These results may be explained by more severe nerve injury due to compression with a larger administered volume. Conclusion In situ administration of 0.4 mL of 100 µmol/L citicoline prevents the occurrence of neuropathic pain and induces motoric recovery, evaluated by EPT test, 4 weeks after sciatic nerve injury. PMID:27284264

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

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    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.

  4. Neuropathic pain in neuromyelitis optica affects activities of daily living and quality of life.

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    Zhao, Sizheng; Mutch, Kerry; Elsone, Liene; Nurmikko, Turo; Jacob, Anu

    2014-10-01

    Though pain in neuromyelitis optica (NMO) has been described in two recent reports, the proportion with true neuropathic pain (NP), its features, impact on activities of daily living (ADL) and quality of life has not been well characterised. A cross-sectional study of 50 NMO patients with transverse myelitis was performed using Douleur Neuropathique 4, Brief Pain Inventory, Extended Disability Status Scale and Short Form 36. NP was identified in 62% of patients. Pain was constant in 68% affecting most ADL. Pain was associated with significant reduction of the SF36 Mental Composite Score. The high prevalence of NP and associated disability necessitates an in-depth enquiry in patients with NMO.

  5. Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain.

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    Trang, Tuan; Beggs, Simon; Salter, Michael W

    2011-02-01

    One of the most significant advances in pain research is the realization that neurons are not the only cell type involved in the etiology of chronic pain. This realization has caused a radical shift from the previous dogma that neuronal dysfunction alone accounts for pain pathologies to the current framework of thinking that takes into account all cell types within the central nervous system (CNS). This shift in thinking stems from growing evidence that glia can modulate the function and directly shape the cellular architecture of nociceptive networks in the CNS. Microglia, in particular, are increasingly recognized as active principal players that respond to changes in physiological homeostasis by extending their processes toward the site of neural damage, and by releasing specific factors that have profound consequences on neuronal function and that contribute to CNS pathologies caused by disease or injury. A key molecule that modulates microglia activity is ATP, an endogenous ligand of the P2 receptor family. Microglia expresses several P2 receptor subtypes, and of these the P2X4 receptor subtype has emerged as a core microglia-neuron signaling pathway: activation of this receptor drives the release of brain-derived neurotrophic factor (BDNF), a cellular substrate that causes disinhibition of pain-transmitting spinal lamina I neurons. Converging evidence points to BDNF from spinal microglia as being a critical microglia-neuron signaling molecule that gates aberrant nociceptive processing in the spinal cord. The present review highlights recent advances in our understanding of P2X4 receptor-mediated signaling and regulation of BDNF in microglia, as well as the implications for microglia-neuron interactions in the pathobiology of neuropathic pain.

  6. Duloxetine versus placebo in the treatment of patients with diabetic neuropathic pain in China

    Institute of Scientific and Technical Information of China (English)

    GAO Yan; CHENG Lu-lu; WEN Chong-yuan; ZHANG Shu-yu; ZHANG Qi; Durisala Desaiah; Vladimir Skljarevski; NING Guang; JIA Wei-ping; ZHOU Zhi-guang; XU Zhang-rong; LIU Zhi-min; LIU Chao; MA Jian-hua; LI Qiang

    2010-01-01

    Background Duloxetine, a selective serotonin and noradrenaline reuptake inhibitor, has been shown to be effective in treatment of diabetic peripheral neuropathic pain and approved for the management of patients with diabetic peripheral neuropathic pain (DPNP) in the United States, European Union, and many other countries. This study assessed the efficacy and safety of duloxetine in Chinese patients with diabetic peripheral neuropathic pain.Methods This double-blind, randomized, placebo-controlled, flexible-dose study treated adult patients with diabetic peripheral neuropathic pain and baseline Brief Pain Inventory (BPI) 24-hour average pain severity ratings ≥4 with duloxetine 60 mg to 120 mg once daily or placebo for 12 weeks. Dose adjustments of duloxetine or matching placebo were based upon investigator's judgment of clinical response. Change from baseline to endpoint in BPI average pain was the primary efficacy outcome. Secondary outcome measures included BPI-severity and -Interference, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, EuroQol: 5 Dimensions, Athens Insomnia Scale, and safety measures.Results Of 215 patients randomized, 88.4% and 82.1% of patients in placebo and duloxetine groups, respectively,completed the study. Mean change from baseline to endpoint in BPI average pain was not statistically different between the treatment groups (P=0.124). Duloxetinetreated patients showed significantly greater pain reduction compared with those in placebo group at weeks 1,2, and 4 (P=0.004, P=0.009, and P=0.006, respectively),but not at weeks 8 (P=0.125) and 12 (P=0.107).Duloxetine-treated patients experienced statistically significant improvement in Patient Global Impression of Improvement, Clinical Global Impression of Severity, area under the curve for pain relief, BPI-severity pain right now,and BPI-interference walking ability. Patients treated with duloxetine 120 mg once daily showed significantly greater pain reduction

  7. Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats.

    Science.gov (United States)

    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.

  8. Central sensitization: implications for the diagnosis and treatment of pain.

    Science.gov (United States)

    Woolf, Clifford J

    2011-03-01

    Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the

  9. 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.

  10. 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.

  11. 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.

  12. 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...

  13. 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

  14. 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.

  15. 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.

  16. The analgesic effect of orexin-A in a murine model of chemotherapy-induced neuropathic pain.

    Science.gov (United States)

    Toyama, Satoshi; Shimoyama, Naohito; Shimoyama, Megumi

    2017-02-01

    Orexins are neuropeptides that are localized to neurons in the lateral and dorsal hypothalamus but its receptors are distributed to many different regions of the central nervous system. Orexins are implicated in a variety of physiological functions including sleep regulation, energy homeostats, and stress reactions. Furthermore, orexins administered exogenously have been shown to have analgesic effects in animal models. A type of intractable pain in patients is pain due to chemotherapy-induced peripheral neuropathy (CIPN). Several chemotherapeutic agents used for the treatment of malignant diseases induce dose-limiting neuropathic pain that compromises patients' quality of life. Here, we examined the analgesic effect of orexin-A in a murine model of CIPN, and compared it with the effect of duloxetine, the only drug recommended for the treatment of CIPN pain in patients. CIPN was induced in male BALB/c mice by repeated intraperitoneal injection of oxaliplatin, a platinum chemotherapeutic agent used for the treatment of advanced colorectal cancer. Neuropathic mechanical allodynia was assessed by the von Frey test, and the effect on acute thermal pain was assessed by the tail flick test. Intracerebroventricularly administered orexin-A dose-dependently attenuated oxaliplatin-induced mechanical allodynia and increased tail flick latencies. Oxaliplatin-induced mechanical allodynia was completely reversed by orexin-A at a low dose that did not increase tail flick latency. Duloxetine only partially reversed mechanical allodynia and had no effect on tail flick latency. The analgesic effect of orexin-A on oxaliplatin-induced mechanical allodynia was completely antagonized by prior intraperitoneal injection of SB-408124 (orexin type-1 receptor antagonist), but not by prior intraperitoneal injection of TCS-OX2-29 (orexin type-2 receptor antagonist). Our findings suggest that orexin-A is more potent than duloxetine in relieving pain CIPN pain and its analgesic effect is

  17. Effects of gabapentin on brain hyperactivity related to pain and sleep disturbance under a neuropathic pain-like state using fMRI and brain wave analysis.

    Science.gov (United States)

    Takemura, Yoshinori; Yamashita, Akira; Horiuchi, Hiroshi; Furuya, Masaharu; Yanase, Makoto; Niikura, Keiichi; Imai, Satoshi; Hatakeyama, Noboru; Kinoshita, Hiroyuki; Tsukiyama, Yoshi; Senba, Emiko; Matoba, Motohiro; Kuzumaki, Naoko; Yamazaki, Mitsuaki; Suzuki, Tsutomu; Narita, Minoru

    2011-07-01

    Neuropathic pain is the most difficult pain to manage in the pain clinic, and sleep problems are common among patients with chronic pain including neuropathic pain. In the present study, we tried to visualize the intensity of pain by assessing neuronal activity and investigated sleep disturbance under a neuropathic pain-like state in mice using functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG)/electromyogram (EMG), respectively. Furthermore, we investigated the effect of gabapentin (GBP) on these phenomena. In a model of neuropathic pain, sciatic nerve ligation caused a marked decrease in the latency of paw withdrawal in response to a thermal stimulus only on the ipsilateral side. Under this condition, fMRI showed that sciatic nerve ligation produced a significant increase in the blood oxygenation level-dependent (BOLD) signal intensity in the pain matrix, which was significantly decreased 2 h after the i.p. injection of GBP. Based on the results of an EEG/EMG analysis, sciatic nerve-ligated animals showed a statistically significant increase in wakefulness and a decrease in non-rapid eye movement (NREM) sleep during the light phase, and the sleep disturbance was almost completely alleviated by a higher dose of GBP in nerve-ligated mice. These findings suggest that neuropathic pain associated with sleep disturbance can be objectively assessed by fMRI and EEG/EMG analysis in animal models. Furthermore, GBP may improve the quality of sleep as well as control pain in patients with neuropathic pain.

  18. [Types of topical treatment for peripheral neuropathic pain : Mechanism of action and indications].

    Science.gov (United States)

    Baron, R; Mahn, F

    2010-08-01

    The term "peripheral neuropathic pain syndromes" summarizes several chronic pain syndromes, which can occur focally or generalized in the peripheral nervous system in the course of an impairment of afferent neurons. Controlled clinical trials gave distinct indications for systemic treatments with antidepressants, anticonvulsants and opioid analgesics in several neuropathic pain syndromes. In addition to these systemic therapies, there are also two topical treatment options: topical application of lidocaine and capsaicin. An important cause of sensitization phenomena of afferent nociceptors is the upregulation of sodium channels and thermosensor channels. In the context of a partial nerve lesion that leaves behind partially preserved or regenerated afferent nerve fibres, just these channels could be used as target structures for topical medications. Topically applied drugs are absorbed systemically only in minute quantities, so systemic side effects are negligible. Pharmacological interactions with systematically acting substances are also virtually absent; thus, topically applied substances are especially appropriate for add-on therapy in addition to systemic pain medication.

  19. Medial plantar nerve ligation as a novel model of neuropathic pain in mice: pharmacological and molecular characterization

    Science.gov (United States)

    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

  20. 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

  1. The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation

    OpenAIRE

    Wenbin Wan; Lan Cao; Ramin Khanabdali; Bill Kalionis; Xiantao Tai; Shijin Xia

    2016-01-01

    Neuropathic pain (NPP) is intolerable, persistent, and specific type of long-term pain. It is considered to be a direct consequence of pathological changes affecting the somatosensory system and can be debilitating for affected patients. Despite recent progress and growing interest in understanding the pathogenesis of the disease, NPP still presents a major diagnostic and therapeutic challenge. High mobility group box 1 (HMGB1) mediates inflammatory and immune reactions in nervous system and ...

  2. Nitrous Oxide Persistently Alleviates Pain Hypersensitivity in Neuropathic Rats: A Dose-Dependent Effect

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    Meric Ben Boujema

    2015-01-01

    Full Text Available BACKGROUND: Despite numerous pharmacological approaches, there are no common analgesic drugs that produce meaningful relief for the majority of patients with neuropathic pain. Although nitrous oxide (N2O is a weak analgesic that acts via opioid-dependent mechanisms, it is also an antagonist of the N-methyl-D-aspartate receptor (NMDAR. The NMDAR plays a critical role in the development of pain sensitization induced by nerve injury.

  3. Niflumic acid, a TRPV1 channel modulator, ameliorates stavudine-induced neuropathic pain.

    Science.gov (United States)

    Marwaha, Lovish; Bansal, Yashika; Singh, Raghunath; Saroj, Priyanka; Sodhi, Rupinder Kaur; Kuhad, Anurag

    2016-12-01

    TRP channels have been discovered as a specialized group of somatosensory neurons involved in the detection of noxious stimuli. Desensitization of TRPV1 located on dorsal root and trigeminal ganglia exhibits analgesic effect and makes it potential therapeutic target for treatment of neuropathic pain. With this background, the present study was aimed to investigate the protective effect of niflumic acid, a TRPV1 modulator, on stavudine (STV)-induced neuropathic pain in rats. Stavudine (50 mg/kg) was administered intravenously via tail vein in rats to induce neuropathic pain. Various behavioral tests were performed to access neuropathic pain (hyperalgesia and allodynia) on 7th, 14th, 21st, and 28th days. Electrophysiology (motor nerve conduction velocity; MNCV) and biochemical estimations were conducted after 28th day. Niflumic acid (10, 15, and 20 mg/kg) was administered intraperitoneally and evaluated against behavioral, electrophysiological (MNCV), and biochemical alterations in stavudine-treated rats. Pregabalin (30 mg/kg) was taken as reference standard and administered intraperitoneally. Four weeks after stavudine injection, rats developed behavioral, electrophysiological (MNCV), and biochemical (oxidative, nitrosative stress, and inflammatory cytokines, TRPV1) alterations. Niflumic acid restored core and associated symptoms of peripheral neuropathy by suppressing oxidative-nitrosative stress, inflammatory cytokines (TNF-α, IL-1β) and TRPV1 level in stavudine-induced neuropathic pain in rats. Pharmacological efficacy of niflumic acid (20 mg/kg) was equivalent to pregabalin (30 mg/kg). In conclusion, niflumic acid attenuates STV-induced behavioral, electrophysiological and biochemical alterations by manipulating TRP channel activity in two manners: (1) direct antagonistic action against TRPV1 channels and (2) indirect inhibition of TRP channels by blocking oxidative and inflammatory surge. Therefore, NA can be developed as a potential pharmacotherapeutic

  4. 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.

  5. Cytidine 5’-diphosphocholine administration prevents peripheral neuropathic pain after sciatic nerve crush injury in rats

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    Emril DR

    2016-05-01

    Full Text Available Dessy R Emril,1 Samekto Wibowo,2 Lucas Meliala,2 Rina Susilowati3 1Department of Neurology, Faculty of Medicine, Syiah Kuala University, Banda Aceh, 2Department of Neurology, 3Department of Histology and Cell Biology, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, IndonesiaBackground: Cytidine 5’-diphosphocholine (citicoline has been shown to have beneficial effects in central nervous system injury as well as in motoric functional recovery after peripheral nerve injury. This study aimed to examine the effect of citicoline on prevention of neuropathic pain in a rat model of sciatic nerve crush injury.Methods: Forty experimental rats were divided into four groups. In three groups, the right sciatic nerves were crushed in the mid-thigh region, and a gelatin sponge moistened with 0.4 or 0.8 mL of 100 µmol/L citicoline, or saline 0.4 mL in the control group, was applied. The fourth group of rats was sham-operated, ie the sciatic nerve was exposed with no crush. Functional assessments were performed 4 weeks after crush injury. von Frey filaments (100 g threshold were used to assess neuropathic pain. In addition, the sciatic functional index and extensor postural thrust (EPT tests were used to assess motoric function.Results: The crush/citicoline 0.4 mL group had a lower percentage of pain (23.53%, n=17 compared with the crush/saline group (53.33%, n=15, P<0.005. The crush/citicoline 0.4 mL group also showed better motoric recovery, as seen in stronger EPT results (P<0.001. However, the sciatic functional index analysis did not show significant differences between groups (P=0.35. The crush/citicoline 0.8 mL group showed a higher percentage of pain (66.67%, n=18 and less EPT recovery. These results may be explained by more severe nerve injury due to compression with a larger administered volume.Conclusion: In situ administration of 0.4 mL of 100 μmol/L citicoline prevents the occurrence of neuropathic pain and induces motoric recovery

  6. Adult Stem Cell as New Advanced Therapy for Experimental Neuropathic Pain Treatment

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    Silvia Franchi

    2014-01-01

    Full Text Available Neuropathic pain (NP is a highly invalidating disease resulting as consequence of a lesion or disease affecting the somatosensory system. All the pharmacological treatments today in use give a long lasting pain relief only in a limited percentage of patients before pain reappears making NP an incurable disease. New approaches are therefore needed and research is testing stem cell usage. Several papers have been written on experimental neuropathic pain treatment using stem cells of different origin and species to treat experimental NP. The original idea was based on the capacity of stem cell to offer a totipotent cellular source for replacing injured neural cells and for delivering trophic factors to lesion site; soon the researchers agreed that the capacity of stem cells to contrast NP was not dependent upon their regenerative effect but was mostly linked to a bidirectional interaction between the stem cell and damaged microenvironment resident cells. In this paper we review the preclinical studies produced in the last years assessing the effects induced by several stem cells in different models of neuropathic pain. The overall positive results obtained on pain remission by using stem cells that are safe, of easy isolation, and which may allow an autologous transplant in patients may be encouraging for moving from bench to bedside, although there are several issues that still need to be solved.

  7. Non-pharmacological treatment for neuropathic pain in children with cancer.

    Science.gov (United States)

    Casanova-García, C; Lerma Lara, S; Pérez Ruiz, M; Ruano Domínguez, D; Santana Sosa, E

    2015-12-01

    Neuropathic pain (NP) associated with childhood cancer is currently a difficult problem to control. It is treated with drugs that not only fail to provide the expected improvements, but which also have side effects. Therefore, the main aim of this pilot study is to assess whether non-pharmacological treatments, Graded Motor Imagery (GMI) and Neural Mobilization (NM), have a positive effect on this pain, thus improving the associated comorbid factors and, consequently, the quality of life of the children. In an n = 6, the results after 4 weeks of treatment show a 10-point improvement in the pain threshold and a 3.1-point improvement in the perception of pain.

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

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    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.

  9. 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.

  10. 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.

  11. Spinal analgesic action of endomorphins in acute, inflammatory and neuropathic pain in rats.

    Science.gov (United States)

    Przewłocka, B; Mika, J; Labuz, D; Toth, G; Przewłocki, R

    1999-02-19

    We studied spinal analgesic and antiallodynic effects of endomorphin-1 and endomorphin-2 administered i.t. in comparison with Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO) or morphine, during acute, inflammatory and neuropathic pain in rats chronically implanted with intrathecal cannulas. Endomorphin-1 and endomorphin-2 (2.5, 5, 10 microg i.t.) increased the tail-flick latency and, to the lesser extent, the paw pressure latency. The range of potencies in both those models of acute pain was as follows: DAMGO > morphine = endomorphin-1 > endomorphin-2. In a model of inflammatory pain, the number of formalin-induced flinching episodes was decreased by endomorphin-1. The effect of endomorphin-2 was much less pronounced. Both DAMGO and morphine significantly inhibited the pain-related behavior evoked by formalin. In a neuropathic pain model (sciatic nerve crushing in rats), endomorphin-1 and -2 (5 microg i.t.) had a statistically significant effect on the tail-flick latency and on the cold-water tail flick latency. Morphine, 5 microg, was found to be ineffective. Endomorphin-1 and -2 (2.5 and 5 microg i.t.) dose-dependently antagonized allodynia. Those effects of endomorphins were antagonized in acute (30 microg), inflammatory (30 microg) and neuropathic pain models (60 microg) by cyprodime, a selective mu-opioid receptor antagonist. In conclusion, our results show a strong analgesic action of endomorphins at the spinal cord level. The most interesting finding is a strong, stronger than in the case of morphine, antiallodynic effect of endomorphins in rats subjected to sciatic nerve crushing, which suggests a possible use of these compounds in a very difficult therapy of neuropathic pain.

  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. Carbamazepine potentiates the effectiveness of morphine in a rodent model of neuropathic pain.

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    Michael R Due

    Full Text Available Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4 may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG, we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ, a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p. were observed in TNI rodents at post-injury day (PID 7-14 and absent at PID21-28, while administration of CBZ (10 mg/kg, i.p. alone failed to produce anti-nociceptive effects at any time following TNI (PID 7-28. In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a

  14. Tolerability of NGX-4010, a capsaicin 8% patch for peripheral neuropathic pain

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    Peppin JF

    2011-11-01

    Full Text Available John F Peppin1, Kristine Majors2, Lynn R Webster3, David M Simpson4, Jeffrey K Tobias5, Geertrui F Vanhove51The Pain Treatment Center of the Bluegrass, Lexington, KY, USA; 2Integrated Clinical Trial Services, Inc, West Des Moines, IA, USA; 3Lifetree Clinical Research and Pain Clinic, Salt Lake City, UT, USA; 4Mount Sinai Medical Center, New York, NY, USA; 5NeurogesX, Inc, San Mateo, CA, USABackground/purpose: NGX-4010 (QUTENZA™; NeurogesX Inc, San Mateo, CA, a capsaicin 8% dermal patch, is licensed in the European Union for the treatment of peripheral neuropathic pain (PNP in nondiabetic adults and in the United States for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN. While NGX-4010 treatment is associated with a low risk of systemic adverse events, patch application-related pain is common and may be managed with local cooling and/or oral analgesics. This article characterizes the tolerability of NGX-4010 and will help to guide any pain management.Methods: This integrated analysis of tolerability data collected from the NGX-4010 clinical study program included 1696 patients with PNP. Patch application-related pain on the treatment day was captured as Numeric Pain Rating Scale (NPRS “pain now” scores while “average pain for the past 24 hours” NPRS scores were analyzed for 7 days following treatment. Other tolerability assessments included the percentage of patients completing ≥90% of the intended treatment duration and patients using medication for patch application-related pain.Results: The mean maximum change in “pain now” NPRS scores from pretreatment levels during and after patch application was 2.6 for all patients. This pain was transient and resolved following patch removal. Mean “average pain for the past 24 hours” NPRS scores returned to baseline by the evening of the treatment day for patients with PHN, and the evening of day 2 for patients with human immunodeficiency virus

  15. Acupuncture effects on the hippocampal cholinergic system in a rat model of neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    Junying Wang; Junling Liu; Shuping Chen; Yonghui Gao; Fanying Meng; Lina Qiao

    2012-01-01

    The present study observed the effects of repeated electroacupuncture of Zusanli (ST36) and Yanglingquan (GB34) on expression of hippocampal acetylcholinesterase, vesicular acetylcholine transporter, and muscarinic M1 receptor mRNA in chronic constrictive injury (neuropathic pain) and/or ovariotomy rats. Results demonstrated increased expression of hippocampal acetylcholinesterase, vesicular acetylcholine transporter, and muscarinic M1 receptor mRNA, as well as decreased pain threshold, in a rat model of chronic neuropathic pain after electroacupuncture. The effects of electroacupuncture increased with prolonged time, but the above-mentioned effects decreased in memory-deficient animals. Results indicated that repeated electroacupuncture has a cumulative analgesic effect, which is closely associated with upregulation of acetylcholinesterase and vesicular acetylcholine transporter activity, as well as M1 receptor mRNA expression and memory.

  16. Chronic neuropathic facial pain after intense pulsed light hair removal. Clinical features and pharmacological management

    Science.gov (United States)

    Párraga-Manzol, Gabriela; Sánchez-Torres, Alba; Moreno-Arias, Gerardo

    2015-01-01

    Intense Pulsed Light (IPL) photodepilation is usually performed as a hair removal method. The treatment is recommended to be indicated by a physician, depending on each patient and on its characteristics. However, the use of laser devices by medical laypersons is frequent and it can suppose a risk of damage for the patients. Most side effects associated to IPL photodepilation are transient, minimal and disappear without sequelae. However, permanent side effects can occur. Some of the complications are laser related but many of them are caused by an operator error or mismanagement. In this work, we report a clinical case of a patient that developed a chronic neuropathic facial pain following IPL hair removal for unwanted hair in the upper lip. The specific diagnosis was painful post-traumatic trigeminal neuropathy, reference 13.1.2.3 according to the International Headache Society (IHS). Key words:Neuropathic facial pain, photodepilation, intense pulse light. PMID:26535105

  17. Neuropathic pain: transcranial electric motor cortex stimulation using high frequency random noise. Case report of a novel treatment

    Directory of Open Access Journals (Sweden)

    Alm PA

    2013-06-01

    Full Text Available Per A Alm, Karolina DreimanisDepartment of Neuroscience, Uppsala University, Uppsala, SwedenObjectives: Electric motor cortex stimulation has been reported to be effective for many cases of neuropathic pain, in the form of epidural stimulation or transcranial direct current stimulation (tDCS. A novel technique is transcranial random noise stimulation (tRNS, which increases the cortical excitability irrespective of the orientation of the current. The aim of this study was to investigate the effect of tRNS on neuropathic pain in a small number of subjects, and in a case study explore the effects of different stimulation parameters and the long-term stability of treatment effects.Methods: The study was divided into three phases: (1 a double-blind 100–600 Hz, varying from 0.5 to 10 minutes and from 50 to 1500 µA, at intervals ranging from daily to fortnightly.crossover study, with four subjects; (2 a double-blind extended case study with one responder; and (3 open continued treatment. The motor cortex stimulation consisted of alternating current random noise (100–600 Hz, varying from 0.5 to 10 minutes and from 50 to 1500 μA, at intervals ranging from daily to fortnightly.Results: One out of four participants showed a strong positive effect (also compared with direct-current-sham, P = 0.006. Unexpectedly, this effect was shown to occur also for very weak (100 µA, P = 0.048 and brief (0.5 minutes, P = 0.028 stimulation. The effect was largest during the first month, but remained at a highly motivating level for the patient after 6 months.Discussion: The study suggests that tRNS may be an effective treatment for some cases of neuropathic pain. An important result was the indication that even low levels of stimulation may have substantial effects.Keywords: neuropathic pain, central pain, transcranial direct current stimulation, motor cortex stimulation, random noise stimulation

  18. Blocking mammalian target of rapamycin (mTOR improves neuropathic pain evoked by spinal cord injury

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    Wang Xiaoping

    2016-01-01

    Full Text Available Spinal cord injury (SCI is an extremely serious type of physical trauma observed in clinics. Neuropathic pain resulting from SCI has a lasting and significant impact on most aspects of daily life. Thus, a better understanding of the molecular pathways responsible for the cause of neuropathic pain observed in SCI is important to develop effective therapeutic agents and treatment strategies. Mammalian target of rapamycin (mTOR is a serine/threonine protein kinase that is well known for its critical roles in regulating protein synthesis and growth. Furthermore, compelling evidence supports the notion that widespread dysregulation of mTOR and its downstream pathways are involved in neuropathic pain. Thus, in this study we specifically examined the underlying mechanisms by which mTOR and its signaling pathways are involved in SCI-evoked neuropathic pain in a rat model. Overall, we demonstrated that SCI increased the protein expression of p-mTOR, and mTORmediated- phosphorylation of 4E–binding protein 4 (4E-BP1 and p70 ribosomal S6 protein kinase 1 (S6K1 in the superficial dorsal horn of the spinal cord. Also, we showed that blocking spinal mTOR by intrathecal injection of rapamycin significantly inhibited pain responses induced by mechanical and thermal stimulation. In addition, blocking spinal phosphatidylinositide 3-kinase (p-PI3K pathway significantly attenuated activities of p-mTOR pathways as well as mechanical and thermal hyperalgesia in SCI rats. Moreover, blocking mTOR and PI3K decreased the enhanced levels of substance P and calcitonin gene-related peptide (CGRP in the dorsal horn of SCI rats. We revealed specific signaling pathways leading to SCI-evoked neuropathic pain, including the activation of PI3K, mTOR and its downstream signaling pathways. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of neuropathic pain often observed in patients with SCI.

  19. Central poststroke pain: somatosensory abnormalities and the presence of associated myofascial pain syndrome

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    de Oliveira Rogério Adas

    2012-09-01

    Full Text Available Abstract Background Central post-stroke pain (CPSP is a neuropathic pain syndrome associated with somatosensory abnormalities due to central nervous system lesion following a cerebrovascular insult. Post-stroke pain (PSP refers to a broader range of clinical conditions leading to pain after stroke, but not restricted to CPSP, including other types of pain such as myofascial pain syndrome (MPS, painful shoulder, lumbar and dorsal pain, complex regional pain syndrome, and spasticity-related pain. Despite its recognition as part of the general PSP diagnostic possibilities, the prevalence of MPS has never been characterized in patients with CPSP patients. We performed a cross-sectional standardized clinical and radiological evaluation of patients with definite CPSP in order to assess the presence of other non-neuropathic pain syndromes, and in particular, the role of myofascial pain syndrome in these patients. Methods CPSP patients underwent a standardized sensory and motor neurological evaluation, and were classified according to stroke mechanism, neurological deficits, presence and profile of MPS. The Visual Analogic Scale (VAS, McGill Pain Questionnaire (MPQ, and Beck Depression Scale (BDS were filled out by all participants. Results Forty CPSP patients were included. Thirty-six (90.0% had one single ischemic stroke. Pain presented during the first three months after stroke in 75.0%. Median pain intensity was 10 (5 to 10. There was no difference in pain intensity among the different lesion site groups. Neuropathic pain was continuous-ongoing in 34 (85.0% patients and intermittent in the remainder. Burning was the most common descriptor (70%. Main aggravating factors were contact to cold (62.5%. Thermo-sensory abnormalities were universal. MPS was diagnosed in 27 (67.5% patients and was more common in the supratentorial extra-thalamic group (P Conclusions The presence of MPS is not an exception after stroke and may present in association with CPSP

  20. 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

  1. Analgesic effect of piracetam on peripheral neuropathic pain induced by chronic constriction injury of sciatic nerve in rats.

    Science.gov (United States)

    Mehta, Ashish K; Bhati, Yogendra; Tripathi, Chakra D; Sharma, Krishna K

    2014-08-01

    Despite immense advances in the treatment strategies, management of neuropathic pain remains unsatisfactory. Piracetam is a prototype of nootropic drugs, used to improve cognitive impairment. The present study was designed to investigate the effect of piracetam on peripheral neuropathic pain in rats. Neuropathic pain was induced by the chronic constriction injury of the sciatic nerve. Following this, piracetam was intraperitoneally administered for 2 weeks in doses of 50, 100 and 200 mg/kg, and pain was assessed by employing the behavioural tests for thermal hyperalgesia (hot plate and tail flick tests) and cold allodynia (acetone test). After the induction of neuropathic pain, significant development of thermal hyperalgesia and cold allodynia was observed. The administration of piracetam (50 mg/kg) did not have any significant effect on all the behavioural tests. Further, piracetam (100 mg/kg) also had no effect on the hot plate and tail flick tests; however it significantly decreased the paw withdrawal duration in the acetone test. Piracetam in a dose of 200 mg/kg significantly modulated neuropathic pain as observed from the increased hot plate and tail flick latencies, and decreased paw withdrawal duration (in acetone test). Therefore, the present study suggests the potential use of piracetam in the treatment of neuropathic pain, which merits further clinical investigation.

  2. Deep brain stimulation versus motor cortex stimulation for neuropathic pain: A minireview of the literature and proposal for future research.

    Science.gov (United States)

    Honey, C Michael; Tronnier, Volker M; Honey, Christopher R

    2016-01-01

    The treatment of neuropathic pain remains a public health concern. A growing cohort of patients is plagued by medically refractory, unrelenting severe neuropathic pain that ruins their quality of life and productivity. For this group, neurosurgery can offer two different kinds of neuromodulation that may help: deep brain simulation (DBS) and motor cortex stimulation (MCS). Unfortunately, there is no consensus on how to perform these procedures, which stimulation parameters to select, how to measure success, and which patients may benefit. This brief review highlights the literature supporting each technique and attempts to provide some comparisons and contrasts between DBS and MCS for the treatment of neuropathic pain. Finally, we highlight the current unanswered questions in the field and suggest future research strategies that may advance the care of our patients with neuropathic pain.

  3. Antinociceptive effects of maprotiline in a rat model of peripheral neuropathic pain: possible involvement of opioid system

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    Hamid Reza Banafshe

    2015-08-01

    Conclusion: Our results suggest that maprotiline can be considered a potential therapeutic for the treatment of neuropathic pain, and the opioid system may be involved in the antihyperalgesic effects of maprotiline.

  4. The CanPain SCI Clinical Practice Guideline for Rehabilitation Management of Neuropathic Pain after Spinal Cord: recommendations for model systems of care

    DEFF Research Database (Denmark)

    Guy, S D; Mehta, S; Harvey, D;

    2016-01-01

    STUDY DESIGN: Clinical practice guidelines. OBJECTIVES: The project objectives were to develop the first Canadian recommendations on a model of care for the management of at- and below-level neuropathic pain in people with spinal cord injury (SCI). SETTING: The guidelines are relevant for inpatient...... process. RESULTS: The Working Group developed five recommendations for the organization of neuropathic pain rehabilitation care in people with SCI. CONCLUSIONS: The Working Group recommendations for a model of care for at- and below-level neuropathic pain after SCI should be used to inform clinical...

  5. Analgesic efficacy of CR4056, a novel imidazoline-2 receptor ligand, in rat models of inflammatory and neuropathic pain

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    Ferrari F

    2011-04-01

    Full Text Available Flora Ferrari1, Simonetta Fiorentino1, Laura Mennuni1, Paolo Garofalo1, Ornella Letari1, Stefano Mandelli2, Antonio Giordani3, Marco Lanza1, Gianfranco Caselli11Department of Pharmacology and Toxicology; 2Department of Medicinal Chemistry; 3R&D Chemistry Drug Development and OS, Rottapharm S.p.A., Monza (MB, ItalyAbstract: Two decades of investigations have failed to unequivocally clarify the functions and the molecular nature of imidazoline-2 receptors (I2R. However, there is robust pharmacological evidence for the functional modulation of monoamino oxidase (MAO and other important enzyme activities by I2 site ligands. Some compounds of this class proved to be active experimental tools in preventing both experimental pain and opioid tolerance and dependence. Unfortunately, even though these compounds bind with high potency to central I2 sites, they fail to represent a valid clinical opportunity due to their pharmacokinetic, selectivity or side-effects profile. This paper presents the preclinical profile of a novel I2 ligand (2-phenyl-6-(1H-imidazol-1ylquinazoline; [CR4056] that selectively inhibits the activity of human recombinant MAO-A in a concentration-dependent manner. A sub-chronic four day oral treatment of CR4056 increased norepinephrine (NE tissue levels both in the rat cerebral cortex (63.1% ± 4.2%; P<0.05 and lumbar spinal cord (51.3% ± 6.7%; P < 0.05. In the complete Freund's adjuvant (CFA rat model of inflammatory pain, CR4056 was found to be orally active (ED50 = 5.8 mg/kg, by mouth [p.o.]. In the acute capsaicin model, CR4056 completely blocked mechanical hyperalgesia in the injured hind paw (ED50 = 4.1 mg/kg, p.o.; ED100 = 17.9 mg/kg, p.o.. This effect was dose-dependently antagonized by the non-selective imidazoline I2/α2 antagonist idazoxan. In rat models of neuropathic pain, oral administration of CR4056 significantly attenuated mechanical hyperalgesia and allodynia. In summary, the present study suggests a novel

  6. Aberrant TRPV1 Expression in Heat Hyperalgesia Associated with Trigeminal Neuropathic Pain

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    Hiroko Urano, Toshiaki Ara, Yoshiaki Fujinami, B. Yukihiro Hiraoka

    2012-01-01

    Full Text Available Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1 in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model.

  7. Synaptic Conversion of Chloride-Dependent Synapses in Spinal Nociceptive Circuits: Roles in Neuropathic Pain

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    Mark S. Cooper

    2011-01-01

    Full Text Available Electrophysiological conversion of chloride-dependent synapses from inhibitory to excitatory function, as a result of aberrant neuronal chloride homeostasis, is a known mechanism for the genesis of neuropathic pain. This paper examines theoretically how this type of synaptic conversion can disrupt circuit logic in spinal nociceptive circuits. First, a mathematical scaling factor is developed to represent local aberration in chloride electrochemical driving potential. Using this mathematical scaling factor, electrophysiological symbols are developed to represent the magnitude of synaptic conversion within nociceptive circuits. When inserted into a nociceptive circuit diagram, these symbols assist in understanding the generation of neuropathic pain associated with the collapse of transmembrane chloride gradients. A more generalized scaling factor is also derived to represent the interplay of chloride and bicarbonate driving potentials on the function of GABAergic and glycinergic synapses. These mathematical and symbolic representations of synaptic conversion help illustrate the critical role that anion driving potentials play in the transduction of pain. Using these representations, we discuss ramifications of glial-mediated synaptic conversion in the genesis, and treatment, of neuropathic pain.

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

    Science.gov (United States)

    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.

  9. Behavior of ion channels controlled by electric potential difference and of Toll-type receptors in neuropathic pain pathophysiology

    OpenAIRE

    Schmidt,André Prato; Schmidt,Sérgio Renato Guimarães

    2016-01-01

    ABSTRACT BACKGROUND AND OBJECTIVES: Neuropathic pain is a severe and refractory medical condition, for which only partially effective treatments are currently available. Recent experimental data on the role of voltage-gated ion channels, particularly sodium and potassium channels, have been described. In this brief review, we aimed at addressing the role of sodium and potassium channels in the pathophysiology of neuropathic pain and recent evidences about their role as a new therapeutic targ...

  10. Ganglioside GM3 synthase depletion reverses neuropathic pain and small fiber neuropathy in diet-induced diabetic mice

    OpenAIRE

    Menichella, Daniela M; Jayaraj, Nirupa D; Wilson, Heather M; Ren, Dongjun; Flood, Kelsey; Wang, Xiao-Qi; Shum, Andrew; Miller, Richard J.; Paller, Amy S.

    2016-01-01

    Background Small fiber neuropathy is a well-recognized complication of type 2 diabetes and has been shown to be responsible for both neuropathic pain and impaired wound healing. In previous studies, we have demonstrated that ganglioside GM3 depletion by knockdown of GM3 synthase fully reverses impaired wound healing in diabetic mice. However, the role of GM3 in neuropathic pain and small fiber neuropathy in diabetes is unknown. Purpose Determine whether GM3 depletion is able to reverse neurop...

  11. Role of capsaicin-sensitive C-fiber afferents in neuropathic pain-induced synaptic potentiation in the nociceptive amygdala

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    Nakao Ayano

    2012-07-01

    Full Text Available Abstract Background Neurons in the capsular part of the central nucleus of the amygdala (CeC, a region also called "nociceptive amygdala," receive nociceptive information from the dorsal horn via afferent pathways relayed from the lateral parabrachial nucleus (LPB. As the central amygdala is known to be involved in the acquisition and expression of emotion, this pathway is thought to play central roles in the generation of affective responses to nociceptive inputs. Excitatory synaptic transmission between afferents arising from the LPB and these CeC neurons is potentiated in arthritic, visceral, neuropathic, inflammatory and muscle pain models. In neuropathic pain models following spinal nerve ligation (SNL, in which we previously showed a robust LPB-CeC potentiation, the principal behavioral symptom is tactile allodynia triggered by non-C-fiber low-threshold mechanoreceptor afferents. Conversely, recent anatomical studies have revealed that most of the spinal neurons projecting to the LPB receive C-fiber afferent inputs. Here, we examined the hypothesis that these C-fiber-mediated inputs are necessary for the full establishment of robust synaptic potentiation of LPB-CeC transmission in the rats with neuropathic pain. Results Postnatal capsaicin treatment, which has been shown to denervate the C-fibers expressing transient receptor potential vanilloid type-1 (TRPV1 channels, completely abolished eye-wiping responses to capsaicin eye instillation in rats, but this treatment did not affect mechanical allodynia in the nerve-ligated animals. However, the postnatal capsaicin treatment prevented LPB-CeC synaptic potentiation after SNL, unlike in the vehicle-treated rats, primarily due to the decreased incidence of potentiated transmission by elimination of TRPV1-expressing C-fiber afferents. Conclusions C-fiber-mediated afferents in the nerve-ligated animals may be a required facilitator of the establishment of nerve injury-evoked synaptic

  12. Bilateral Changes of Cannabinoid Receptor Type 2 Protein and mRNA in the Dorsal Root Ganglia of a Rat Neuropathic Pain Model

    OpenAIRE

    2013-01-01

    Cannabinoid receptor type 2 (CB2R) plays a critical role in nociception. In contrast to cannabinoid receptor type 1 ligands, CB2R agonists do not produce undesirable central nervous system effects and thus promise to treat neuropathic pain that is often resistant to medical therapy. In the study presented here, we evaluated the bilateral distribution of the CB2R protein and messenger RNA (mRNA) in rat dorsal root ganglia (DRG) after unilateral peripheral nerve injury using immunohistochemistr...

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

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    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

  14. Latest research progress and treatment strategy of neuropathic pain%神经病理痛的最新研究进展与治疗策略

    Institute of Scientific and Technical Information of China (English)

    万丽萍; 王向东; 张晓丹; 柯丰年; 刘曾旭

    2015-01-01

    神经病理痛是临床上最常见的慢性疼痛,可见于炎症、肿瘤、内分泌及中枢神经损伤等多种疾病,其发生是外周机制与中枢机制共同参与的结果. 当前对神经病理痛的治疗是医学上公认的难题. 本文梳理了神经病理痛治疗的研究思路和最新进展,以期对研究者和临床医生提供借鉴.%Neuropathic pain is the most common chronic pain in many diseases, such as inflammation, tumor, endocrine and central nervous system damage, which is the result of joint participation of the peripheral mechanism and the central mechanism.At present, the treatment of neu-ropathic pain is a difficult problem in medical science.This article re-viewed the research ideas and the latest progress of the research on the treatment of neuropathic pain, in order to provide reference for the re-searchers and clinicians.

  15. Uncovering new pharmacological targets to treat neuropathic pain by understanding how the organism reacts to nerve injury.

    Science.gov (United States)

    Martin, Yasmina B; Herradón, Gonzalo; Ezquerra, Laura

    2011-01-01

    The neuropathic pain syndrome is complex. Current drugs to treat neuropathic pain, including anticonvulsivants and antidepressants, fail in up to 40-50% of the patients, while in the rest of them total alleviation is not normally achieved. Increased research advances in the neurobiology of neuropathic pain have not translated in more successful pharmacological treatments by the moment, but recent progress in the experimental methods available for this purpose could result in significant advances in the short term. One rational possibility for the pharmaceutical development of new drugs, including target identification, drug design and evaluation studies, could be to focus on mimicking what organism does to limit nerve damage or to enhance the regeneration of injured axons. Following this strategy, neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been postulated as potential pharmacological targets to treat neuropathic pain. In addition, during the last few years, strong scientific evidences point to novel neurotrophic factors, such as pleiotrophin (PTN), as important factors to limit neuropathic pain development because of their remodeling and angiogenic actions in the injured area. This review focuses on recent research advances identifying new pharmacological targets in the treatment of the cause, not only the symptoms, of neuropathic pain.

  16. Antinociceptive effect of ambroxol in rats with neuropathic spinal cord injury pain

    Science.gov (United States)

    Hama, Aldric T.; Plum, Ann Woodhouse; Sagen, Jacqueline

    2010-01-01

    Symptoms of neuropathic spinal cord injury (SCI) pain include evoked cutaneous hypersensitivity and spontaneous pain, which can be present below the level of the injury. Adverse side-effects obtained with currently available analgesics complicate effective pain management in SCI patients. Voltage-gated Na+ channels expressed in primary afferent nociceptors have been identified to mediate persistent hyperexcitability in dorsal root ganglia (DRG) neurons, which in part underlies the symptoms of nerve injury-induced pain. Ambroxol has previously demonstrated antinociceptive effects in rat chronic pain models and has also shown to potently block Na+ channel current in DRG neurons. Ambroxol was tested in rats that underwent a mid-thoracic spinal cord compression injury. Injured rats demonstrated robust hind paw (below-level) heat and mechanical hypersensitivity. Orally administered ambroxol significantly attenuated below-level hypersensitivity at doses that did not affect performance on the rotarod test. Intrathecal injection of ambroxol did not ameliorate below-level hypersensitivity. The current data suggest that ambroxol could be effective for clinical neuropathic SCI pain. Furthermore, the data suggests that peripherally expressed Na+ channels could lend themselves as targets for the development of pharmacotherapies for SCI pain. PMID:20732348

  17. A pain model with a neuropathic somatosensory lesion: Morton neuroma.

    Science.gov (United States)

    Quiding, Hans; Åkermark, Christian; Segerdahl, Märta; Reinholdsson, Ingalill; Svensson, Hanna; Jonzon, Bror

    2013-11-01

    A randomized, double-blind, three-period cross-over study was performed to characterize the sensory phenotype and pain demographics in patients with Morton neuroma (n=27) and to explore the effects of local administration (2mL) of placebo and lidocaine (1 and 10mg/mL) around the neuroma. Using the pain quality assessment scale (PQAS), the highest rating was seen for unpleasant pain and intensity of deep pain and the lowest for sensitive skin. Ongoing pain was reported in 32% of patients. Patients reported mild to moderate average pain, and that pain had interfered with sleep only marginally. Quantitative sensory testing (QST) measurements in the innervation territory showed hypophenomena or hyperphenomena in all patients, indicating that all had neuropathy. There was no particular QST modality that appeared to be specifically affected. Even the high-dose lidocaine resulted in limited effects on nerve-impulse conduction as judged by the effect on QST variables. However, both doses of lidocaine significantly reduced pain after step-ups, compared to placebo, indicating that lidocaine in this setting affected predominantly impulse generation and not impulse conduction. Following placebo treatment, pain after step-ups was similar in patients with and without hyperalgesia, indicating that the presence of hyperalgesia does not affect the pain intensity evoked by step-ups or walking. This pain model in patients with Morton neuroma allows investigation of drugs in a cross-over design and provides an opportunity to explore drug effects on both pain and QST variables. Commonly, neuromas are surgically removed and can be characterized in depth in vitro, thereby allowing close links to be established between pathophysiology and drug effect.

  18. Antinociceptive effects of topical mepivacaine in a rat model of HIV-associated peripheral neuropathic pain

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    Sagen J

    2016-06-01

    Full Text Available Jacqueline Sagen, Daniel A Castellanos,† Aldric T Hama The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA †Daniel A Castellanos passed away on April 14, 2010 Background: A consequence of HIV infection is sensory neuropathy, a debilitating condition that degrades the quality of life of HIV patients. Furthermore, life-extending antiretroviral treatment may exacerbate HIV sensory neuropathy. Analgesics that relieve other neuropathic pains show little or no efficacy in ameliorating HIV sensory neuropathy. Thus, there is a need for analgesics for people with this particular pain. While lidocaine is used in the management of painful peripheral neuropathies, another local anesthetic mepivacaine, with a potentially improved bioavailability, could be utilized for the management of HIV neuropathic pain.Methods: The efficacy of topical anesthetics was evaluated in a preclinical rodent model of painful peripheral neuropathy induced by epineural administration of the HIV envelope protein gp120 delivered using saturated oxidized cellulose implanted around the sciatic nerve. Beginning at 2 weeks following gp120 administration, the effects of local anesthetics topically applied via gauze pads were tested on heat and mechanical hyperalgesia in the hind paw. Rats were tested using several concentrations of mepivacaine or lidocaine during the following 2 weeks.Results: By 2 weeks following epineural gp120 implantation, the ipsilateral hind paw developed significant hypersensitivity to noxious pressure and heat hyperalgesia. A short-lasting, concentration-dependent amelioration of pressure and heat hyperalgesia was observed following topical application of mepivacaine to the ipsilateral plantar hind paw. By contrast, topical lidocaine ameliorated heat hyperalgesia in a concentration-dependent manner but not pressure hyperalgesia. Equipotent concentrations of mepivacaine and lidocaine applied topically to the

  19. Lipid- and sugar-modified endomorphins: novel targets for the treatment of neuropathic pain

    OpenAIRE

    Pegah eVaramini; Istvan eToth

    2013-01-01

    Endomorphins are endogenous opioid peptides that cause potent antinociception in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, endomorphins are poorly suited to clinical applications because of low membrane permeability and a susceptibility to enzymatic degradation. Glycosylation and lipidation have proven to be two of the most robust approaches for the generation of new therapeutic endomorphin derivatives. Conjugation with lipo...

  20. Activation of neurotrophins in lumbar dorsal root probably contributes to neuropathic pain after spinal nerve ligation

    Science.gov (United States)

    Kazemi, Abdolreza; Rahmati, Masoud; Eslami, Rasoul; Sheibani, Vahid

    2017-01-01

    Objective(s): Neurotrophins (NTs) exert various effects on neuronal system. Growing evidence indicates that NTs are involved in the pathophysiology of neuropathic pain. However, the exact role of these proteins in modulating nociceptive signaling requires being defined. Thus, the aim of this study was to evaluate the effects of spinal nerve ligation (SNL) on NTs activation in the lumbar dorsal root. Materials and Methods: Ten male Wistar rats were randomly assigned to two groups: tight ligation of the L5 spinal nerve (SNL: n=5) and Sham (n=5). In order to produce neuropathic pain, the L5 spinal nerve was tightly ligated (SNL). Then, allodynia and hyperalgesia tests were conducted weekly. After 4 weeks, tissue samples were taken from the two groups for laboratory evaluations. Here, Real-Time PCR quantity method was used for measuring NTs gene expression levels. Results: SNL resulted in a significant weight loss in the soleus muscle (Pthermal hyperalgesia thresholds (respectively, P<0.05; P<0.05). Also, NGF, NT-4, NT-3, TrkA, TrkB and TrkC expression were up-regulated following spinal nerve ligation group (respectively, P=0.025, P=0.013, P=0.001, P=0.002, P<0.001, P=001) (respectively, 4.7, 5.2, 7.5, 5.1, 7.2, 6.2 folds). Conclusion: The present study provides new evidence that neuropathic pain induced by spinal nerve ligation probably activates NTs and Trk receptors expression in DRG. However, further studies are needed to better elucidate the role of NTs in a neuropathic pain. PMID:28133521

  1. Ameliorative potential of Ocimum sanctum in chronic constriction injury-induced neuropathic pain in rats

    Directory of Open Access Journals (Sweden)

    GURPREET KAUR

    2015-03-01

    Full Text Available The present study was designed to investigate the ameliorative potential of Ocimumsanctum and its saponin rich fraction in chronic constriction injury-induced neuropathic pain in rats. The chronic constriction injury was induced by placing four loose ligatures around the sciatic nerve, proximal to its trifurcation. 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, super-oxide anion content (markers of oxidative stress and total calcium levels were measured. Chronic constriction injury was associated with the development of mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia along with an increase in oxidative stress and calcium levels. However, administration of Ocimumsanctum (100 and 200 mg/kg p.o. and its saponin rich fraction (100 and 200 mg/kg p.o. for 14 days significantly attenuated chronic constriction injury-induced neuropathic pain as well as decrease the oxidative stress and calcium levels. It may be concluded that saponin rich fraction of Ocimum sanctum has ameliorative potential in attenuating painful neuropathic state, which may be attributed to a decrease in oxidative stress and calcium levels.

  2. Antinociceptive effects of fucoidan in rat models of vincristine-induced neuropathic pain.

    Science.gov (United States)

    Hu, Chuanyin; Zhao, Yun-Tao; Zhang, Guoping; Xu, Ming-Feng

    2017-02-01

    Chemotherapeutic drugs commonly induce peripheral neuropathic pain, which limit their clinic use. In the present study, the effect of fucoidan on the development of vincristine‑induced neuropathic pain was evaluated and the underlying mechanism was examined. A neuropathy model was established in Sprague‑Dawley rats by intraperitoneal injection of vincristine sulfate 50 µg/kg once a day for 10 consecutive days. Fucoidan (50, 100 or 200 mg/kg.) and pregabalin (10 mg/kg) were injected for 14 consecutive days. Behavioral assessments were then performed and the expression of GABAB receptor was determined. The results showed that a single treatment with fucoidan did not prevent the induction of vincristine‑induced mechanical or cold allodynia. However, repeated fucoidan administration attenuated vincristine‑induced mechanical and cold allodynia in a dose‑dependent manner. Additionally, the analgesic effects of fucoidan contributed to an upregulation in the expression of GABAB receptor in the spinal cord. Furthermore, all the effects of fucoidan against vincristine‑induced neuropathy were reversed by saclofen, a selective GABAB receptor antagonist. These results suggested that the antinociceptive effects of fucoidan may be through activation of GABAB receptor, and fucoidan may be a promising drug for the treatment of chemotherapeutic drug-induced neuropathic pain.

  3. Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain

    OpenAIRE

    Ratté, Stéphanie; Zhu, Yi; Lee, Kwan Yeop; Prescott, Steven A.

    2014-01-01

    eLife digest Although the pain associated with an injury is unpleasant, it normally serves an important purpose: to make you avoid its source. However, some pain appears to arise from nowhere. Frustratingly, this type of pain, known as neuropathic pain, does not respond to common painkillers and is thus very difficult to treat. The neurons that transmit pain and other sensory information do so using electrical signals. In response to a stimulus, ions travel through channels in the membrane of...

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

    Science.gov (United States)

    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.

  5. 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.

  6. 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

  7. Nerve injury-induced neuropathic pain causes disinhibition of the anterior cingulate cortex.

    Science.gov (United States)

    Blom, Sigrid Marie; Pfister, Jean-Pascal; Santello, Mirko; Senn, Walter; Nevian, Thomas

    2014-04-23

    Neuropathic pain caused by peripheral nerve injury is a debilitating neurological condition of high clinical relevance. On the cellular level, the elevated pain sensitivity is induced by plasticity of neuronal function along the pain pathway. Changes in cortical areas involved in pain processing contribute to the development of neuropathic pain. Yet, it remains elusive which plasticity mechanisms occur in cortical circuits. We investigated the properties of neural networks in the anterior cingulate cortex (ACC), a brain region mediating affective responses to noxious stimuli. We performed multiple whole-cell recordings from neurons in layer 5 (L5) of the ACC of adult mice after chronic constriction injury of the sciatic nerve of the left hindpaw and observed a striking loss of connections between excitatory and inhibitory neurons in both directions. In contrast, no significant changes in synaptic efficacy in the remaining connected pairs were found. These changes were reflected on the network level by a decrease in the mEPSC and mIPSC frequency. Additionally, nerve injury resulted in a potentiation of the intrinsic excitability of pyramidal neurons, whereas the cellular properties of interneurons were unchanged. Our set of experimental parameters allowed constructing a neuronal network model of L5 in the ACC, revealing that the modification of inhibitory connectivity had the most profound effect on increased network activity. Thus, our combined experimental and modeling approach suggests that cortical disinhibition is a fundamental pathological modification associated with peripheral nerve damage. These changes at the cortical network level might therefore contribute to the neuropathic pain condition.

  8. Efficacy of ultrasound-stellate ganglion block in breast cancer with postoperative neuropathic pain

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    LIU Cheng-jun

    2013-10-01

    Full Text Available Objective To compare the efficacy of ultrasound-stellate ganglion block (US-SGB with that of blind SGB (B-SGB in the management of breast cancer patients with postoperative neuropathic pain (NP. Methods Forty-eight breast cancer patients with postoperative neuropathic pain were randomly assigned to either US-SGB group (N = 24 or B-SGB group (N = 24. The mean age of US-SGB and B-SGB groups were (51.35 ± 5.63 and (49.54 ± 4.77 years, respectively. Two blockade procedures with 8-day interval were performed on the affected side. Visual Analogue Scale (VAS was assessed before treatment, and in the 4th and 8th week after treatment. Results In both groups, VAS scores were significantly decreased after 4 and 8 weeks. The VAS score in US-SGB group was decreased from 5.44 ± 1.52 before treatment to 2.68 ± 1.33 at 4th week and to 1.32 ± 0.85 at 8th week after treatment, while in B-SGB group decreased from 5.36 ± 1.21 before treatment to 3.31 ± 1.27 at 4th week and to 2.09 ± 1.02 at 8th week after treatment. The alleviation of pain in US-SGB group was more significant than that in B-SGB group (4th week: t = 2.251, P = 0.038; 8th week: t = 1.971, P = 0.029. Conclusion Both US-SGB and B-SGB techniques were effective in relieving pain in breast cancer patients with neuropathic pain. However, with postoperative favorable clinical efficacy, US-SGB was better in pain relief in comparison with B-SGB.

  9. Animal models of diabetes-induced neuropathic pain.

    Science.gov (United States)

    Lee-Kubli, Corinne A; Mixcoatl-Zecuatl, Teresa; Jolivalt, Corinne G; Calcutt, Nigel A

    2014-01-01

    Neuropathy will afflict over half of the approximately 350 million people worldwide who currently suffer from diabetes and around one-third of diabetic patients with neuropathy will suffer from painful symptoms that may be spontaneous or stimulus evoked. Diabetes can be induced in rats or mice by genetic, dietary, or chemical means, and there are a variety of well-characterized models of diabetic neuropathy that replicate either type 1 or type 2 diabetes. Diabetic rodents display aspects of sensorimotor dysfunction such as stimulus-evoked allodynia and hyperalgesia that are widely used to model painful neuropathy. This allows investigation of pathogenic mechanisms and development of potential therapeutic interventions that may alleviate established pain or prevent onset of pain.

  10. Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain

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    Ellis Connie L

    2010-03-01

    Full Text Available Abstract Background Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN and neuropathic pain (NeP, our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state. Results Tactile allodynia and thermal hypersensitivity were observed over 8 months in diabetic mice without intervention. Microglial density increases were seen in the dorsal spinal cord and in thalamic nuclei and were accompanied by elevation of phosphorylated p38 MAPK, a marker of microglial activation. When initiated coincidentally with diabetes, moderate-high doses of intranasal cannabidiol (cannaboid receptor 2 agonist and intraperitoneal cannabidiol attenuated the development of an NeP state, even after their discontinuation and without modification of the diabetic state. Cannabidiol was also associated with restriction in elevation of microglial density in the dorsal spinal cord and elevation in phosphorylated p38 MAPK. When initiated in an established DPN NeP state, both CB1 and CB2 agonists demonstrated an antinociceptive effect until their discontinuation. There were no pronociceptive effects demonstated for either CB1 or CB2 antagonists. Conclusions The prevention of microglial accumulation and activation in the dorsal spinal

  11. Antinociceptive effect of intracerebroventricular administration of glycine transporter-2 inhibitor ALX1393 in rat models of inflammatory and neuropathic pain.

    Science.gov (United States)

    Takahashi, Yoshihiro; Hara, Koji; Haranishi, Yasunori; Terada, Tadanori; Obara, Goh; Sata, Takeyoshi

    2015-03-01

    Glycinergic transmission has an important role in regulating nociception in the spinal cord. The glycine transporter-2 (GlyT2) is localized at presynaptic terminals of glycinergic neurons and eliminates glycine from the synaptic cleft to terminate glycinergic transmission. Systemic and intrathecal administration of GlyT2 inhibitors alleviate various types of pain. Although the GlyT2s and glycine receptors are widely distributed in the central nervous system, little is known about the role of glycinergic transmission in pain perception at supraspinal regions. The present study examined the antinociceptive effect of intracerebroventricular (i.c.v.) administration of the selective GlyT2 inhibitor ALX1393 on inflammatory and neuropathic pain in experimental models. For i.c.v. administration, a guide cannula was implanted into the right lateral ventricle of male Sprague-Dawley rats. Normal rats were used to assess inflammatory nociception using the formalin test and motor function using the rotarod test. Chronic constriction injury (CCI) to the sciatic nerve was induced in the rats. The CCI rats were then used to assess mechanical, cold, and thermal hyperalgesia using the electronic von Frey test, cold plate test, and the plantar test, respectively. ALX1393 (25, 50, and 100 μg) was administered i.c.v. to examine its effects on supraspinal antinociception. Supraspinal ALX1393 in normal rats suppressed the late-phase response in the formalin test but did not affect motor performance. In the CCI rats, ALX1393 inhibited mechanical and cold hyperalgesia in a dose-dependent manner. The antihyperalgesic effects of ALX1393 (100 μg) were reversed completely by i.c.v. pretreatment with a glycine receptor antagonist strychnine (10 μg). These results suggest that GlyT2 contributes to nociceptive transmission at supraspinal level and that the selective GlyT2 inhibitor is a promising candidate for the treatment of inflammatory and neuropathic pain without causing motor dysfunction.

  12. Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy

    Institute of Scientific and Technical Information of China (English)

    Jie Yu; Guo-Dong Lou; Jia-Xing Yue; Ying-Ying Tang; Wei-Wei Hou; Wen-Ting Shou; Hiroshi Ohtsu

    2013-01-01

    The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain (NP) induced by peripheral axotomy.Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP (the neuroma model).Rats were then treated with drugs once daily for 30 days (histidine and Ioratadine,i.p.) or 21 days (histamine,i.c.v.).Autotomy behavior was scored daily until day 50 post-operation (PO).On days 14 to 21 PO,some rats in the control group were subjected to single-fiber recording.Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC~) and wild-type mice for 42 days.We found that both histidine (500 mg/kg) (a precursor of histamine that increases histamine levels in the tissues) and histamine (50 μg/5 μL) significantly suppressed autotomy behavior in rats.HDC-/-mice lacking endogenous histamine showed higher levels of autotomy than the wild-type.In addition,the analgesic effect of histidine was not antagonized by Ioratadine (a peripherally-acting H1 receptor antagonist),while Ioratadine alone significantly suppressed autotomy.Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H1 receptor antagonist).Our results suggest that histamine plays an important role in spontaneous NP.It is likely that histamine in the central nervous system is analgesic,while in the periphery,via H1 receptors,it is algesic.This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.

  13. Electroacupuncture improves neuropathic pain Adenosine,adenosine 5'-triphosphate disodium and their receptors perhaps change simultaneously

    Institute of Scientific and Technical Information of China (English)

    Wen Ren; Wenzhan Tu; Songhe Jiang; Ruidong Cheng; Yaping Du

    2012-01-01

    Applying a stimulating current to acupoints through acupuncture needles-known as electroacupuncture-has the potential to produce analgesic effects in human subjects and experimental animals.When acupuncture was applied in a rat model,adenosine 5'-triphosphate disodium in the extracellular space was broken down into adenosine,which in turn inhibited pain transmission by means of an adenosine A1 receptor-dependent process.Direct injection of an adenosine A1 receptor agonist enhanced the analgesic effect of acupuncture.The analgesic effect of acupuncture appears to be mediated by activation of A1 receptors located on ascending nerves.In neuropathic pain,there is upregulation of P2X purinoceptor 3(P2X3)receptor expression in dorsal root ganglion neurons.Conversely,the onset of mechanical hyperalgesia was diminished and established hyperalgesia was significantly reversed when P2X3 receptor expression was downregulated.The pathways upon which electroacupuncture appear to act are interwoven with pain pathways,and electroacupuncture stimuli converge with impulses originating from painful areas.Electroacupuncture may act via purinergic A1 and P2X3 receptors simultaneously to induce an analgesic effect on neuropathic pain.

  14. Alterations in the Anandamide Metabolism in the Development of Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Natalia Malek

    2014-01-01

    Full Text Available Endocannabinoids (EC, particularly anandamide (AEA, released constitutively in pain pathways might be accountable for the inhibitory effect on nociceptors. Pathogenesis of neuropathic pain may reflect complex remodeling of the dorsal root ganglia (DRGs and spinal cord EC system. Multiple pathways involved both in the biosynthesis and degradation of AEA have been suggested. We investigated the local synthesis and degradation features of AEA in DRGs and spinal cord during the development and maintenance of pain in a model of chronic constriction injury (CCI. All AEA synthesis and degradation enzymes are present on the mRNA level in DRGs and lumbar spinal cord of intact as well as CCI-treated animals. Deregulation of EC system components was consistent with development of pain phenotype at days 3, 7, and 14 after CCI. The expression levels of enzymes involved in AEA degradation was significantly upregulated ipsilateral in DRGs and spinal cord at different time points. Expression of enzymes of the alternative, sPLA2-dependent and PLC-dependent, AEA synthesis pathways was elevated in both of the analyzed structures at all time points. Our data have shown an alteration of alternative AEA synthesis and degradation pathways, which might contribute to the variation of AEA levels and neuropathic pain development.

  15. 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.

  16. 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.

  17. 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

  18. CB1 receptors modulate affective behaviour induced by neuropathic pain.

    Science.gov (United States)

    Rácz, Ildikó; Nent, Elisa; Erxlebe, Edda; Zimmer, Andreas

    2015-05-01

    Patients suffering from chronic pain are often diagnosed with a psychiatric condition, in particular generalized anxiety and major depression. The underlying pathomechanisms contributing to this comorbidity, however, are not entirely clear. In this manuscript we have focussed on the potential role of the cannabinoid receptor CB1, because it is known to modulate neuronal circuits contributing to chronic pain states and affective behaviours. For this purpose we analysed the consequences of a partial sciatic nerve ligation on anxiety- and depression-related behaviours in mice lacking CB1 receptors. Our results show that the development of mechanical hypersensitivity was similar in CB1 deficient mice and wild type controls. However, CB1 knockouts showed much more pronounced behavioural manifestations of anxiety-related behaviours in the light-dark and zero-maze tests, sucrose anhedonia, and disturbed home-cage activity. These results indicate that the endocannabinoid system affects chronic pain-induced mood changes through CB1 receptors.

  19. 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.

  20. H2S and Pain: A Novel Aspect for Processing of Somatic, Visceral and Neuropathic Pain Signals.

    Science.gov (United States)

    Terada, Yuka; Kawabata, Atsufumi

    2015-01-01

    Hydrogen sulfide (H2S) formed by multiple enzymes including cystathionine-γ-lyase (CSE) targets Cav3.2 T-type Ca2+ channels (T-channels) and transient receptor potential ankyrin-1 (TRPA1). Intraplantar and intracolonic administration of H2S donors promotes somatic and visceral pain, respectively, via activation of Cav3.2 and TRPA1 in rats and/or mice. Injection of H2S donors into the plantar tissues, pancreatic duct, colonic lumen, or bladder causes T-channel-dependent excitation of nociceptors, determined as phosphorylation of ERK or expression of Fos in the spinal dorsal horn. Electrophysiological studies demonstrate that exogenous and/or endogenous H2S facilitates membrane currents through T-channels in NG108-15 cells and isolated mouse dorsal root ganglion (DRG) neurons that abundantly express Cav3.2 and also in Cav3.2-transfected HEK293 cells. In mice with cerulein-induced pancreatitis and cyclophosphamide-induced cystitis, visceral pain and/or referred hyperalgesia are inhibited by CSE inhibitors and by pharmacological blockade or genetic silencing of Cav3.2, and CSE protein is upregulated in the pancreas and bladder. In rats with neuropathy induced by L5 spinal nerve cutting or by repeated administration of paclitaxel, an anticancer drug, the neuropathic hyperalgesia is reversed by inhibitors of CSE or T-channels and by silencing of Cav3.2. Upregulation of Cav3.2 protein in DRG is detectable in the former, but not in the latter, neuropathic pain models. Thus, H2S appears to function as a nociceptive messenger by facilitating functions of Cav3.2 and TRPA1, and the enhanced function of the CSE/H2S/Cav3.2 pathway is considered to be involved in the pancreatitis- and cystitis-related pain and in neuropathic pain.

  1. Effect of lycopene on the expression of pain-related molecules in spinal cord of model rats with neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    Dong-Hua Peng

    2016-01-01

    Objective:To analyze the effect of lycopene on the expression of pain-related molecules in spinal cord of model rats with neuropathic pain.Methods:A total of 30 healthy female SD rats were collected to establish neuropathic pain models according to the literatures, including 10 in sham operation group, 10 in model control group and 10 in model treatment group. Rats were executed to obtain L2-L6 segment of spinal cord, and then serum levels of pain-related indicators as well as gene and protein expression in it were detected.Results:Serum IL-17, HMGB-1, Aβ, Tau and C3 levels of sham operation group were lower than those of model control group and model treatment group while CGRP level was higher than that of model control group and model treatment group, and serum IL-17, HMGB-1, Aβ, Tau and C3 levels of model treatment group were lower than those of model control group while CGRP level was higher than that of model control group; ERK, CREB, BDNF, NMDA, AMPA and c-fos mRNA expression levels of sham operation group were lower than those of model control group and model treatment group, and ERK, CREB, BDNF, NMDA, AMPA and c-fos mRNA expression levels of model treatment group were lower than those of model control group; TRPV1, NF-κB, NOS, GFAP, ERK and CREB protein expression levels of sham operation group were lower than those of model control group and model treatment group while Reg expression level was higher than that of model control group and model treatment group, and TRPV1, NF-κB, NOS, GFAP, ERK and CREB protein expression levels of model treatment group were lower than those of model control group while Reg expression level was higher than that of model control group.Conclusion: Lycopene can effectively decrease the expression of pain-promoting genes in model rats with neuropathic pain, and is expected to become new treatment means of neuropathic pain in the future.

  2. 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

    syndrome (FBSS) and complex regional pain syndrome (CRPS) type I (level B recommendation). High-frequency transcutaneous electrical nerve stimulation (TENS) may be better than placebo (level C) although worse than electro-acupuncture (level B). One kind of repetitive transcranial magnetic stimulation (r...

  3. Suppressing SNAP-25 and reversing glial glutamate transporters relieves neuropathic pain in rats by ameliorating imbalanced neurotransmission

    Institute of Scientific and Technical Information of China (English)

    LIU Chang; GUO Qu-lian; HUANG Chang-sheng; ZOU Wang-yuan; SONG Zong-bin

    2013-01-01

    Background Neuropathic pain results from a lesion or disease affecting the somatosensory system at either the peripheral or central level.The transmission of nociception within the central nervous system is subject to modulation by release and reuptake of neurotransmitters,which maintain a dynamic balance through the assembly and disassembly of the SNARE complex as well as a series of neurotransmitter transporters (inhibitory GABA transporters GAT and excitatory glutamate transporters GT).Neuronal hyper-excitability or defected inhibition involved in neuropathic pain is one of the outcomes caused by imbalanced neurotransmission.SNAP-25,which is one of the SNARE complexes,can modulate the release of neurotransmitters.Glia glutamate transporter (GLT) is one of the two glutamate transporters which account for most synaptic glutamate uptake in the CNS.The role of SNAP-25 and GLT as well as GAT is not clearly understood.Methods We used the rat chronic constriction injury (CCI) model for research,and degraded SNAP-25 by a single intrathecal administration of BoNT/A.The mechanical (MWT) and thermal withdrawal latency (TWL) were tested.The level of SNAP-25,GLT,and GAT-1 were assayed using RT-PCR and Western blotting.Results SNAP-25 was suppressed by a single intrathecal administration of 0.01U BoNT/A and the reduction of SNAP-25 was correlated with the relief of nociceptive responses in CCI rats.MWT and TWL returned to normal from the 5th to 14th day (P <0.05) after the administration.On the 14th day after surgery,compared to the sham group,the upregulation of SNAP-25 in CCI rats was reversed after BoNT/A treatment (P <0.05).The decreased GLT was reversed after BoNT/A treatment but increased GAT-1 was not influenced by BoNT/A treatment.Conclusions SNAP-25 and GLT play important roles in the development of neuropathic pain,and the mechanism may involve the imbalance of neurotransmission after peripheral nerve injury.Intrathecal administration of BoNT/A reversed the

  4. Tapentadol extended release in the management of peripheral diabetic neuropathic pain

    Directory of Open Access Journals (Sweden)

    Vadivelu N

    2015-01-01

    Full Text Available Nalini Vadivelu,1 Alice Kai,2 Benjamin Maslin,1 Gopal Kodumudi,3 Aron Legler,1 Jack M Berger4 1Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA; 2Stony Brook University School of Medicine, Stony Brook, NY, USA; 3Department of Structural and Cellular Biology, Tulane University, New Orleans, LA, USA; 4Department of Anesthesiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Abstract: Tapentadol, a µ-opioid agonist and norepinephrine reuptake inhibitor, has been found to be an effective medication for a wide variety of chronic pain conditions, including back pain, cancer-related pain, and arthritic pain. It has also been found to have fewer gastrointestinal side effects than more traditional opioid-based therapies. More recently, tapentadol extended release has been demonstrated to be effective in the management of painful diabetic neuropathy, an often debilitating condition affecting approximately one-third of all patients with diabetes. This review highlights the most up-to-date basic and clinical studies by focusing on the mechanisms of action of tapentadol and its clinical efficacy, especially with regard to painful diabetic neuropathy. Keywords: chronic pain, neuropathic pain, pharmacology, analgesia, pain management

  5. 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.

  6. Re-innervation patterns by peptidergic Substance-P, non-peptidergic P2X3, and myelinated NF-200 nerve fibers in epidermis and dermis of rats with neuropathic pain

    NARCIS (Netherlands)

    Duraku, Liron S.; Hossaini, Mehdi; Schuettenhelm, Barthold N.; Holstege, Joan C.; Baas, Martijn; Ruigrok, Tom J. H.; Walbeehm, Erik T.

    2013-01-01

    Nerve endings in the epidermis, termed nociceptors, conduct information on noxious stimuli to the central nervous system. The precise role of epidermal nerve fibers in neuropathic pain is however still controversial. Here, we have investigated the re-innervation patterns of epidermal and dermal nerv

  7. MicroRNAs as modulators and biomarkers of inflammatory and neuropathic pain conditions.

    Science.gov (United States)

    Andersen, Hjalte H; Duroux, Meg; Gazerani, Parisa

    2014-11-01

    The post-transcriptional regulator molecules, microRNAs, have emerged as important biomarkers and modulators of numerous pathophysiological processes including oncogenesis and cardiovascular diseases. Recently, a significant number of dysregulations in microRNAs have been reported in patients suffering from painful disorders such as complex regional pain syndrome, cystitis-induced chronic pain and irritable bowel disorder, in both affected tissues and the circulation. Moreover, microRNAs are known to be involved in pain processing based on several recent findings in animal models of inflammatory and neuropathic pain. The basis of this review was to cover and summarize available articles in English encompassing "microRNA and pain". In animal pain models widespread microRNA modulation is present and manifests on multiple levels i.e.: the dorsal root ganglia, the spinal dorsal horn and the brain. Numerous functional in vivo studies have found that dysregulated microRNAs are involved in the post-transcriptional modulation of genes implicated in pain generation and maintenance. Lastly, a few animal studies have delivered promising results as to the possibility of applying microRNAs as therapeutics to alleviate established pain and several clinical studies have highlighted the potential in applying microRNAs as biomarkers in painful conditions such as complex regional pain syndrome and fibromyalgia. This review briefly introduces the basics of microRNAs, their biogenesis and function, and mainly focuses on the recent advances made in understanding the role of microRNAs in relation to pain processing and painful conditions. It also provides an overview of widely diverse methodological approaches and results with a potential for future implications of microRNAs in the diagnosis and treatment of pain.

  8. 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....

  9. The Effect of Intrathecal Administration of Muscimol on Modulation of Neuropathic Pain Symptoms Resulting from Spinal Cord Injury; an Experimental Study

    OpenAIRE

    Marjan Hosseini; Zohreh Karami; Atousa Janzadenh; Seyed Behnamedin Jameie; Zahra Haji Mashadi; Mahmoud Yousefifard; Farinaz Nasirinezhad

    2014-01-01

    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 exp...

  10. Pregabalin, the lidocaine plaster and duloxetine in patients with refractory neuropathic pain: a systematic review

    Directory of Open Access Journals (Sweden)

    Budhia Sangeeta

    2010-11-01

    Full Text Available Abstract Background Patients frequently fail to receive adequate pain relief from, or are intolerant of, first-line therapies prescribed for neuropathic pain (NeP. This refractory chronic pain causes psychological distress and impacts patient quality of life. Published literature for treatment in refractory patients is sparse and often published as conference abstracts only. The aim of this study was to identify published data for three pharmacological treatments: pregabalin, lidocaine plaster, and duloxetine, which are typically used at 2nd line or later in UK patients with neuropathic pain. Methods A systematic review of the literature databases MEDLINE, EMBASE and CCTR was carried out and supplemented with extensive conference and grey literature searching. Studies of any design (except single patient case studies that enrolled adult patients with refractory NeP were included in the review and qualitatively assessed. Results Seventeen studies were included in the review: nine of pregabalin, seven of the lidocaine plaster, and one of duloxetine. No head-to-head studies of these treatments were identified. Only six studies included treatments within UK licensed indications and dose ranges. Reported efficacy outcomes were not consistent between studies. Pain scores were most commonly assessed in studies including pregabalin; trials of pregabalin and the lidocaine plaster reported the proportion of responders. Significant improvements in the total, sensory and affective scores of the Short-form McGill Pain Questionnaire, and in function interference, sleep interference and pain associated distress, were associated with pregabalin treatment; limited or no quality of life data were available for the other two interventions. Limitations to the review are the small number of included studies, which are generally small, of poor quality and heterogeneous in patient population and study design. Conclusions Little evidence is available relevant to the

  11. B vitamins alleviate indices of neuropathic pain in diabetic rats.

    Science.gov (United States)

    Jolivalt, Corinne G; Mizisin, Leah M; Nelson, Austin; Cunha, Joice M; Ramos, Khara M; Bonke, Dieter; Calcutt, Nigel A

    2009-06-10

    There are sporadic reports that assorted combinations of B vitamins can alleviate pain in diabetic patients, but there is neither agreement on the relative efficacy of individual B vitamins nor understanding of the mechanisms involved. We therefore investigated the efficacy of a cocktail of the vitamins B1, B6 and B12 in alleviating behavioral indices of sensory dysfunction such as allodynia and hyperalgesia in diabetic rats and also the relative contribution of individual components of the cocktail. Repeated daily treatment with the cocktail of B vitamins for 7-9 days ameliorated tactile allodynia and formalin-evoked hyperalgesia in a dose-dependent manner and also improved sensory nerve conduction velocity in diabetic rats. Investigation of the contribution of individual B vitamins suggested that all three participated with variable efficacy in the alleviation of allodynia after protracted, but not single dose treatment. Only vitamin B6 improved sensory nerve conduction velocity slowing in diabetic rats when given alone. To address potential mechanisms of action, we measured markers of oxidative stress (lipid and protein oxidation) and inflammation (cyclooxygenase-2 (COX-2) and TNFalpha protein) in the nerve but treatment with the vitamin B cocktail did not significantly affect any of these parameters. The positive effects of B vitamins on functional and behavioral disorders of diabetic rats suggest a potential for use in treating painful diabetic neuropathy.

  12. Targeting the affective and cognitive aspects of chronic neuropathic pain using basal forebrain neuromodulation: rationale, review and proposal.

    Science.gov (United States)

    Oluigbo, Chima O; Salma, Asem; Rezai, Ali R

    2012-09-01

    Chronic pain is a major health problem in developed countries where it may affect as much as 20% of the adult population. There have been no significant clinical breakthroughs in therapeutic options for persons with chronic neuropathic pain. These limitations underscore the importance of developing new therapies for this disabling pain syndrome. We have reviewed the limitations of the present treatment strategies for chronic pain, neurophysiology of somatosensory transmission and nociception, mechanisms of neuropathic pain, the concept of a "pain matrix" and the "top-down" modulation of pain, and the cognitive affective role in processing of the pain experience. We found that affective and cognitive aspects of pain constitute important considerations in achieving improvements in the outcomes of pain neuromodulation in patients with chronic neuropathic pain. Based on our review, we propose that future novel neuromodulatory therapeutic strategies should be directed at areas in the brain that are involved in the neural mechanisms of reward valuation and appetitive motivation such as nucleus accumbens, ventral tegmental area, and prefrontal cortex.

  13. 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.

  14. Mechanisms-based classifications of musculoskeletal pain: part 2 of 3: symptoms and signs of peripheral neuropathic pain in patients with low back (± leg) pain.

    LENUS (Irish Health Repository)

    Smart, Keith M

    2012-08-01

    As a mechanisms-based classification of pain \\'peripheral neuropathic pain\\' (PNP) refers to pain arising from a primary lesion or dysfunction in the peripheral nervous system. Symptoms and signs associated with an assumed dominance of PNP in patients attending for physiotherapy have not been extensively studied. The purpose of this study was to identify symptoms and signs associated with a clinical classification of PNP in patients with low back (± leg) pain. Using a cross-sectional, between-subjects design; four hundred and sixty-four patients with low back (± leg) pain were assessed using a standardised assessment protocol. Patients\\' pain was assigned a mechanisms-based classification based on experienced clinical judgement. Clinicians then completed a clinical criteria checklist specifying the presence or absence of various clinical criteria. A binary logistic regression analysis with Bayesian model averaging identified a cluster of two symptoms and one sign predictive of PNP, including: \\'Pain referred in a dermatomal or cutaneous distribution\\

  15. A Case of Chronic Abdominal Neuropathic Pain and Burning after Female Genital Cutting

    Directory of Open Access Journals (Sweden)

    Vicky Hadid

    2015-01-01

    Full Text Available Introduction. Female genital cutting is prevalent in the Middle Eastern and African countries. This ritual entails not only immediate complications such as infection, pain, and haemorrhage, but also chronic ones including dysmenorrhea and dyspareunia. However, there is limited data on neuropathic pain secondary to female genital mutilation when searching the literature. Case. This case discusses a 38-year-old female with a history of infibulation who presented with a chronic burning abdominal and anterior vulvar pain including the related investigations and treatment. Discussion. This case brings to light the additional delayed complication of this ritual: sensory neuropathy. Our goal is to educate health professionals to be aware of these complications and to appropriately investigate and treat them in order to find a solution to relieve the patients’ symptoms.

  16. Effects of Intravenous Ketamine Infusions in a Neuropathic Pain Patient with Lichen Sclerosus et Atrophicus

    Science.gov (United States)

    Hanna, Ashraf F.; Armstrong, Josh S.; Smith, Adam J.

    2016-01-01

    A patient reported to the Florida Spine Institute (Clearwater, Fla., USA) with severe lichen sclerosus of the anogenital region and legs. The patient's pain presentation was neuropathic with hypersensitivity, allodynia, swelling, and weakness. The patient had failed multiple pain management modalities including opioid therapy, anticonvulsants, and antidepressants. The patient completed a standard intravenous ketamine infusion regimen developed at the Florida Spine Institute and reported complete abolishment of her pain syndrome. For the first time, we report that ketamine infusions also dramatically improved a patient's lichen sclerosus. That ketamine is known to have immunomodulatory properties, and given the clinical observations described in this case report, suggests that ketamine should be explored as a possible new therapeutic option for managing lichen sclerosus, especially in cases that are refractory to conventional therapies. PMID:27462225

  17. Long term treatment with gabapentin in an animal model of chronic neuropathic pain

    DEFF Research Database (Denmark)

    Baastrup, C. S.; Andrews, N.; Wegener, Gregers

    2013-01-01

    In preclinical animal pain research potential efficacy of a drug is often evaluate after a single exposure, which is in contrast to the long lasting treatment needed in chronic neuropathic pain (CNP) patients. Gabapentin remains one of the most efficacious drugs in the treatment of CNP. The aims...... of the study were to evaluate the spinal cord contusion (SCC) model and 2 different measures of painlike behaviour using a long term treatment schedule with gabapentin. Furthermore the effect on mobility and on anxiety, a pain-related behaviour, was included. 40 Female SD rats with a T13 SCC and sham animals...... was measured after initial dose, 1 and 6 weeks of treatment. Preliminary results show that saline-treated SCC animals (N=10) have significantly lower MST with supra-spinal responses on the thorax compared to saline-treated shams (N=10), and gabapentin-treated SCC (N=10) and sham animals (N=10) throughout...

  18. Untangling nociceptive, neuropathic and neuroplastic mechanisms underlying the biological domain of back pain.

    Science.gov (United States)

    Hush, Julia M; Stanton, Tasha R; Siddall, Philip; Marcuzzi, Anna; Attal, Nadine

    2013-05-01

    SUMMARY Current clinical practice guidelines advocate a model of diagnostic triage for back pain, underpinned by the biopsychosocial paradigm. However, limitations of this clinical model have become apparent: it can be difficult to classify patients into the diagnostic triage categories; patients with 'nonspecific back pain' are clearly not a homogenous group; and mean effects of treatments based on this approach are small. In this article, it is proposed that the biological domain of the biopsychosocial model needs to be reconceptualized using a neurobiological mechanism-based approach. Recent evidence about nociceptive and neuropathic contributors to back pain is outlined in the context of maladaptive neuroplastic changes of the somatosensory system. Implications for clinical practice and research are discussed.

  19. 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.

  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. 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.

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

    Science.gov (United States)

    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.

  3. The topical 5% lidocaine medicated plaster in localized neuropathic pain: a reappraisal of the clinical evidence

    Directory of Open Access Journals (Sweden)

    de León-Casasola OA

    2016-02-01

    Full Text Available Oscar A de León-Casasola,1,2 Victor Mayoral3 1Department of Anesthesiology, Division of Pain Medicine, Roswell Park Cancer Institute, 2University at Buffalo, School of Medicine and Biomedical Sciences. NY, USA; 3Anesthesiology Department, Pain Management Unit, University Hospital of Bellvitge, L'Hospitalet de Llobregat, Spain Abstract: Topical 5% lidocaine medicated plasters represent a well-established first-line option for the treatment of peripheral localized neuropathic pain (LNP. This review provides an updated overview of the clinical evidence (randomized, controlled, and open-label clinical studies, real-life daily clinical practice, and case series. The 5% lidocaine medicated plaster effectively provides pain relief in postherpetic neuralgia, and data from a large open-label controlled study indicate that the 5% lidocaine medicated plaster is as effective as systemic pregabalin in postherpetic neuralgia and painful diabetic polyneuropathy but with an improved tolerability profile. Additionally, improved analgesia and fewer side effects were experienced by patients treated synchronously with the 5% lidocaine medicated plaster, further demonstrating the value of multimodal analgesia in LNP. The 5% lidocaine medicated plaster provides continued benefit after long-term (≤7 years use and is also effective in various other LNP conditions. Minor application-site reactions are the most common adverse events associated with the 5% lidocaine medicated plaster; there is minimal risk of systemic adverse events and drug–drug interactions. Although further well-controlled studies are warranted, the 5% lidocaine medicated plaster is efficacious and safe in LNP and may have particular clinical benefit in elderly and/or medically compromised patients because of the low incidence of adverse events. Keywords: 5% lidocaine medicated plaster, clinical evidence, localized neuropathic pain, postherpetic neuralgia, review

  4. Inflammatory and neuropathic pain animals exhibit distinct responses to innocuous thermal and motoric challenges

    Directory of Open Access Journals (Sweden)

    Apkarian A Vania

    2006-01-01

    Full Text Available Abstract Most current methods for assessing pain in animals are based on reflexive measures and require constant interaction between the observer and the animal. Here we explore two new fully automated methods to quantify the impact of pain on the overall behavior of the organism. Both methods take advantage of the animals' natural preference for a dark environment. We used a box divided into two compartments: dark and bright. In the motoric operant task, "AngleTrack", one end of the box was raised so that the animals had to climb uphill to go from the light to the dark compartment. In the thermal operant task, "ThermalTrack", the floor of the dark compartment was heated to a given temperature, while the light compartment remained at 25°C. Rats were individually placed in the light box and their crossing between chambers monitored automatically for 30 minutes. The angle of the box, or the temperature of the dark compartment, was altered to challenge the animals' natural preference. We test the hypothesis that different models of pain (inflammatory or neuropathic can be differentiated based on performance on these devices. Three groups of rats were tested at five different challenge levels on both tasks: 1 normal, 2 neuropathic injury pain (Spared Nerve Injury, and 3 inflammatory pain (intraplantar injection of Carrageenan. We monitored the position of the animals as well as their rate of switching between compartments. We find significant differences between the three groups and between the challenge levels both in their average position with respect to time, and in their switching rates. This suggests that the angle-track and thermal-track may be useful in assessing automatically the global impact of different types of pain on behavior.

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

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    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.

  6. DDD-028: a potent potential non-opioid, non-cannabinoid analgesic for neuropathic and inflammatory pain.

    Science.gov (United States)

    Rajagopalan, Parthasarathi; Tracey, Heather; Chen, Zhoumou; Bandyopadhyaya, Acintya; Veeraraghavan, Sridhar; Rajagopalan, Desikan R; Salvemini, Daniela; McPhee, Ian; Viswanadha, Srikant; Rajagopalan, Raghavan

    2014-07-15

    DDD-028 (4), a novel pentacyclic pyridoindolobenzazepine derivative was evaluated in vitro for receptor binding affinity and in vivo for analgesic activity using rodent models of neuropathic and inflammatory pain. DDD-028 does not bind to opioid, cannabinoid, dopamine, or histamine receptors. DDD-028 is very active even at the low oral dose of 1-5 mg/kg in both neuropathic, (spinal nerve ligation and chronic constriction injury) and inflammatory (Complete Freund's Adjuvant Induced) models of pain. DDD-028 appears to be about 6-fold more potent than pregabalin and indomethacin. Visual observation of all the animals used in these studies indicated that DDD-028 is well tolerated without any sedation. Thus, DDD-028 seems to be a promising candidate for the treatment of neuropathic and inflammatory pain without the possible side effects or abuse potential associated with opioid or cannabinoid activities.

  7. Peripheral nerve stimulation (PNS) in the trapezius muscle region alleviate chronic neuropathic pain after lower brachial plexus root avulsion lesion: A case report

    DEFF Research Database (Denmark)

    Sørensen, Jens Christian Hedemann; Meier, Kaare; Perinpam, Larshan;

    Peripheral nerve stimulation (PNS) in the trapezius muscle region alleviate chronic neuropathic pain after lower brachial plexus root avulsion lesion: A case report......Peripheral nerve stimulation (PNS) in the trapezius muscle region alleviate chronic neuropathic pain after lower brachial plexus root avulsion lesion: A case report...

  8. THE ORIGIN OF THE CONCEPT OF NEUROPATHIC PAIN IN EARLY MEDIEVAL PERSIA (9TH-12TH CENTURY CE).

    Science.gov (United States)

    Heydari, Mojtaba; Shams, Mesbah; Hashempur, Mohammad Hashem; Zargaran, Arman; Dalfardi, Behnam; Borhani-Haghighi, Afshin

    2015-01-01

    Neuropathic pain is supposed to be a post-renaissance described medical entity. Although it is often believed that John Fothergill (1712-1780) provided the first description of this condition in 1773, a review of the medieval Persian medical writings will show the fact that neuropathic pain was a medieval-originated concept. "Auojae Asab" [Nerve-originated Pain] was used as a medical term in medieval Persian medical literature for pain syndromes which etiologically originated from nerves. Physicians like Rhazes (d. 925 CE), Haly Abbas (d. 982 CE), Avicenna (d. 1037 CE), and Jorjani (d. 1137 CE) have discussed multiple aspects of nerve-originated pain including its classification, etiology, differentiating characteristics, different qualities, and pharmacologic and non-pharmacologic treatments. Recognizing medieval scholars' views on nerve-originated pain can lighten old historical origins of this concept.

  9. Rostral Agranular Insular Cortex Lesion with Motor Cortex Stimulation Enhances Pain Modulation Effect on Neuropathic Pain Model

    Directory of Open Access Journals (Sweden)

    Hyun Ho Jung

    2016-01-01

    Full Text Available It is well known that the insular cortex is involved in the processing of painful input. The aim of this study was to evaluate the pain modulation role of the insular cortex during motor cortex stimulation (MCS. After inducing neuropathic pain (NP rat models by the spared nerve injury method, we made a lesion on the rostral agranular insular cortex (RAIC unilaterally and compared behaviorally determined pain threshold and latency in 2 groups: Group A (NP + MCS; n=7 and Group B (NP + RAIC lesion + MCS; n=7. Also, we simultaneously recorded neuronal activity (NP; n=9 in the thalamus of the ventral posterolateral nucleus and RAIC to evaluate electrophysiological changes from MCS. The pain threshold and tolerance latency increased in Group A with “MCS on” and in Group B with or without “MCS on.” Moreover, its increase in Group B with “MCS on” was more than that of Group B without MCS or of Group A, suggesting that MCS and RAIC lesioning are involved in pain modulation. Compared with the “MCS off” condition, the “MCS on” induced significant threshold changes in an electrophysiological study. Our data suggest that the RAIC has its own pain modulation effect, which is influenced by MCS.

  10. Health care utilization and expenditures among Medicaid beneficiaries with neuropathic pain following spinal cord injury

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    Margolis JM

    2014-07-01

    Full Text Available Jay M Margolis,1 Paul Juneau,1 Alesia Sadosky,2 Joseph C Cappelleri,3 Thomas N Bryce,4 Edward C Nieshoff5 1Truven Health Analytics, Bethesda, MD, USA; 2Pfizer Inc., New York, NY, USA; 3Pfizer Inc., Groton, CT, USA; 4Department of Rehabilitation Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY, USA; 5Department of Physical Medicine and Rehabilitation, Wayne State University School of Medicine, Detroit, MI, USA Background: The study aimed to evaluate health care resource utilization (HRU and costs for neuropathic pain (NeP secondary to spinal cord injury (SCI among Medicaid beneficiaries. Methods: The retrospective longitudinal cohort study used Medicaid beneficiary claims with SCI and evidence of NeP (SCI-NeP cohort matched with a cohort without NeP (SCI-only cohort. Patients had continuous Medicaid eligibility 6 months pre- and 12 months postindex, defined by either a diagnosis of central NeP (ICD-9-CM code 338.0x or a pharmacy claim for an NeP-related antiepileptic or antidepressant drug within 12 months following first SCI diagnosis. Demographics, clinical characteristics, HRU, and expenditures were compared between cohorts. Results: Propensity score-matched cohorts each consisted of 546 patients. Postindex percentages of patients with physician office visits, emergency department visits, SCI- and pain-related procedures, and outpatient prescription utilization were all significantly higher for SCI-NeP (P<0.001. Using regression models to account for covariates, adjusted mean expenditures were US$47,518 for SCI-NeP and US$30,150 for SCI only, yielding incremental costs of US$17,369 (95% confidence interval US$9,753 to US$26,555 for SCI-NeP. Factors significantly associated with increased cost included SCI type, trauma-related SCI, and comorbidity burden. Conclusion: Significantly higher HRU and total costs were incurred by Medicaid patients with NeP secondary to SCI compared with matched SCI-only patients. Keywords: spinal

  11. 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.

  12. Parents' perspective of their journey caring for a child with chronic neuropathic pain.

    Science.gov (United States)

    Gaughan, Veronica; Logan, Deirdre; Sethna, Navil; Mott, Sandra

    2014-03-01

    When a child has chronic pain, it affects the parents. Their response and how it is factored into their lives and family function was the phenomenon of interest that drove this study. The available literature was sparse, especially when the pain etiology was neuropathic. The purpose of this study was to describe the parents' perception of the pain journey from the initial occurrence of their child's pain through the labyrinth of treatment options to successful outcome, to gain a better understanding of parental beliefs about pain, and to learn how parental attitudes and behaviors relate to children's response to treatment for chronic pain. Qualitative descriptive design was used to better understand the phenomenon from those who were the experts because they had experienced it. Parents whose child was enrolled in a pain rehabilitation program participated in open-ended interviews. The children/adolescents were 8-18 years old and diagnosed with complex regional pain syndrome or a related chronic pain condition. During data immersion, the investigators uncovered the pervasive underlying themes of suffering and disempowerment. In addition, the multiple meaning elements were grouped into three categories and supportive subcategories labeled as follows: parent distress, with subcategories schism in parenting, searching, and disabled parenting; and lack of control, with the subcategories family/community, fear, and empowerment. The voices of parents were heard in their description of the exhausting and difficult journey in search of pain relief for their child. Their comments provided insight into how they defined the child's pain and their related parental role.

  13. 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....

  14. Building a diagnostic algorithm on localized neuropathic pain (LNP and targeted topical treatment: focus on 5% lidocaine-medicated plaster

    Directory of Open Access Journals (Sweden)

    Casale R

    2014-04-01

    Full Text Available Roberto Casale,1,2 Consalvo Mattia31Department 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 Medical-Surgical Sciences, Section of Anaesthesia, Intensive Care and Pain Medicine, Faculty of Medicine and Pharmacy, Sapienza University of Rome, ItalyAbstract: Within the broad definition of neuropathic pain, the refinement of clinical diagnostic procedures has led to the introduction of the concept of localized neuropathic pain (LNP. It is characterized by consistent and circumscribed area(s of maximum pain, which are associated with negative or positive sensory signs and/or spontaneous symptoms typical of neuropathic pain. This description outlines the clinical features (currently lacking in guidelines and treatment recommendations in patients for whom topical targeted treatment with 5% lidocaine-medicated plaster is suggested as first-line therapy. Few epidemiologic data are present in the literature but it is generally estimated that about 60% of neuropathic pain conditions are localized, and therefore identifiable as LNP. A mandatory clinical criterion for the diagnosis of LNP is that signs and symptoms must be present in a clearly identified and defined area(s. Cartographic recordings can help to define each area and to assess variations. The diagnosis of LNP relies on careful neurological examination more than on pain questionnaires, but it is recognized that they can be extremely useful for recording the symptom profiles and establishing a more targeted treatment. The most widely studied frequent/relevant clinical presentations of LNP are postherpetic neuralgia, diabetic neuropathy, and neuropathic postoperative pain. They successfully respond to treatment with 5% lidocaine-medicated plaster with equal if not better pain control but with fewer side effects versus conventional systemic

  15. Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

    Science.gov (United States)

    Romero, Haylie K.; Christensen, Sean B.; Gajewiak, Joanna; Ramachandra, Renuka; Elmslie, Keith S.; Vetter, Douglas E.; Ghelardini, Carla; Iadonato, Shawn P.; Mercado, Jose L.; Olivera, Baldomera M.; McIntosh, J. Michael

    2017-01-01

    Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABAB receptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABAB receptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain. PMID:28223528

  16. 加巴喷丁在神经性疼痛中的应用%Application of gabapentin in the treatment of neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    朱珠; 王毅

    2015-01-01

    作为一种抗癫痫药物,加巴喷丁可通过中枢和外周的多种机制,在神经性疼痛的治疗中发挥着重要作用.研究表明,加巴喷丁对于卒中和脊髓损伤相关疼痛、带状疱疹后神经痛以及糖尿病周围神经病所致疼痛等均有较好的疗效.加巴喷丁的不良反应轻、耐受性好、药物相互作用少,是治疗神经性疼痛的理想药物.%As an anti-epilepsy drug,gabapentin plays an important role in the treatment of neuropathic pain through a variety of central and peripheral mechanisms.Studies have shown that gabapentin has better efficacy for post-stroke pain,spinal cord injury-related pain,postherpetic neuralgia,and pain in diabetic peripheral neuropathy.For mild adverse effects,good tolerance and lack of interactions,gabapentin is an ideal drug for the treatment of neuropathic pain.

  17. Resveratrol attenuates neuropathic pain through balancing pro-inflammatory and anti-inflammatory cytokines release in mice.

    Science.gov (United States)

    Tao, Lei; Ding, Qian; Gao, Changjun; Sun, Xude

    2016-05-01

    Anti-inflammatory activity of resveratrol has been widely studied, while its beneficial effect on the management of neuropathic pain, a refractory chronic syndrome with pro-inflammation implicated in, is very little investigated. In the present study, the effects of different doses and various time window of administration of resveratrol were explored in a neuropathic mouse model of chronic constriction injury (CCI) of the sciatic nerve. It was demonstrated that pretreatment of resveratrol (5, 10, 20 and 40 mg/kg) for 7 consecutive days before CCI did not alleviate neuropathic pain, while it clearly relieved the pain when administrated after CCI and such pain relief effect was more pronounced when administrated right after the peak of pain symptom at day 7 after CCI, as evidenced by the alleviation of thermal hyperalgesia and mechanical allodynia. Such a beneficial effect of resveratrol was in a dose-dependent manner. Mechanistic study showed that resveratrol repressed the expression of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, and promoted the expression of anti-inflammatory cytokine IL-10 at the same time, which was further confirmed in a cell model of microglia. It was also shown that neuropathic pain inversely correlated with pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, but not with anti-inflammatory cytokine IL-10 in all experimental mice from Spearman correlation coefficient. Our study reveals that resveratrol displays a significant neuropathic pain relief effect and paved a way for novel treatment of chronic pain.

  18. Self-reported somatosensory symptoms of neuropathic pain in fibromyalgia and chronic widespread pain correlate with tender point count and pressure-pain thresholds

    DEFF Research Database (Denmark)

    Amris, Kirstine; Jespersen, Anders; Bliddal, Henning

    2010-01-01

    of patients with chronic widespread pain (CWP). The aims of the study were to assess the patient-reported sensory neuropathic symptoms by PDQ and to correlate these with tender point (TP) count and pressure-pain thresholds. Eighty-one patients (75 F, 6 M) with CWP (ACR-criteria) filled in the PDQ. Manual TP......-37). Mean PDT was 8.8 kPa (range: 2-36) and mean PTT 30.9 kPa (range: 4-85). Deep-tissue hyperalgesia was the predominant somatosensory symptom reported in 83%, but other neuropathic symptoms were also frequent, e.g. burning 51% and prickling 47%. Statistically significant correlations were found between...

  19. Anthropogenic Radio-Frequency Electromagnetic Fields Elicit Neuropathic Pain in an Amputation Model.

    Directory of Open Access Journals (Sweden)

    Bryan Black

    Full Text Available Anecdotal and clinical reports have suggested that radio-frequency electromagnetic fields (RF EMFs may serve as a trigger for neuropathic pain. However, these reports have been widely disregarded, as the epidemiological effects of electromagnetic fields have not been systematically proven, and are highly controversial. Here, we demonstrate that anthropogenic RF EMFs elicit post-neurotomy pain in a tibial neuroma transposition model. Behavioral assays indicate a persistent and significant pain response to RF EMFs when compared to SHAM surgery groups. Laser thermometry revealed a transient skin temperature increase during stimulation. Furthermore, immunofluorescence revealed an increased expression of temperature sensitive cation channels (TRPV4 in the neuroma bulb, suggesting that RF EMF-induced pain may be due to cytokine-mediated channel dysregulation and hypersensitization, leading to thermal allodynia. Additional behavioral assays were performed using an infrared heating lamp in place of the RF stimulus. While thermally-induced pain responses were observed, the response frequency and progression did not recapitulate the RF EMF effects. In vitro calcium imaging experiments demonstrated that our RF EMF stimulus is sufficient to directly contribute to the depolarization of dissociated sensory neurons. Furthermore, the perfusion of inflammatory cytokine TNF-α resulted in a significantly higher percentage of active sensory neurons during RF EMF stimulation. These results substantiate patient reports of RF EMF-pain, in the case of peripheral nerve injury, while confirming the public and scientific consensus that anthropogenic RF EMFs engender no adverse sensory effects in the general population.

  20. Case Report: Neuropathic pain in a patient with congenital insensitivity to pain [v2; ref status: indexed, http://f1000r.es/5iu

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    Daniel W. Wheeler

    2015-06-01

    Full Text Available We report a unique case of a woman with Channelopathy-associated Insensitivity to Pain (CIP Syndrome, who developed features of neuropathic pain after sustaining pelvic fractures and an epidural hematoma that impinged on the right fifth lumbar (L5 nerve root. Her pelvic injuries were sustained during painless labor, which culminated in a Cesarean section. She had been diagnosed with CIP as child, which was later confirmed when she was found to have null mutations of the SCN9A gene that encodes the voltage-gated sodium channel Nav1.7. She now complains of troubling continuous buzzing in both legs and a vice-like squeezing in the pelvis on walking. Quantitative sensory testing showed that sensory thresholds to mechanical stimulation of the dorsum of both feet had increased more than 10-fold on both sides compared with tests performed before her pregnancy. These findings fulfill the diagnostic criteria for neuropathic pain. Notably, she mostly only experiences the negative symptoms (such as numbness and tingling, but also electric shocks, and she has not reported sharp or burning sensations, although the value of verbal descriptors is somewhat limited in a person who has never felt pain before. However, her case strongly suggests that at least some of the symptoms of neuropathic pain can persist despite the absence of the Nav1.7 channel. Pain is a subjective experience and this case sheds light on the transmission of neuropathic pain in humans that cannot be learned from knockout mice.

  1. The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury

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    Rajpal Sharad

    2008-09-01

    Full Text Available Abstract Background Altered Cl- homeostasis and GABAergic function are associated with nociceptive input hypersensitivity. This study investigated the role of two major intracellular Cl- regulatory proteins, Na+-K+-Cl- cotransporter 1 (NKCC1 and K+-Cl- cotransporter 2 (KCC2, in neuropathic pain following spinal cord injury (SCI. Results Sprague-Dawley rats underwent a contusive SCI at T9 using the MASCIS impactor. The rats developed hyperalgesia between days 21 and 42 post-SCI. Thermal hyperalgesia (TH was determined by a decrease in hindpaw thermal withdrawal latency time (WLT between days 21 and 42 post-SCI. Rats with TH were then treated with either vehicle (saline containing 0.25% NaOH or NKCC1 inhibitor bumetanide (BU, 30 mg/kg, i.p. in vehicle. TH was then re-measured at 1 h post-injection. Administration of BU significantly increased the mean WLT in rats (p Conclusion Taken together, expression of NKCC1 and KCC2 proteins was differentially altered following SCI. The anti-hyperalgesic effect of NKCC1 inhibition suggests that normal or elevated NKCC1 function and loss of KCC2 function play a role in the development and maintenance of SCI-induced neuropathic pain.

  2. [Effects of fasudil on neuropathic pain-like state in mice].

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    Shiokawa, Mitsuru; Yamaguchi, Takanori; Narita, Minoru; Okutsu, Daiki; Nagumo, Yasuyuki; Miyoshi, Kan; Suzuki, Masami; Inoue, Tadao; Suzuki, Tsutomu

    2007-08-01

    The aim of the present study was to investigate the role of protein kinases within the spinal cord in the development of a neuropathic pain-like state induced by partial sciatic nerve ligation in mice. Thermal hyperalgesia induced by nerve ligation in mice was markedly suppressed by either repeated intrathecal (i.t.) pre-treatment or post-treatment with the selective protein kinase (PKC) inhibitor RO-32-0432 and the selective Rho kinase inhibitor Y-27632. In contrast, sciatic nerve ligation-induced thermal hyperalgesia was not observed by repeated i.t. pre-treatment with the selective PKA inhibitor KT5720. Interestingly, thermal hyperalgesia induced by nerve ligation in mice was significantly suppressed by repeated i.t. post-treatment with fasudil, which possesses the inhibitory effect of several protein kinases including PKC and Rho kinase. Collectively, these findings suggest that a long-lasting activation of PKC and RhoA/Rho kinase pathways in the spinal cord may be responsible for the development of thermal hyperalgesia induced by nerve ligation in mice. The present data raise the fascinating possibility that i.t. or epidural administration with fasudil may be useful for the treatment of neuropathic pain.

  3. Fucoidan attenuates the existing allodynia and hyperalgesia in a rat model of neuropathic pain.

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    Hu, Chuanyin; Zhang, Guoping; Zhao, Yun-Tao

    2014-06-13

    Fucoidan is an active constituent found in brown seaweeds, which have potential neuroprotection. The current study aimed to investigate the effects of fucoidan on the maintenance of neuropathic pain induced by L5 spinal nerve ligation (SNL) and the underlying mechanism related to the spinal neuroimmune responses. Animals were randomized into 5 groups: sham-operation with vehicle and SNL with vehicle or fucoidan (15, 50, and 100mg/kg). Different doses of fucoidan or vehicle were administered intrathecally once daily from postoperative day (POD) 11-20. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) was measured on 1 day before operation and days 10, 20, 22, 24, 26, 28, 30 after operation. Glial activation markers such as glial fibrillary acidic protein (GFAP) and macrophage antigen complex-1 (mac-1), inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 activation, and extracellular signalregulated protein kinase (ERK) activation in the lumbar spinal cord were determined on day 30 after operation. The results showed that fucoidan caused dose-dependently attenuation of mechanical allodynia and thermal hyperalgesia. Furthermore, fucoidan could markedly inhibit neuroimmune activation characterized by glial activation, production of cytokines as well as ERK activation. The analgesic effect of intrathecal fucoidan in rats receiving SNL might partly attribute to the inhibition of neuroimmune activation associated with the maintenance of neuropathic pain.

  4. An Exploratory Study into Objective and Reported Characteristics of Neuropathic Pain in Women with Chronic Pelvic Pain.

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    Lucy H R Whitaker

    Full Text Available Chronic pelvic pain (CPP affects 5.7-26.6% women worldwide. 55% have no obvious pathology and 40% have associated endometriosis. Neuropathic pain (NeP is pain arising as a consequence of a lesion/disease affecting the somatosensory system. The prevalence of NeP in women with CPP is not known. The diagnosis of NeP is challenging because there is no gold-standard assessment. Questionnaires have been used in the clinical setting to diagnose NeP in other chronic pain conditions and quantitative sensory testing (QST has been used in a research setting to identify abnormal sensory function. We aimed to determine if women with chronic pelvic pain (CPP have a neuropathic pain (NeP component to their painful symptoms and how this is best assessed. We performed an exploratory prospective cohort study of 72 pre-menopausal women with a diagnosis of CPP. They underwent a clinician completed questionnaire (DN4 and completed the S-LANSS and PainDETECT™ questionnaires. Additionally QST testing was performed by a clinician. They also completed a patient acceptability questionnaire. Clinical features of NeP were identified by both questionnaires and QST. Of the women who were NeP positive, 56%, 35% and 26% were identified by the S-LANSS, DN4 and PainDETECT™ respectively. When NeP was identified by questionnaire, the associated laparoscopy findings were similar irrespective of which questionnaire was used. No subject had entirely unchanged QST parameters. There were distinct loss and gain subgroups, as well as mixed alteration in function, but this was not necessarily clinically significant in all patients. 80% of patients were confident that questionnaires could diagnose NeP, and 90% found them easy to complete. Early identification of NeP in women with CPP with a simple questionnaire could facilitate targeted therapy with neuromodulators, which are cheap, readily available, and have good safety profiles. This approach could prevent unnecessary or fertility

  5. Identification of differentially expressed genes by gabapentin in cultured dorsal root ganglion in a rat neuropathic pain model.

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    Heo, Ji Hye; Lee, Seung Ha; Chang, Kyung Ha; Han, Eun Hye; Lee, Seung Gwan; Choi, Dal Woong; Kim, Suhng Wook

    2013-03-01

    Neuropathic pain is a chronic pain disorder caused by nervous system lesions as a direct consequence of a lesion or by disease of the portions of the nervous system that normally signal pain. The spinal nerve ligation (SNL) model in rats that reflect some components of clinical pain have played a crucial role in the understanding of neuropathic pain. To investigate the direct effects of gabapentin on differential gene expression in cultured dorsal root ganglion (DRG) cells of SNL model rats, we performed a differential display reverse transcription-polymerase chain reaction analysis with random priming approach using annealing control primer. Genes encoding metallothionein 1a, transforming growth factor-β1 and palmitoyl-protein thioesterase-2 were up-regulated in gabapentin-treated DRG cells of SNL model rats. The functional roles of these differentially expressed genes were previously suggested as neuroprotective genes. Further study of these genes is expected to reveal potential targets of gabapentin.

  6. sec-Butylpropylacetamide (SPD), a new amide derivative of valproic acid for the treatment of neuropathic and inflammatory pain.

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    Kaufmann, Dan; West, Peter J; Smith, Misty D; Yagen, Boris; Bialer, Meir; Devor, Marshall; White, H Steve; Brennan, K C

    2017-03-01

    Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect ∼20% of the world's population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study, we defined the pharmacokinetic parameters of SPD in rat and mouse, and then evaluated its antinociceptive potential in neuropathic and acute inflammatory pain models. In the sciatic nerve ligation (SNL) model of neuropathic pain, SPD was equipotent to gabapentin and more potent than its parent compound VPA. SPD also showed either higher or equal potency to VPA in the formalin, carrageenan, and writhing tests of inflammatory pain. SPD showed no effects on compound action potential properties in a sciatic nerve preparation, suggesting that its mechanism of action is distinct from local anesthetics and membrane stabilizing drugs. SPD's activity in both neuropathic and inflammatory pain warrants its development as a potential broad-spectrum anti-nociceptive drug.

  7. 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.

  8. EMA401: an old antagonist of the AT2R for a new indication in neuropathic pain

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    Keppel Hesselink, Jan M; Schatman, Michael E

    2017-01-01

    EMA401 is an old molecule, synthesized by Parke-Davis in the last century and characterized at that time as an AT2R antagonist. Professor Maree Smith and her group from the University of Queensland (Australia) patented the drug and many related derivatives and other compounds with high affinity for the AT2R for the indication neuropathic pain in 2004, an example of drug repositioning. After some years of university work, the Australian biotech company Spinifex Pharmaceuticals took over further research and development and characterized the S-enantiomer, code name EMA401, and related compounds in a variety of animal models for neuropathic and cancer pain. EMA401 was selected as the lead compound, based on high selectivity for the AT2R and good oral bioavailability (33%). EMA401, however, was only administered once in a chronic neuropathic pain model, and no data have been published in other pain models, or during steady state, although such data were available for the racemate EMA400 and some related compounds (EMA200, EMA400). A pilot phase IIa study demonstrated the efficacy and safety of the drug taken twice daily as two capsules of 50 mg (400 mg/day). In 2015, Novartis took over the clinical development. Two phase IIb studies designed by Spinifex Pharmaceuticals were put on hold, probably because Novartis wanted to improve the clinical design or collect additional preclinical data. Further data are eagerly awaited, especially since EMA401 is first-in-class in neuropathic pain. PMID:28255254

  9. Serotonergic system and its role in epilepsy and neuropathic pain treatment: a review based on receptor ligands.

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    Panczyk, Katarzyna; Golda, Sylwia; Waszkielewicz, Anna; Zelaszczyk, Dorota; Gunia-Krzyzak, Agnieszka; Marona, Henryk

    2015-01-01

    The serotonergic system is involved in pathomechanisms of both epilepsy and neuropathic pain. So far, participation in the epileptogenesis and maintenance of epilepsy was proved for 5-HT1A, 5-HT2C, 5-HT3, 5-HT4 and 5-HT7 receptors as well as 5-HTT serotonin transporter. Depending on the receptor type or its localization, its stimulation may increase or decrease neuronal excitability. According to the available data, neuropathic pain mechanisms involve 5-HT1A/1B/1D, 5-HT2A/2B/2C, 5-HT3, 5-HT4, 5-HT6, 5-HT7 receptors and 5-HTT serotonin transporter. Changes in their expression modulate pain mainly by affecting the transmission through serotonergic descending pathways. Several compounds, whose mechanisms of action base on influence on the serotonergic system, are already in use. These are 5-HT3 agonists (triptans) in case of migraine, tricyclic antidepressants or monoamine reuptake inhibitors in neuropathic pain treatment. In addition, selective and non-selective ligands are tested for their anticonvulsant or analgesic properties. Some ED50 values have been already obtained in such animal models as maximal electroshock (MES)-induced seizures (epilepsy), spinal nerve ligation (SNL), chronic constriction injury (CCI) or formalin (neuropathic pain). This review shows that in case of drug discovery within the serotonergic system one must take into account special significance of factors such as: the species, the type of model, the route of administration, and the dose range.

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

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    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.

  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. Mitogen activated protein kinase phosphatase-1 prevents the development of tactile sensitivity in a rodent model of neuropathic pain

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    Ndong Christian

    2012-04-01

    Full Text Available Abstract Background Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of spinal MKP-1 will prevent the development of peripheral nerve-injury-induced hypersensitivity and p-p38 overexpression. Results We cloned rat spinal cord MKP-1 and optimize MKP-1 cDNA in vitro using transfections to BV-2 cells. We observed that in vitro overexpression of MKP-1 blocked lipopolysaccharide-induced phosphorylation of p38 (and other MAPKs as well as release of pro-algesic effectors (i.e., cytokines, chemokines, nitric oxide. Using this cDNA MKP-1 and a non-viral, in vivo nanoparticle transfection approach, we found that spinal cord overexpression of MKP-1 prevented development of peripheral nerve-injury-induced tactile hypersensitivity and reduced pro-inflammatory cytokines and chemokines and the phosphorylated form of p38. Conclusions Our results indicate that MKP-1, the natural regulator of p-p38, mediates resolution of the spinal cord pro-inflammatory milieu induced by peripheral nerve injury, resulting in prevention of chronic mechanical hypersensitivity. We propose that MKP-1 is a potential therapeutic target for pain treatment or prevention.

  13. Symptom profiles in the painDETECT questionnaire in patients with peripheral neuropathic pain stratified according to sensory loss in quantitative sensory testing

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    Vollert, Jan; Kramer, M; Barroso, A;

    2016-01-01

    BACKGROUND: The painDETECT Questionnaire (PDQ) is commonly used as a screening tool to discriminate between neuropathic pain (NP) and nociceptive pain, based on the self-report of symptoms, including pain qualities, numbness and pain to touch, cold or heat. However, there is little data about...... burning sensations and pain evoked by light touch. CONCLUSION: Although the PDQ was not designed to assess sensory loss, single items reflect thermal and / or mechanical sensory loss at group level, but due to substantial variability, the PDQ does not allow for individual allocation of patients...

  14. A randomized, placebo-controlled trial of levetiracetam in central pain in multiple sclerosis

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    Falah, M; Madsen, C; Holbech, J V

    2012-01-01

    Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signalling in the pain pathway. The aim of this study was to test the analgesic effect of levetiracetam in central pain in multiple...... sclerosis. This was a randomized, double-blind, placebo-controlled, cross-over trial with levetiracetam 3000 mg/day versus placebo (6-week treatment periods). Patients with multiple sclerosis, symptoms and signs complying with central neuropathic pain and pain symptoms for more than 6 months, as well......-selected patients with central pain in multiple sclerosis, but an effect in subgroups with specific pain symptoms was indicated....

  15. 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.

  16. Analgesic Effect of Harpagophytum procumbens on Postoperative and Neuropathic Pain in Rats

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    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.

  17. TLR signaling adaptor protein MyD88 in primary sensory neurons contributes to persistent inflammatory and neuropathic pain and neuroinflammation

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    Liu, Xing-Jun; Liu, Tong; Chen, Gang; Wang, Bing; Yu, Xiao-Lu; Yin, Cui; Ji, Ru-Rong

    2016-01-01

    Increasing evidence suggests that neuro-immune and neuro-glial interactions are critically involved in chronic pain sensitization. It is well studied how immune/glial mediators sensitize pain, but how sensory neurons control neuroinflammation remains unclear. We employed Myd88 conditional knockout (CKO) mice, in which Myd88 was deleted in sodium channel subunit Nav1.8-expressing primary sensory neurons, to examine the unique role of neuronal MyD88 in regulating acute and chronic pain, and possible underlying mechanisms. We found that baseline pain and the formalin induced acute inflammatory pain were intact in CKO mice. However, the late phase inflammatory pain following complete Freund’s adjuvant injection and the late phase neuropathic pain following chronic constriction injury (CCI), were reduced in CKO mice. CCI induced up-regulation of MyD88 and chemokine C-C motif ligand 2 expression in DRG neurons and macrophage infiltration into DRGs, and microglia activation in spinal dorsal horns in wild-type mice, but all these changes were compromised in CKO mice. Finally, the pain hypersensitivity induced by intraplantar IL-1β was reduced in CKO mice. Our findings suggest that MyD88 in primary sensory neurons plays an active role in regulating IL-1β signaling and neuroinflammation in the peripheral and the central nervous systems, and contributes to the maintenance of persistent pain. PMID:27312666

  18. Effective management of intractable neuropathic pain using an intrathecal morphine pump in a patient with acute transverse myelitis

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    Wu WT

    2013-07-01

    Full Text Available Wei-Ting Wu,1 Yu-Hui Huang,2,3 Der-Cherng Chen,4 Yu-Hsuan Huang,1 Li-Wei Chou1,5 1Department of Physical Medicine and Rehabilitation, China Medical University Hospital, Taichung, Taiwan; 2School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 3Department of Physical Medicine and Rehabilitation, Chung Shan Medical University Hospital, Taichung, Taiwan; 4Center of Neuropsychiatry, Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan, 5School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, TaiwanAbstract: Transverse myelitis is a rare inflammatory myelopathy characterized by loss of motor and sensory function below the affected level of the spinal cord, and causes neurogenic bowel and bladder. Occasionally, it also causes neuropathic pain with spasticity. Traditional therapies for neuropathic pain are multiple, including multimodal analgesic regimens, antiepileptic or antidepressant medications, opioids, sympathetic blocks, and spinal cord stimulation. Persistent neuropathic pain can cause emotional distress by affecting sleep, work, recreation, and emotional well-being. Here we report the case of a patient suffering from intractable neuropathic pain following acute transverse myelitis that was not relieved by combinations of nonsteroidal anti-inflammatory, antiepileptic, antidepressant, and opioid medications, or by acupuncture. Implantation of an intrathecal morphine pump controlled the pain successfully without side effects, and enabled the patient to embark on intensive rehabilitation. The patient's muscle strength has improved significantly and the patient may soon be able to use a walker with minimal assistance.Keywords: intrathecal morphine pump, neuropathic pain, rehabilitation, transverse myelitis

  19. Phase-specific plasticity of synaptic structures in the somatosensory cortex of living mice during neuropathic pain

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    Kim Sun

    2011-11-01

    Full Text Available Abstract Background Postsynaptic dendritic spines in the cortex are highly dynamic, showing rapid morphological changes including elongation/retraction and formation/elimination in response to altered sensory input or neuronal activity, which achieves experience/activity-dependent cortical circuit rewiring. Our previous long-term in vivo two-photon imaging study revealed that spine turnover in the mouse primary somatosensory (S1 cortex markedly increased in an early development phase of neuropathic pain, but was restored in a late maintenance phase of neuropathic pain. However, it remains unknown how spine morphology is altered preceding turnover change and whether gain and loss of presynaptic boutons are changed during neuropathic pain. Findings Here we used short-term (2-hour and long-term (2-week time-lapse in vivo two-photon imaging of individual spines and boutons in the S1 cortical layer 1 of the transgenic mice expressing GFP in pyramidal neurons following partial sciatic nerve ligation (PSL. We found in the short-term imaging that spine motility (Δ length per 30 min significantly increased in the development phase of neuropathic pain, but returned to the baseline in the maintenance phase. Moreover, the proportion of immature (thin and mature (mushroom spines increased and decreased, respectively, only in the development phase. Long-term imaging data showed that formation and elimination of boutons moderately increased and decreased, respectively, during the first 3 days following PSL and was subsequently restored. Conclusions Our results indicate that the S1 synaptic structures are rapidly destabilized and rearranged following PSL and subsequently stabilized in the maintenance phase of neuropathic pain, suggesting a novel therapeutic target in intractable chronic pain.

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

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    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

  1. The analgesic effect on neuropathic pain of retrogradely transported botulinum neurotoxin A involves Schwann cells and astrocytes.

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    Sara Marinelli

    Full Text Available In recent years a growing debate is about whether botulinum neurotoxins are retrogradely transported from the site of injection. Immunodetection of cleaved SNAP-25 (cl-SNAP-25, the protein of the SNARE complex targeted by botulinum neurotoxin serotype A (BoNT/A, could represent an excellent approach to investigate the mechanism of action on the nociceptive pathways at peripheral and/or central level. After peripheral administration of BoNT/A, we analyzed the expression of cl-SNAP-25, from the hindpaw's nerve endings to the spinal cord, together with the behavioral effects on neuropathic pain. We used the chronic constriction injury of the sciatic nerve in CD1 mice as animal model of neuropathic pain. We evaluated immunostaining of cl-SNAP-25 in the peripheral nerve endings, along the sciatic nerve, in dorsal root ganglia and in spinal dorsal horns after intraplantar injection of saline or BoNT/A, alone or colocalized with either glial fibrillar acidic protein, GFAP, or complement receptor 3/cluster of differentiation 11b, CD11b, or neuronal nuclei, NeuN, depending on the area investigated. Immunofluorescence analysis shows the presence of the cl-SNAP-25 in all tissues examined, from the peripheral endings to the spinal cord, suggesting a retrograde transport of BoNT/A. Moreover, we performed in vitro experiments to ascertain if BoNT/A was able to interact with the proliferative state of Schwann cells (SC. We found that BoNT/A modulates the proliferation of SC and inhibits the acetylcholine release from SC, evidencing a new biological effect of the toxin and further supporting the retrograde transport of the toxin along the nerve and its ability to influence regenerative processes. The present results strongly sustain a combinatorial action at peripheral and central neural levels and encourage the use of BoNT/A for the pathological pain conditions difficult to treat in clinical practice and dramatically impairing patients' quality of life.

  2. The Analgesic Effect on Neuropathic Pain of Retrogradely Transported botulinum Neurotoxin A Involves Schwann Cells and Astrocytes

    Science.gov (United States)

    Ricordy, Ruggero; Uggenti, Carolina; Tata, Ada Maria; Luvisetto, Siro; Pavone, Flaminia

    2012-01-01

    In recent years a growing debate is about whether botulinum neurotoxins are retrogradely transported from the site of injection. Immunodetection of cleaved SNAP-25 (cl-SNAP-25), the protein of the SNARE complex targeted by botulinum neurotoxin serotype A (BoNT/A), could represent an excellent approach to investigate the mechanism of action on the nociceptive pathways at peripheral and/or central level. After peripheral administration of BoNT/A, we analyzed the expression of cl-SNAP-25, from the hindpaw’s nerve endings to the spinal cord, together with the behavioral effects on neuropathic pain. We used the chronic constriction injury of the sciatic nerve in CD1 mice as animal model of neuropathic pain. We evaluated immunostaining of cl-SNAP-25 in the peripheral nerve endings, along the sciatic nerve, in dorsal root ganglia and in spinal dorsal horns after intraplantar injection of saline or BoNT/A, alone or colocalized with either glial fibrillar acidic protein, GFAP, or complement receptor 3/cluster of differentiation 11b, CD11b, or neuronal nuclei, NeuN, depending on the area investigated. Immunofluorescence analysis shows the presence of the cl-SNAP-25 in all tissues examined, from the peripheral endings to the spinal cord, suggesting a retrograde transport of BoNT/A. Moreover, we performed in vitro experiments to ascertain if BoNT/A was able to interact with the proliferative state of Schwann cells (SC). We found that BoNT/A modulates the proliferation of SC and inhibits the acetylcholine release from SC, evidencing a new biological effect of the toxin and further supporting the retrograde transport of the toxin along the nerve and its ability to influence regenerative processes. The present results strongly sustain a combinatorial action at peripheral and central neural levels and encourage the use of BoNT/A for the pathological pain conditions difficult to treat in clinical practice and dramatically impairing patients’ quality of life. PMID:23110146

  3. Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain.

    Science.gov (United States)

    Chobanian, Harry R; Guo, Yan; Liu, Ping; Chioda, Marc D; Fung, Selena; Lanza, Thomas J; Chang, Linda; Bakshi, Raman K; Dellureficio, James P; Hong, Qingmei; McLaughlin, Mark; Belyk, Kevin M; Krska, Shane W; Makarewicz, Amanda K; Martel, Elliot J; Leone, Joseph F; Frey, Lisa; Karanam, Bindhu; Madeira, Maria; Alvaro, Raul; Shuman, Joyce; Salituro, Gino; Terebetski, Jenna L; Jochnowitz, Nina; Mistry, Shruti; McGowan, Erin; Hajdu, Richard; Rosenbach, Mark; Abbadie, Catherine; Alexander, Jessica P; Shiao, Lin-Lin; Sullivan, Kathleen M; Nargund, Ravi P; Wyvratt, Matthew J; Lin, Linus S; DeVita, Robert J

    2014-06-12

    We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.

  4. Assessment of neuropathic pain in patients with cancer: the interobserver reliability. An observational study in daily practice

    NARCIS (Netherlands)

    Timmerman, H.; Heemstra, I.; Schalkwijk, A.; Verhagen, C.; Vissers, K.; Engels, Y.

    2013-01-01

    BACKGROUND: Neuropathic pain (NeP) is a burdensome problem in all stages of cancer. Although clinical judgment is accepted as a surrogate for an objective gold standard in diagnosing NeP, no publications were found about its reliability. OBJECTIVES: Therefore, levels of agreement on the clinical exa

  5. Yokukansan Improves Mechanical Allodynia through the Regulation of Interleukin-6 Expression in the Spinal Cord in Mice with Neuropathic Pain

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    Shigeru Ebisawa

    2015-01-01

    Full Text Available Neuropathic pain is caused by nerve injury. Yokukansan (Yi-Gan San, a traditional Japanese (Kampo medicine, has been widely used for neuropathic pain control. However, the analgesic mechanisms remain unknown. In this study, we investigated the analgesic mechanisms of yokukansan in a mouse model of neuropathic pain. Partial sciatic nerve ligation (PSL induced mechanical allodynia in mice. Repetitive oral administration of the extracts of yokukansan and the constituent herbal medicine Atractylodis Lanceae Rhizoma, but not Glycyrrhizae Radix, relieved mechanical allodynia in the PSL mice and inhibited the PSL-induced expression of interleukin- (IL- 6 mRNA in the spinal cord. Yokukansan did not attenuate intrathecal IL-6-induced mechanical allodynia. IL-6 immunoreactivity was detected in microglia and astrocytes in the spinal dorsal horn. These results suggest that yokukansan relieves mechanical allodynia in PSL mice by regulating the expression of IL-6 in astrocytes and/or microglia in the spinal cord. In addition, the components of Atractylodis Lanceae Rhizoma, one of the constituent herbal medicines in yokukansan, may play an important role in the regulation of IL-6 expression and neuropathic pain control.

  6. Antiallodynic and antihyperalgesic effects of zerumbone on a mouse model of chronic constriction injury-induced neuropathic pain.

    Science.gov (United States)

    Zulazmi, Nurul Atiqah; Gopalsamy, Banulata; Farouk, Ahmad Akira Omar; Sulaiman, Mohd Roslan; Bharatham, B Hemabarathy; Perimal, Enoch Kumar

    2015-09-01

    Neuropathic pain is a chronic condition that is difficult to be treated. Current therapies available are either ineffective or non-specific thus requiring newer treatment approaches. In this study, we investigated the antiallodynic and antihyperalgesic effects of zerumbone, a bioactive sesquiterpene from Zingiber zerumbet in chronic constriction injury (CCI)-induced neuropathic pain animal model. Our findings showed that single and repeated dose of intra-peritoneal administration of zerumbone (5, 10, 50, 100 mg/kg) significantly attenuated the CCI-induced neuropathic pain when evaluated using the electronic von Frey anesthesiometer, cold plate, Randall-Selitto analgesiometer and the Hargreaves plantar test. Zerumbone significantly alleviated tactile and cold allodynia as well as mechanical and thermal hyperalgesia. Our findings are in comparison to the positive control drugs thatused gabapentin (20 mg/kgi.p.) and morphine (1 mg/kgi.p.). Together, these results showed that the systemic administration of zerumbone produced marked antiallodynic and antihyperalgesic effects in the CCI-induced neuropathic pain in mice and may serve as a potential lead compound for further analysis.

  7. Real-life efficacy of pregabalin for the treatment of peripheral neuropathic pain in daily clinical practice in Denmark

    DEFF Research Database (Denmark)

    Crawford, Michael E; Poulsen, Peter Bo; Schiøttz-Christensen, Berit;

    2016-01-01

    OBJECTIVE: The aim of this study was to provide evidence regarding the real-life efficacy of pregabalin in the treatment of peripheral neuropathic pain (NeP) in Denmark. METHODS: In this prospective, observational, noninterventional study, pregabalin (Lyrica(®)) was prescribed following usual cli...

  8. Anti-hyperalgesic effects of calcitonin on neuropathic pain interacting with its peripheral receptors

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    Ito Akitoshi

    2012-06-01

    Full Text Available Abstract Background The polypeptide hormone calcitonin is clinically well known for its ability to relieve neuropathic pain such as spinal canal stenosis, diabetic neuropathy and complex regional pain syndrome. Mechanisms for its analgesic effect, however, remain unclear. Here we investigated the mechanism of anti-hyperalgesic action of calcitonin in a neuropathic pain model in rats. Results Subcutaneous injection of elcatonin, a synthetic derivative of eel calcitonin, relieved hyperalgesia induced by chronic constriction injury (CCI. Real-time reverse transcriptase-polymerase chain reaction analysis revealed that the CCI provoked the upregulation of tetrodotoxin (TTX-sensitive Nav.1.3 mRNA and downregulation of TTX-resistant Nav1.8 and Nav1.9 mRNA on the ipsilateral dorsal root ganglion (DRG, which would consequently increase the excitability of peripheral nerves. These changes were reversed by elcatonin. In addition, the gene expression of the calcitonin receptor and binding site of 125I-calcitonin was increased at the constricted peripheral nerve tissue but not at the DRG. The anti-hyperalgesic effect and normalization of sodium channel mRNA by elcatonin was parallel to the change of the calcitonin receptor expression. Elcatonin, however, did not affect the sensitivity of nociception or gene expression of sodium channel, while it suppressed calcitonin receptor mRNA under normal conditions. Conclusions These results suggest that the anti-hyperalgesic action of calcitonin on CCI rats could be attributable to the normalization of the sodium channel expression, which might be exerted by an unknown signal produced at the peripheral nerve tissue but not by DRG neurons through the activation of the calcitonin receptor. Calcitonin signals were silent in the normal condition and nerve injury may be one of triggers for conversion of a silent to an active signal.

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

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    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.

  10. Dural neurogenic inflammation induced by neuropathic pain is specific to cranial region.

    Science.gov (United States)

    Filipović, B; Matak, I; Lacković, Z

    2014-05-01

    Up to now, dural neurogenic inflammation (DNI) has been studied primarily as a part of migraine pain pathophysiology. A recent study from our laboratory demonstrated the occurrence of DNI in response to peripheral trigeminal nerve injury. In this report, we characterize the occurrence of DNI after different peripheral nerve injuries in and outside of the trigeminal region. We have used the infraorbital nerve constriction injury model (IoNC) as a model of trigeminal neuropathic pain. Greater occipital nerve constriction injury (GoNC), partial transection of the sciatic nerve (ScNT) and sciatic nerve constriction injury (SCI) were employed to characterize the occurrence of DNI in response to nerve injury outside of the trigeminal region. DNI was measured as colorimetric absorbance of Evans blue plasma protein complexes. In addition, cellular inflammatory response in dural tissue was histologically examined in IoNC and SCI models. In comparison to the strong DNI evoked by IoNC, a smaller but significant DNI has been observed following the GoNC. However, DNI has not been observed either in cranial or in lumbar dura following ScNT and SCI. Histological evidence has demonstrated a dural proinflammatory cell infiltration in the IoNC model, which is in contrast to the SCI model. Inflammatory cell types (lymphocytes, plasma cells, and monocytes) have indicated the presence of sterile cellular inflammatory response in the IoNC model. To our knowledge, this is the first observation that the DNI evoked by peripheral neuropathic pain is specific to the trigeminal area and the adjacent occipital area. DNI after peripheral nerve injury consists of both plasma protein extravasation and proinflammatory cell infiltration.

  11. 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.

  12. Interleukin-1 alpha has antiallodynic and antihyperalgesic activities in a rat neuropathic pain model.

    Science.gov (United States)

    Mika, Joanna; Korostynski, Michal; Kaminska, Dorota; Wawrzczak-Bargiela, Agnieszka; Osikowicz, Maria; Makuch, Wioletta; Przewlocki, Ryszard; Przewlocka, Barbara

    2008-09-15

    Nerve injury and the consequent release of interleukins (ILs) are processes implicated in pain transmission. To study the potential role of IL-1 in the pathogenesis of allodynia and hyperalgesia, IL-1alpha and comparative IL-1beta, IL-6, and IL-10 mRNA levels were quantified using competitive RT-PCR of the lumbar spinal cord and dorsal root ganglia (DRG; L5-L6) three and seven days after chronic constriction injury (CCI) in rats. Microglial and astroglial activation in the ipsilateral spinal cord and DRG were observed after injury. In naive and CCI-exposed rats, IL-1alpha mRNA and protein were not detected in the spinal cord. IL-1beta and IL-6 mRNAs were strongly ipsilaterally elevated on day seven after CCI. In the ipsilateral DRG, IL-1alpha, IL-6, and IL-10 mRNA levels were increased on days three and seven; IL-1beta was elevated only on day seven. Western blot analysis revealed both the presence of IL-1alpha proteins (45 and 31 kDa) in the DRG and the down-regulation of these proteins after CCI. Intrathecal administration of IL-1alpha (50-500 ng) in naive rats did not influence nociceptive transmission, but IL-1beta (50-500 ng) induced hyperalgesia. In rats exposed to CCI, an IL-1alpha or IL-1 receptor antagonist dose-dependently attenuated symptoms of neuropathic pain; however, no effect of IL-1beta was observed. In sum, the first days after CCI showed a high abundance of IL-1alpha in the DRG. Together with the antiallodynic and antihyperalgesic effects observed after IL-1alpha administration, this finding indicates an important role for IL-1alpha in the development of neuropathic pain symptoms.

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

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    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.

  14. Functional and metabolic changes in the brain in neuropathic pain syndrome against the background of chronic epidural electrostimulation of the spinal cord.

    Science.gov (United States)

    Sufianov, A A; Shapkin, A G; Sufianova, G Z; Elishev, V G; Barashin, D A; Berdichevskii, V B; Churkin, S V

    2014-08-01

    Changes in functional and metabolic activities of the brain were evaluated by EEG and positron-emission/computer tomography with 18F-fluorodeoxyglucose in patients with neuropathic pain syndrome previous to and 3 months after implantation of a system for chronic epidural spinal cord stimulation. In most cases, the use of a nerve stimulator was followed by alleviation of neuropathic pain and partial normalization of functional and metabolic activities of brain structures responsible for pain perception, emotiogenic, behavioral, and autonomic responses.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. Neuropathic pruritus.

    Science.gov (United States)

    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.

  20. Lipo-endomorphin-1 derivatives with systemic activity against neuropathic pain without producing constipation.

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    Pegah Varamini

    Full Text Available To enhance the drug-like properties of the endogenous opioid peptide endomorphin-1 (1 = Tyr-Pro-Trp-Phe-NH(2, the N-terminus of the peptide was modified with 2-aminodecanoic acid, resulting in compound 3. Tyr in compound 1 was replaced with 2,6-dimethyltyrosine yielding compound 2. Derivative 2 was also substituted with 2-aminodecanoic acid producing compound, 4. Lipoamino acid-modified derivatives showed improved metabolic stability and membrane permeability while maintaining high μ-opioid (MOP receptor binding affinity and acting as a potent agonist. In vivo studies showed dose-dependent antinociceptive activity following intravenous (i.v. administration of compounds 3 and 4 in a chronic constriction injury (CCI-rat model of neuropathic pain with ED(50 values of 1.22 (± 0.93 and 0.99 (± 0.89 µmol/kg, respectively. Pre-treatment of animals with naloxone hydrochloride significantly attenuated the anti-neuropathic effects of compound 3, confirming the key role of opioid receptors in mediating antinociception. In contrast to morphine, no significant constipation was produced following i.v. administration of compound 3 at 16 µmol/kg. Furthermore, following chronic administration of equi-potent doses of compound 3 and morphine to rats, there was less antinociceptive tolerance for compound 3 compared with morphine.

  1. Spinal NF-κB and chemokine ligand 5 expression during spinal glial cell activation in a neuropathic pain model.

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    Qin Yin

    Full Text Available BACKGROUND: The NF-κB pathway and chemokine (C-C motif ligand 5 (CCL5 are involved in pain modulation; however, the precise mechanisms of their interactions in chronic neuropathic pain have yet to be established. METHODS: The present study examined the roles of spinal NF-κB and CCL5 in a neuropathic pain model after chronic constriction injury (CCI surgery. CCI-induced pain facilitation was evaluated using the Plantar and von Frey tests. The changes in NF-κB and CCL5 expression were analyzed by immunohistochemistry and Western blot analyses. RESULTS: Spinal NF-κB and CCL5 expression increased after CCI surgery. Repeated intrathecal infusions of pyrrolidine dithiocarbamate (PDTC, a NF-κB inhibitor decreased CCL5 expression, inhibited the activation of microglia and astrocytes, and attenuated CCI-induced allodynia and hyperalgesia. Intrathecal injection of a CCL5-neutralizing antibody attenuated CCI-induced pain facilitation and also suppressed spinal glial cell activation after CCI surgery. However, the CCL5-neutralizing antibody did not affect NF-κB expression. Furthermore, selective glial inhibitors, minocycline and fluorocitrate, attenuated the hyperalgesia induced by intrathecal CCL5. CONCLUSIONS: The inhibition of spinal CCL5 expression may provide a new method to prevent and treat nerve injury-induced neuropathic pain.

  2. Comparison of burrowing and stimuli-evoked pain behaviors as end-points in rat models of inflammatory pain and peripheral neuropathic pain

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    Arjun eMuralidharan

    2016-05-01

    Full Text Available Establishment and validation of ethologically-relevant, non-evoked behavioral end-points as surrogate measures of spontaneous pain in rodent pain models has been proposed as a means to improve preclinical to clinical research translation in the pain field. Here, we compared the utility of burrowing behavior with hypersensitivity to applied mechanical stimuli for pain assessment in rat models of chronic inflammatory and peripheral neuropathic pain. Briefly, groups of male Sprague-Dawley rats were habituated to the burrowing environment and trained over a 5-day period. Rats that burrowed ≤450g of gravel on any two days of the individual training phase were excluded from the study. The remaining rats received either a unilateral intraplantar injection of Freund’s complete adjuvant (FCA or saline, or underwent unilateral chronic constriction injury (CCI of the sciatic nerve- or sham-surgery. Baseline burrowing behavior and evoked pain behaviors were assessed prior to model induction, and twice-weekly until study completion on day 14. For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws. Although burrowing behavior also decreased in a temporal manner for both FCA- and CCI-rats, there was considerable inter-animal variability. By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter-animal variability. Our data collectively show that burrowing behavior is altered in rodent models of chronic inflammatory pain and peripheral neuropathic pain. However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability.

  3. 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.

  4. 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

  5. Single-unit analysis of the spinal dorsal horn in patients with neuropathic pain.

    Science.gov (United States)

    Guenot, Marc; Bullier, Jean; Rospars, Jean-Pierre; Lansky, Petr; Mertens, Patrick; Sindou, Marc

    2003-04-01

    Despite the key role played by the dorsal horn of the spinal cord in pain modulation, single-unit recordings have only been performed very rarely in this structure in humans. The authors report the results of a statistical analysis of 64 unit recordings from the human dorsal horn. The recordings were done in three groups of patients: patients with deafferentation pain resulting from brachial plexus avulsion, patients with neuropathic pain resulting from peripheral nerve injury, and patients with pain resulting from disabling spasticity. The patterns of neuronal activities were compared among these three groups. Nineteen neurons were recorded in the dorsal horns of five patients undergoing DREZotomy for a persistent pain syndrome resulting from peripheral nerve injury (i.e., nondeafferented dorsal horns), 31 dorsal horn neurons were recorded in nine patients undergoing DREZotomy for a persistent pain syndrome resulting from brachial plexus avulsion (i.e., deafferented dorsal horns), and 14 neurons were recorded in eight patients undergoing DREZotomy for disabling spasticity. These groups were compared in terms of mean frequency, coefficient of variation of the discharge, other properties of the neuronal discharge studied by the nonparametric test of Wald-Wolfowitz, and the possible presence of bursts. The coefficient of variation tended to be higher in the deafferented dorsal horn group than in the other two groups. Two neurons displaying burst activity could be recorded, both of which belonged to the deafferented dorsal horn group. A significant difference was found in term of neuronal behavior between the peripheral nerve trauma group and the other groups: The brachial plexus avulsion and disabling spasticity groups were very similar, including various types of neuronal behavior, whereas the peripheral nerve lesion group included mostly neurons with "nonrandom" patterns of discharge (i.e., with serial dependency of interspike intervals).

  6. Colocalized structural and functional changes in the cortex of patients with trigeminal neuropathic pain.

    Directory of Open Access Journals (Sweden)

    Alexandre F DaSilva

    Full Text Available BACKGROUND: Recent data suggests that in chronic pain there are changes in gray matter consistent with decreased brain volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has evaluated cortical thickness in relation to specific functional changes in evoked pain. In this study we sought to investigate structural (gray matter thickness and functional (blood oxygenation dependent level - BOLD changes in cortical regions of precisely matched patients with chronic trigeminal neuropathic pain (TNP affecting the right maxillary (V2 division of the trigeminal nerve. The model has a number of advantages including the evaluation of specific changes that can be mapped to known somatotopic anatomy. METHODOLOGY/PRINCIPAL FINDINGS: Cortical regions were chosen based on sensory (Somatosensory cortex (SI and SII, motor (MI and posterior insula, or emotional (DLPFC, Frontal, Anterior Insula, Cingulate processing of pain. Both structural and functional (to brush-induced allodynia scans were obtained and averaged from two different imaging sessions separated by 2-6 months in all patients. Age and gender-matched healthy controls were also scanned twice for cortical thickness measurement. Changes in cortical thickness of TNP patients were frequently colocalized and correlated with functional allodynic activations, and included both cortical thickening and thinning in sensorimotor regions, and predominantly thinning in emotional regions. CONCLUSIONS: Overall, such patterns of cortical thickness suggest a dynamic functionally-driven plasticity of the brain. These structural changes, which correlated with the pain duration, age-at-onset, pain intensity and cortical activity, may be specific targets for evaluating therapeutic interventions.

  7. Evaluation of selective NK(1) receptor antagonist CI-1021 in animal models of inflammatory and neuropathic pain.

    Science.gov (United States)

    Gonzalez, M I; Field, M J; Hughes, J; Singh, L

    2000-08-01

    CI-1021 ([(2-benzofuran)-CH(2)OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH (3))Ph) is a selective and competitive neurokinin-1 (NK(1)) receptor antagonist. This study examines its activity in animal models of inflammatory and neuropathic pain. In mice, CI-1021 (1-30 mg/kg, s.c.) dose dependently blocked the development of the late phase of the formalin response with a minimum effective dose (MED) of 3 mg/kg. Two chemically unrelated NK(1) receptor antagonists, CP-99,994 (3-30 mg/kg) and SR 140333 (1-100 mg/kg), also dose dependently blocked the late phase, with respective MEDs of 3 and 10 mg/kg. PD 156982, a NK(1) receptor antagonist with poor central nervous system penetration, failed to have any effect. However, when administered i. c.v., it selectively blocked the late phase of the formalin response. Chronic constrictive injury (CCI) to a sciatic nerve in the rat induced spontaneous pain, thermal and mechanical hyperalgesia, and cold, dynamic, and static allodynia. CI-1021 (10-100 mg/kg) and morphine (3 mg/kg) blocked all the responses except dynamic allodynia. Carbamazepine (100 mg/kg) was weakly effective against all the responses. Once daily administration of morphine (3 mg/kg, s. c.) in CCI rats led to the development of tolerance within 6 days. Similar administration of CI-1021 (100 mg/kg, s.c.) for up to 10 days did not induce tolerance. Moreover, the morphine tolerance failed to cross-generalize to CI-1021. CI-1021 blocked the CCI-induced hypersensitivity in the guinea pig, with a MED of 0.1 mg/kg, p.o. CI-1021 (10-100 mg/kg, s.c.) did not show sedative/ataxic action in the rat rota-rod test. It is suggested that NK(1) receptor antagonists possess a superior side effect profile to carbamazepine and morphine and may have a therapeutic use for the treatment of inflammatory and neuropathic pain.

  8. A multimodal approach to management of suspected neuropathic pain in a prairie falcon (Falco mexicanus).

    Science.gov (United States)

    Shaver, Stephanie L; Robinson, Narda G; Wright, Bonnie D; Kratz, Gail E; Johnston, Matthew S

    2009-09-01

    An adult male prairie falcon (Falco mexicanus) was presented for evaluation and treatment of self-inflicted wounds along the right proximal patagium. The bird had started self-traumatizing approximately 1 month after fracturing the right metacarpus, although the fracture had stabilized, surface wounds had healed completely, and treatment with a nonsteroidal antiinflammatory drug had been administered. The bird was treated with gabapentin (11 mg/kg p.o. q12h), ketamine (0.5 mg/kg i.m. q24h), and low level laser therapy (LLLT) (fracture site, then the original LLLT protocol was applied once daily. After 2.5 months, the wounds healed completely and no further mutilation took place. Once deemed ready for release, the falcon was returned to the wild after 181 days in captivity. This is the first reported application of successful multimodal analgesia in a raptor with uncontrolled neuropathic pain.

  9. Use of cortical stimulation in neuropathic pain, tinnitus, depression, and movement disorders.

    Science.gov (United States)

    Panov, Fedor; Kopell, Brian Harris

    2014-07-01

    Medical treatment must strike a balance between benefit and risk. As the field of neuromodulation develops, decreased invasiveness, in combination with maintenance of efficacy, has become a goal. We provide a review of the history of cortical stimulation from its origins to the current state. The first part discusses neuropathic pain and the nonpharmacological treatment options used. The second part covers transitions to tinnitus, believed by many to be another deafferentation disorder, its classification, and treatment. The third part focuses on major depression. The fourth section concludes with the discussion of the use of cortical stimulation in movement disorders. Each part discusses the development of the field, describes the current care protocols, and suggests future avenues for research needed to advance neuromodulation.

  10. Lipid- and sugar-modified endomorphins: Novel targets for the treatment of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Pegah eVaramini

    2013-12-01

    Full Text Available Endomorphins are endogenous opioid peptides that cause potent antinociception in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, endomorphins are poorly suited to clinical applications because of low membrane permeability and a susceptibility to enzymatic degradation. Glycosylation and lipidation have proven to be two of the most robust approaches for the generation of new therapeutic endomorphin derivatives. Conjugation with lipoamino acids (LAA confers an amphipathic character to the peptide, which improved interaction between the peptide and the lipid bilayer of the cell membranes, increasing permeability. Glycosylation can also improve peptide stability and blood brain barrier (BBB transport. It is believed that an endocytotic mechanism (transcytosis is responsible for the systemic delivery of water-soluble glycopeptides. This review discusses the application of glycosylation and lipidation strategies to improve the drug-like properties of endomorphins. Pharmacologically active endomorphin analogues with less adverse effects are also discussed.

  11. Lipid- and sugar-modified endomorphins: novel targets for the treatment of neuropathic pain.

    Science.gov (United States)

    Varamini, Pegah; Toth, Istvan

    2013-12-13

    Endomorphins are endogenous opioid peptides that cause potent antinociception in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, endomorphins are poorly suited to clinical applications because of low membrane permeability and a susceptibility to enzymatic degradation. Glycosylation and lipidation have proven to be two of the most robust approaches for the generation of new therapeutic endomorphin derivatives. Conjugation with lipoamino acids (LAA) confers an amphipathic character to the peptide, which improved interaction between the peptide and the lipid bilayer of the cell membranes, increasing permeability. Glycosylation can also improve peptide stability and blood brain barrier (BBB) transport. It is believed that an endocytotic mechanism (transcytosis) is responsible for the systemic delivery of water-soluble glycopeptides. This review discusses the application of glycosylation and lipidation strategies to improve the drug-like properties of endomorphins. Pharmacologically active endomorphin analogs with less adverse effects are also discussed.

  12. Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.

    Science.gov (United States)

    Betti, Cecilia; Starnowska, Joanna; Mika, Joanna; Dyniewicz, Jolanta; Frankiewicz, Lukasz; Novoa, Alexandre; Bochynska, Marta; Keresztes, Attila; Kosson, Piotr; Makuch, Wioletta; Van Duppen, Joost; Chung, Nga N; Vanden Broeck, Jozef; Lipkowski, Andrzej W; Schiller, Peter W; Janssens, Frans; Ceusters, Marc; Sommen, François; Meert, Theo; Przewlocka, Barbara; Tourwé, Dirk; Ballet, Steven

    2015-12-10

    Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds.

  13. 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.

  14. Systematic review and comparison of pharmacologic therapies for neuropathic pain associated with spinal cord injury

    Directory of Open Access Journals (Sweden)

    Snedecor SJ

    2013-07-01

    Full Text Available Sonya J Snedecor,1 Lavanya Sudharshan,1 Joseph C Cappelleri,2 Alesia Sadosky,3 Pooja Desai,4 Yash J Jalundhwala,5 Marc Botteman1 1Pharmerit International, Bethesda, MD, USA; 2Global Research and Development, Pfizer, Groton, CT, USA; 3Biostatistics, Pfizer, New York, NY, USA; 4College of Pharmacy, University of Texas at Austin, Austin, TX, USA; 5Pharmacy Administration, University of Illinois at Chicago, Chicago, IL, USA Background: Management of neuropathic pain (NeP associated with spinal cord injury (SCI is difficult. This report presents a systematic literature review and comparison of the efficacy and safety of pharmacologic therapies for treating SCI-associated NeP. Methods: Medline, Embase, Cochrane, and Database of Abstracts of Reviews of Effects were searched through December 2011 for randomized, blinded, and controlled clinical trials of SCI-associated NeP meeting predefined inclusion criteria. Efficacy outcomes of interest were pain reduction on the 11-point numeric rating scale (NRS or 100 mm visual analog scale and proportion of patients achieving ≥30% or ≥50% pain reduction. Discontinuations and adverse events (AEs were also assessed, for which Bayesian meta-analytic indirect comparisons were performed. Results: Of the nine studies included in the analysis, samples were <100 patients, except for one pregabalin study (n = 136. Standard errors for the NRS outcome were often not reported, precluding quantitative comparisons across treatments. Estimated 11-point NRS pain reduction relative to placebo was –1.72 for pregabalin, –1.65 for amitriptyline, –1.0 for duloxetine, –1 (median for levetiracetam, –0.27 for gabapentin, 1 (median for lamotrigine, and 2 for dronabinol. Risk ratios relative to placebo for 30% improvement were 0.71 for levetiracetam and 2.56 for pregabalin, and 0.94 and 2.91, respectively, for 50% improvement. Meta-analytic comparisons showed significantly more AEs with pregabalin and tramadol compared with

  15. Synergistic antihypersensitive effects of pregabalin and tapentadol in a rat model of neuropathic pain.

    Science.gov (United States)

    Christoph, Thomas; De Vry, Jean; Schiene, Klaus; Tallarida, Ronald J; Tzschentke, Thomas M

    2011-09-01

    Neuropathic pain is a clinical condition which remains poorly treated and combinations of pregabalin, an antagonist of the α2δ-subunit of Ca(2+) channels, with tapentadol, a μ-opioid receptor agonist/noradrenaline reuptake inhibitor, or with classical opioids such as oxycodone and morphine might offer increased therapeutic potential. In the rat spinal nerve ligation model, a dose dependent increase in ipsilateral paw withdrawal thresholds was obtained using an electronic von Frey filament after IV administration of pregabalin (1-10mg/kg), tapentadol (0.316-10mg/kg), morphine (1-4.64 mg/kg) and oxycodone (0.316-3.16 mg/kg), with ED(50) values (maximal efficacy) of 4.21 (67%), 1.65 (94%), 1.70 (96%) and 0.63 mg/kg (100%), respectively. Equianalgesic dose combinations of pregabalin and tapentadol (dose ratio 2.5:1), morphine (2.5:1) or oxycodone (6.5:1) resulted in ED(50) values (maximal efficacy) of 0.83 (89%), 2.33 (97%) and 1.14 mg/kg (100%), respectively. The concept of dose-equivalence suggested an additive interaction of pregabalin and either oxycodone or morphine, while a synergistic interaction was obtained with pregabalin and tapentadol (demonstrated by isobolographic analysis). There was no increase in contralateral paw withdrawal thresholds and no locomotor impairment, as measured in the open field, for the combination of pregabalin and tapentadol; while a significant increase and impairment was demonstrated for the combinations of pregabalin and either morphine or oxycodone. Because combination of pregabalin and tapentadol resulted in a synergistic antihypersensitive activity, it is suggested that, beside the use of either drug alone, this drug combination may offer a beneficial treatment option for neuropathic pain.

  16. 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.

  17. Beneficial properties of maraviroc on neuropathic pain development and opioid effectiveness in rats.

    Science.gov (United States)

    Kwiatkowski, Klaudia; Piotrowska, Anna; Rojewska, Ewelina; Makuch, Wioletta; Jurga, Agnieszka; Slusarczyk, Joanna; Trojan, Ewa; Basta-Kaim, Agnieszka; Mika, Joanna

    2016-01-04

    Targeting chemokine signaling pathways is crucial in neuropathy development. In this study, we investigated the influence of chronic administration of maraviroc (CCR5 antagonist) on nociception and opioid effectiveness during neuropathy, which develops as a result of chronic constriction injury (CCI) of the sciatic nerve. To investigate the mechanism of action of maraviroc, we measured the expression of glial cell markers, CCR5 and certain CCR5 ligands (CCL3, CCL4, CCL5, CCL7, CCL11), in the spinal cord and dorsal root ganglia (DRG) of vehicle- and maraviroc-treated, CCI-exposed rats. Our results demonstrate that chronic intrathecal administration of maraviroc diminished neuropathic pain symptoms on day 7 post-CCI. Western blot analysis showed that maraviroc diminished protein level of Iba-1 and GFAP and reversed the up-regulated CCR5 expression observed in spinal cord and DRG after CCI. Additionally, using qRT-PCR, we demonstrated that CCR5 and some of its pronociceptive ligands (CCL3, CCL4, CCL5) increased in the spinal cord after nerve injury, and maraviroc effectively diminished those changes. However, CCL11 spinal expression was undetectable, even after injury. In vitro primary culture studies showed that CCL3, CCL4, CCL5 and CCL7 (but not CCL11) were of microglial and astroglial origin and were up-regulated after LPS stimulation. Our results indicate that maraviroc not only attenuated the development of neuropathic pain symptoms due to significant modulation of neuroimmune interactions but also intensified the analgesic properties of morphine and buprenorphine. In sum, our results suggest the pharmacological modulation of CCR5 by maraviroc as a novel therapeutic approach for co-treatment of patients receiving opioid therapy for neuropathy.

  18. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study

    DEFF Research Database (Denmark)

    Demant, Dyveke T; Lund, Karen; Vollert, Jan

    2014-01-01

    by hypersensitivity and preserved small nerve fibre function determined by detailed quantitative sensory testing. Ninety-seven patients with peripheral neuropathic pain due to polyneuropathy, surgical or traumatic nerve injury, or postherpetic neuralgia were randomised. The intention-to-treat population comprised 83...

  19. Central hypersensitivity in chronic musculoskeletal pain.

    Science.gov (United States)

    Curatolo, Michele; Arendt-Nielsen, Lars

    2015-05-01

    Clinical research has consistently detected alteration in central pain processing leading to hypersensitivity. Most methods used in humans are reliable and have face validity to detect widespread central hypersensitivity. However, construct validity is difficult to investigate due to lack of gold standards. Reference values in the pain-free population have been generated, but need replication. Research on pain biomarkers that reflect specific central hypersensitivity processes is warranted. Few studies have analyzed the prognostic value of central hypersensitivity. Most medications acting at central level and some non-pharmacological approaches, including psychological interventions, are likely to attenuate central hypersensitivity.

  20. Central hypersensitivity in chronic musculoskeletal pain

    DEFF Research Database (Denmark)

    Curatolo, Michele; Arendt-Nielsen, Lars

    2015-01-01

    Clinical research has consistently detected alteration in central pain processing leading to hypersensitivity. Most methods used in humans are reliable and have face validity to detect widespread central hypersensitivity. However, construct validity is difficult to investigate due to lack of gold...... standards. Reference values in the pain-free population have been generated, but need replication. Research on pain biomarkers that reflect specific central hypersensitivity processes is warranted. Few studies have analyzed the prognostic value of central hypersensitivity. Most medications acting at central...... level and some non-pharmacological approaches, including psychological interventions, are likely to attenuate central hypersensitivity....

  1. Cross-cultural Adaptation and Linguistic Validation of the Korean Version of the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale.

    Science.gov (United States)

    Park, Cholhee; Lee, Youn-Woo; Yoon, Duck Mi; Kim, Do Wan; Nam, Da Jeong; Kim, Do-Hyeong

    2015-09-01

    Distinction between neuropathic pain and nociceptive pain helps facilitate appropriate management of pain; however, diagnosis of neuropathic pain remains a challenge. The aim of this study was to develop a Korean version of the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale and assess its reliability and validity. The translation and cross-cultural adaptation of the original LANSS pain scale into Korean was established according to the published guidelines. The Korean version of the LANSS pain scale was applied to a total of 213 patients who were expertly diagnosed with neuropathic (n = 113) or nociceptive pain (n = 100). The Korean version of the scale had good reliability (Cronbach's α coefficient = 0.815, Guttman split-half coefficient = 0.800). The area under the receiver operating characteristic curve was 0.928 with a 95% confidence interval of 0.885-0.959 (P < 0.001), suggesting good discriminate value. With a cut-off score ≥ 12, sensitivity was 72.6%, specificity was 98.0%, and the positive and negative predictive values were 98% and 76%, respectively. The Korean version of the LANSS pain scale is a useful, reliable, and valid instrument for screening neuropathic pain from nociceptive pain.

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

    Science.gov (United States)

    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. 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.

  4. Trachyspermum ammi 10 % topical cream versus placebo on neuropathic pain, a randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Petramfar, Peyman; Moein, Mahmoodreza; Samani, Soliman Mohammadi; Tabatabaei, Sayed Hamidreza; Zarshenas, Mohammad M

    2016-09-01

    A four-week, double-blind, randomized, placebo-controlled trial was conducted to assay the effectiveness of Ajwain 10 % (Trachyspermum ammi Sprague) topical cream on neuropathic pain. Intervention encompassed Ajwain 10 % and placebo creams. Ninety-two patients who specifically mentioned daily and nocturnal burning feet were randomly assigned to receive one of those interventions. Presence and decline in patients' numbness, tingling and allodynia were also evaluated. Major outcome measure was alteration in feet burning intensity (final week versus baseline week) regarding to a visual analog scale on a 0-10 cm scale (0 being "no pain", 10 being "worst pain"). Significant reduction in feet burning scores as well as numbness, tingling and allodynia were found in Ajwain group compared to placebo. This trial examining a cream of Ajwain essential oil versus placebo revealed the significance difference between two groups. This medicament can be a good candidate for the alleviation of feet burning, a neuropathic complication.

  5. 17beta-estradiol counteracts neuropathic pain: a behavioural, immunohistochemical, and proteomic investigation on sex-related differences in mice

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    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

  6. Breathing-controlled electrical stimulation could modify the affective component of neuropathic pain after amputation: a case report

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    Melton DH

    2012-04-01

    Full Text Available Sheng Li1,2, Danielle H Melton1, Jeffrey C Berliner11Department of Physical Medicine and Rehabilitation, University of Texas Medical School – Houston, Houston, TX; 2UTHealth Motor Recovery Laboratory, Institute for Rehabilitation and Research, Memorial Hermann Hospital, Houston, TX, USAAbstract: In this case, a 31-year-old male suffered phantom neuropathic pain for more than 3 years after an above-the-knee amputation. His shooting phantom pain disappeared after the first session of breathing-controlled electrical stimulation, and reappeared or was triggered 28 days after an experimental error during which he received sustained electrical stimulation. In other words, painful shooting stimuli may not have been “cured” but forgotten and retriggered by a fearful event due to the experimental error. Therefore, this accidental finding provides a unique opportunity to understand sensory and affective components of neuropathic pain, and a novel intervention could modify the affective component of it.Keywords: neuropathic pain, amputation, electrical stimulation, voluntary breathing

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

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    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.

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

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    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

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

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    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

  10. D-Aspartate Modulates Nociceptive-Specific Neuron Activity and Pain Threshold in Inflammatory and Neuropathic Pain Condition in Mice

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    Boccella, Serena; Vacca, Valentina; Errico, Francesco; Marinelli, Sara; Squillace, Marta; Di Maio, Anna; Vitucci, Daniela; Palazzo, Enza; De Novellis, Vito; Maione, Sabatino; Pavone, Flaminia; Usiello, Alessandro

    2015-01-01

    D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo−/−) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo−/− mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo−/− mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4–L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions. PMID:25629055

  11. D-Aspartate Modulates Nociceptive-Specific Neuron Activity and Pain Threshold in Inflammatory and Neuropathic Pain Condition in Mice

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    Serena Boccella

    2015-01-01

    Full Text Available D-Aspartate (D-Asp is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO. D-Asp acts as an agonist on NMDA receptors (NMDARs. Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo−/− or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo−/− mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo−/− mice show an increased evoked activity of the nociceptive specific (NS neurons of the dorsal horn of the spinal cord (L4–L6 and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions.

  12. Early evoked pain or dysesthesia is a predictor of central poststroke pain.

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    Klit, Henriette; Hansen, Anne P; Marcussen, Ninna S; Finnerup, Nanna B; Jensen, Troels S

    2014-12-01

    Central poststroke pain (CPSP) is a central neuropathic pain condition caused by a cerebrovascular lesion affecting the central somatosensory nervous system. Once developed, CPSP is difficult to treat, so there is an interest in identifying stroke patients at risk for the development of CPSP. This study examined if sensory abnormalities, including evoked dysesthesia, allodynia, or hyperalgesia to static and dynamic touch, cold, and pinprick, at stroke onset are a predictor for the development of CPSP. Consecutive stroke patients were recruited from a large prospective study of poststroke pain in Aarhus, Denmark, between 2007 and 2008. Patients underwent a structured pain interview and a standardized sensory examination within 4 days of admission, and a structured telephone interview was conducted after 3 and 6months. Patients who developed poststroke pain in the affected side without any other plausible cause were classified as having possible CPSP. A total of 275 stroke patients completed the study, and 29 patients (10.5%) were classified as having possible CPSP. The diagnosis was confirmed by a clinical examination in 15 of 17 patients, corresponding to a prevalence of 8.3%. The presence of allodynia, hyperalgesia, or dysesthesia in response to the sensory examination at stroke onset increased the odds for CPSP at 6months by 4.6 (odds ratio; 95% confidence interval 1.5-13.9). The combination of reduced or absent sensation to pinprick or cold and early evoked pain or dysesthesia at onset increased odds by 8.0 (odds ratio; 95% confidence interval 2.6-24.8). In conclusion, early evoked pain or dysesthesia is a predictor for CPSP.

  13. A double-blinded randomised controlled study of the value of sequential intravenous and oral magnesium therapy in patients with chronic low back pain with a neuropathic component.

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    Yousef, A A; Al-deeb, A E

    2013-03-01

    Persistent mechanical irritation of the nerve root sets up a series of events mediating sensitisation of the dorsal roots and dorsal horns in the spinal cord. Current evidence supports the role of magnesium in blocking central sensitisation through its effect on N-methyl-d-aspartate receptors. We studied the role of sequential intravenous and oral magnesium infusion in patients with chronic low back pain with a neuropathic component. We recruited a cohort of 80 patients with chronic low back pain with a Leeds Assessment of Neuropathic Signs and Symptoms pain scale score ≥ 12, who were receiving a physical therapy programme. All patients were treated with anticonvulsants, antidepressants and simple analgesics; in addition 40 patients received placebo for 6 weeks (control group), while the other 40 patients received an intravenous magnesium infusion for 2 weeks followed by oral magnesium capsules for another 4 weeks (magnesium group). Patients were asked to rate their pain using a numerical rating scale. Lumbar spine range of motion was also determined using a long-arm goniometer. In the magnesium group, the patients' numerical rating scales revealed a significant reduction in pain intensity. The mean (SD) pre-treatment value was 7.5 (2.2) compared with 4.7 (1.8) at 6 months (p = 0.034). The reduction in pain intensity was accompanied by significant improvement in lumbar spine range of motion during the follow-up period. The mean (SD) values of flexion, extension and lateral flexion movements before treatment and at 6-month follow up were 22.2 (8.4) vs 34.7 (11.5) (p = 0.018), 11.8 (3.4) vs 16.9 (3.5) (p = 0.039), 11.4 (3.6) vs 17.2 (4.4) (p = 0.035), respectively. Our findings show that a 2-week intravenous magnesium infusion followed by 4 weeks of oral magnesium supplementation can reduce pain intensity and improve lumbar spine mobility during a 6-month period in patients with refractory chronic low back pain with a neuropathic component.

  14. Role of JNK isoforms in the development of neuropathic pain following sciatic nerve transection in the mouse

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    Manassero Giusi

    2012-05-01

    Full Text Available Abstract Background Current tools for analgesia are often only partially successful, thus investigations of new targets for pain therapy stimulate great interest. Consequent to peripheral nerve injury, c-Jun N-terminal kinase (JNK activity in cells of the dorsal root ganglia (DRGs and spinal cord is involved in triggering neuropathic pain. However, the relative contribution of distinct JNK isoforms is unclear. Using knockout mice for single isoforms, and blockade of JNK activity by a peptide inhibitor, we have used behavioral tests to analyze the contribution of JNK in the development of neuropathic pain after unilateral sciatic nerve transection. In addition, immunohistochemical labelling for the growth associated protein (GAP-43 and Calcitonin Gene Related Peptide (CGRP in DRGs was used to relate injury related compensatory growth to altered sensory function. Results Peripheral nerve injury produced pain–related behavior on the ipsilateral hindpaw, accompanied by an increase in the percentage of GAP43-immunoreactive (IR neurons and a decrease in the percentage of CGRP-IR neurons in the lumbar DRGs. The JNK inhibitor, D-JNKI-1, successfully modulated the effects of the sciatic nerve transection. The onset of neuropathic pain was not prevented by the deletion of a single JNK isoform, leading us to conclude that all JNK isoforms collectively contribute to maintain neuropathy. Autotomy behavior, typically induced by sciatic nerve axotomy, was absent in both the JNK1 and JNK3 knockout mice. Conclusions JNK signaling plays an important role in regulating pain threshold: the inhibition of all of the JNK isoforms prevents the onset of neuropathic pain, while the deletion of a single splice JNK isoform mitigates established sensory abnormalities. JNK inactivation also has an effect on axonal sprouting following peripheral nerve injury.

  15. PSD95 Gene Specific siRNAs Attenuate Neuropathic Pain through Modulating Neuron Sensibility and Postsynaptic CaMKⅡα Phosphorylation

    Institute of Scientific and Technical Information of China (English)

    Le Shen; Xu Li; Nen Chen; Li Xu; Wei Liu; Xue-rong Yu; Yu-guang Huang

    2011-01-01

    Objective To observe the effects of PSD95 gene specific siRNAs on neuropathic pain relief,neuron viability,and postsynaptic calcium/calmodulin-dependent protein kinase Ⅱα (CaMKⅡα) phosphorylation in vitro and in vivo.Methods Gene-specific siRNAs of rat PSD95 were synthesized chemically for transfection.Adult male Sprague-Dawley (SD) rats were randomly divided into 3 groups:naive group (n=6),sham group (n=6),and sciatic nerve chronic constriction injury (CCI) group (n=24).The CCI group was further divided into 4 groups (n=6 in each group),which were pretreated with normal saline,transfection vehicle,negative control siRNAs,and PSD95 gene specific siRNAs respectively.All the subgroups received corresponding agents intrathecally for 3 days,started one day before the CCI of sciatic nerve.Both mechanical allodynia and thermal hyperalgesia were measured on post-operative day 3 and 7.PSD95 gene silenced NG108-15 cells were further stimulated by glutamate,with the cell viability and the expression/phosphorylation of CaMKⅡα measured by MTT cell proliferation assay andWestern blot,respectively.Results The siRNAs decreased PSD95 mRNA level significantly both in vivo and in vitro.Neuropathic pain rats pretreated with PSD95 gene specific siRNAs exhibited significant elevation in the mechanical withdrawal threshold and paw withdrawal thermal latency,without affecting the baseline nociception.PSD95 gene silencing enhanced neuronal tolerance against the glutamate excitotoxicity,meanwhile the phosphorylation of CaMKⅡαThr286 was attenuated.Conclusion Pre-emptive administration of PSD95 gene specific siRNAs may attenuate the central sensitization CaMKⅡα-related signaling cascades,leading to the relief of neuropathic pain.

  16. 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

  17. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain

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    Le Trong

    2009-02-01

    Full Text Available Abstract Background Few direct head-to-head comparisons have been conducted between drugs for the treatment of diabetic peripheral neuropathic pain (DPNP. Approved or recommended drugs in this indication include duloxetine (DLX, pregabalin (PGB, gabapentin (GBP and amitriptyline (AMT. We conducted an indirect meta-analysis to compare the efficacy and tolerability of DLX with PGB and GBP in DPNP, using placebo as a common comparator. Methods We searched PubMed, EMBASE, CENTRAL databases and regulatory websites for randomized, double-blind, placebo-controlled, parallel group or crossover clinical trials (RCTs assessing DLX, PGB, GBP and AMT in DPNP. Study arms using approved dosages with assessments after 5–13 weeks were eligible. Efficacy criteria were: reduction in 24-hour pain severity (24 h PS for all three drugs, and response rate (≥ 50% pain reduction and Patient Global Impression of Improvement/Change (PGI-I/C for DLX and PGB only. Tolerability criteria included: discontinuation, diarrhoea, dizziness, headache, nausea and somnolence. Direct comparisons versus placebo were conducted with pooled fixed – and random-effects analyses on endpoints reported in at least two studies of each drug. Indirect comparisons were performed between DLX and each of PGB and GBP using Bayesian simulation. Results Three studies of DLX, six of PGB, two of GBP and none of AMT met the inclusion criteria. In random-effects and fixed-effects analyses of DLX, PGB and GBP, all were superior to placebo for all efficacy parameters, with some tolerability trade-offs. Indirect comparison of DLX with PGB found no differences in 24 h PS, but significant differences in PGI-I/C, favouring PGB, and in dizziness, favouring DLX were apparent. Comparing DLX and GBP, there were no statistically significant differences. Conclusion From the few available studies suitable for indirect comparison, DLX shows comparable efficacy and tolerability to GBP and PGB in DPNP. Duloxetine

  18. 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.

  19. Change in microRNAs associated with neuronal adaptive responses in the nucleus accumbens under neuropathic pain.

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    Imai, Satoshi; Saeki, Mai; Yanase, Makoto; Horiuchi, Hiroshi; Abe, Minako; Narita, Michiko; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru

    2011-10-26

    Neuropathic pain is the most difficult type of pain to control, and patients lose their motivation for the purposive pursuit with a decrease in their quality of life. Using a functional magnetic resonance imaging analysis, we demonstrated that blood oxygenation level-dependent signal intensity was increased in the ipsilateral nucleus accumbens (N.Acc.) following peripheral nerve injury. microRNAs are small, noncoding RNA molecules that direct the post-transcriptional suppression of gene expression, and play an important role in regulating synaptic plasticity. In this study, we found that sciatic nerve ligation induced a drastic decrease in the expression of miR200b and miR429 in N.Acc. neurons. The expression of DNA methyltransferase 3a (DNMT3a), which is the one of the predicted targets of miR200b/429, was significantly increased in the limbic forebrain including N.Acc. at 7 d after sciatic nerve ligation. Double-immunolabeling with antibodies specific to DNMT3a and NR1 showed that DNMT3a-immunoreactivity in the N.Acc. was located in NR1-labeled neurons, indicating that increased DNMT3a proteins were dominantly expressed in postsynaptic neurons in the N.Acc. area under a neuropathic pain-like state. The results of these analyses provide new insight into an epigenetic modification that is accompanied by a dramatic decrease in miR200b and miR429 along with the dysfunction of "mesolimbic motivation/valuation circuitry" under a neuropathic pain-like state. These phenomena may result in an increase in DNMT3a in neurons of the N.Acc. under neuropathic pain, which leads to the long-term transcription-silencing of several genes.

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

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    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.

  1. Long-term administration of high doses of transdermal buprenorphine in cancer patients with severe neuropathic pain

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    Leppert W

    2015-12-01

    Full Text Available Wojciech Leppert, Grzegorz Kowalski Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland Background: Buprenorphine is often administered by the transdermal route (transdermal buprenorphine [TB] in cancer patients with severe neuropathic pain. However, high doses of TB of 140 µg/h are rarely used.Patients and methods: Three cancer patients with severe neuropathic Numeric Rating Scale (NRS pain scores of 8–10 who were successfully treated with high doses of TB up to 140 µg/h along with other opioids and adjuvant analgesics.Results: TB was administered for a long period of follow-up (9 months to 4 years, including 34–261 days of treatment with the dose of 140 µg/h, which allowed achievement of satisfactory analgesia (NRS 3–5 and good treatment tolerance. In all three patients, TB dose was gradually titrated from 35 to 140 µg/h, and all patients used morphine at least for some time for breakthrough and background pain management along with adjuvant analgesics. Two patients continued the treatment with TB until the end of life, and one patient is still receiving the treatment.Conclusion: TB at doses of up to 140 µg/h in cancer patients with severe neuropathic pain seems to be effective and safe in combination with other opioids and with adjuvant analgesics, and may significantly improve patients’ quality of life. Clinical studies may explore higher than maximal 140 µg/h TB doses recommended by a manufacturer, and also in combination with other opioids and adjuvant analgesics. Keywords: adverse effects, analgesia, cancer, neuropathic pain, transdermal buprenorphine, treatment

  2. The Effects of Two-Week Swimming Training on Neuropathic Pain Induced by Chronic Constriction Injury and the Expression of GAD65 in Adult Male Rats

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    Babak Farzad

    2016-09-01

    Full Text Available Background & Objective: Unknown mechanisms are involved in neuropathic pain. Among the non-pharmacological treatments, it seems that physical activity improves neuropathic pain. However, the possible reasons for the effectiveness of regular physical activity on neuropathic pain are unknown. Therefore, the present study was performed to determine the effects of two-week swimming training on the expression of GAD65 enzyme and P2X3 receptor in Chronic Constriction Injury (CCI of the sciatic nerve. Materials & Methods: 40Wistar adult rats were divided into five groups randomly: 1 CCI neuropathic pain with swimming training (CCIST2; 2 CCI neuropathic pain without swimming training (CCI; 3 No CCI neuropathic pain with swimming training (ST2; No CCI neuropathic pain without swimming training (control group; 5 CCI sham surgery (Sham CCI. CCI and CCIST2 groups underwent peripheral nerve injury by four loose ligatures around sciatic nerve. Swimming program included two weeks with five sessions per week, and 30-60 min per session. The protein expressions of GAD65 enzyme and P2X3 receptor were evaluated by western blotting technique. Results: CCI surgery decreased the expression of GAD65, but two weeks swimming training increased expression of GAD65 comparing to CCI and Sham CCI groups (P≤0.001, but P2X3 receptor expression were not significantly different among groups in lumbar segment of rats (P>0.05. Conclusion: Totally, our findings showed that two-week swimming training improves neuropathic pain possibly through maintenance of inhibitory neurons and subsequently increased GAD65, which converts glutamate excitatory neurotransmitter to GABA inhibitory neurotransmitter.

  3. Involvement of TRPM2 in peripheral nerve injury-induced infiltration of peripheral immune cells into the spinal cord in mouse neuropathic pain model.

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    Kouichi Isami

    Full Text Available Recent evidence suggests that transient receptor potential melastatin 2 (TRPM2 expressed in immune cells plays an important role in immune and inflammatory responses. We recently reported that TRPM2 expressed in macrophages and spinal microglia contributes to the pathogenesis of inflammatory and neuropathic pain aggravating peripheral and central pronociceptive inflammatory responses in mice. To further elucidate the contribution of TRPM2 expressed by peripheral immune cells to neuropathic pain, we examined the development of peripheral nerve injury-induced neuropathic pain and the infiltration of immune cells (particularly macrophages into the injured nerve and spinal cord by using bone marrow (BM chimeric mice by crossing wildtype (WT and TRPM2-knockout (TRPM2-KO mice. Four types of BM chimeric mice were prepared, in which irradiated WT or TRPM2-KO recipient mice were transplanted with either WT-or TRPM2-KO donor mouse-derived green fluorescence protein-positive (GFP(+ BM cells (TRPM2(BM+/Rec+, TRPM2(BM-/Rec+, TRPM2(BM+/Rec-, and TRPM2(BM-/Rec- mice. Mechanical allodynia induced by partial sciatic nerve ligation observed in TRPM2(BM+/Rec+ mice was attenuated in TRPM2(BM-/Rec+, TRPM2(BM+/Rec-, and TRPM2(BM-/Rec- mice. The numbers of GFP(+ BM-derived cells and Iba1/GFP double-positive macrophages in the injured sciatic nerve did not differ among chimeric mice 14 days after the nerve injury. In the spinal cord, the number of GFP(+ BM-derived cells, particularly GFP/Iba1 double-positive macrophages, was significantly decreased in the three TRPM2-KO chimeric mouse groups compared with TRPM2(BM+/Rec+ mice. However, the numbers of GFP(-/Iba1(+ resident microglia did not differ among chimeric mice. These results suggest that TRPM2 plays an important role in the infiltration of peripheral immune cells, particularly macrophages, into the spinal cord, rather than the infiltration of peripheral immune cells into the injured nerves and activation of spinal

  4. 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

  5. Anti-hypernociceptive effect of mangiferin in persistent and neuropathic pain models in rats.

    Science.gov (United States)

    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.

  6. Higher pain perception and lack of recovery from neuropathic pain in females: 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

    2014-02-01

    In experimental and clinical pain studies, the sex of subjects was rarely taken into account, even if nociceptive inputs appear to be processed and modulated by partially distinct neural mechanisms in each sex. In this study we analysed, in male and female mice, behavioural and neuronal responses in developing, maintaining, and recovering from neuropathic pain. Experiments were carried out in adult CD1 mice by using Chronic Constriction Injury (CCI) as neuropathic pain model. We investigated the temporal trend of mechanical nociceptive threshold together with functional recovery of the injured paw, and the immunofluorescence staining of proteins associated with nerve injury and repair and with spinal gliosis, 7 and 121days after CCI. A proteomic analysis on proteins extracted from sciatic nerves was also performed. Male mice showed a gradual decrease of CCI-induced allodynia, the complete recovery occurring 81days after the sciatic nerve ligation. On the contrary, in female mice, allodynia was still present 121days after CCI. Sex-dependent differences also resulted from immunofluorescence experiments: in sciatic nerve, the expression of P0 and Neu200 is greater in neuropathic males than in neuropathic females, suggesting faster nerve regeneration. Proteomic analysis confirmed sex-related differences of proteins associated with nerve regenerative processes. In addition, the reactive gliosis induced by CCI at day 7, as revealed by colocalization of glial fibrillary acidic protein (astrocytes) and CD11b (microglia) with phosphorylated p38, disappeared 121 days after CCI in male but not in female mice. These results may have important therapeutic implications for the treatment of neuropathic pain.

  7. EFFECT OF HIGH TENS ON NEUROPATHIC PAIN IN DIABETIC NEUROPATHY PATIENTS

    Directory of Open Access Journals (Sweden)

    Shahanawaz SD

    2014-08-01

    innervate the painful area. Conclusion: TENS has shown a significant improvement on neuropathic pain in diabetic neuropathy patients when compare to the Placebo TENS and hence alternate Hypothesis is accepted Null Hypothesis is rejected.

  8. Poly(ADP-ribose) polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    Prashanth Komirishetty; Aparna Areti; Ranadeep Gogoi; Ramakrishna Sistla; Ashutosh Kumar

    2016-01-01

    Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially per-oxynitrite atfer the nerve injury. hTey provoke oxidative DNA damage and consequent over-activation of the poly(ADP-ribose) polymerase (PARP) upregulates pro-inlfammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neu-ronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown beneifts in treating experimental neuropathy. hTis article reviews the in-volvement of PARP over-activation in trauma induced neuropathy and therapeutic signiifcance of PARP inhibitors in the experimental neuropathy and neuropathic pain.

  9. 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

  10. Poly(ADP-ribose polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain

    Directory of Open Access Journals (Sweden)

    Prashanth Komirishetty

    2016-01-01

    Full Text Available Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially peroxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly(ADP-ribose polymerase (PARP upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neuronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the involvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.

  11. Poly(ADP-ribose) polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain.

    Science.gov (United States)

    Komirishetty, Prashanth; Areti, Aparna; Gogoi, Ranadeep; Sistla, Ramakrishna; Kumar, Ashutosh

    2016-10-01

    Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially peroxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly(ADP-ribose) polymerase (PARP) upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neuronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the involvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.

  12. Feasibility of Human Amniotic Fluid Derived Stem Cells in Alleviation of Neuropathic Pain in Chronic Constrictive Injury Nerve Model.

    Directory of Open Access Journals (Sweden)

    Chien-Yi Chiang

    Full Text Available The neurobehavior of neuropathic pain by chronic constriction injury (CCI of sciatic nerve is very similar to that in humans, and it is accompanied by a profound local inflammation response. In this study, we assess the potentiality of human amniotic fluid derived mesenchymal stem cells (hAFMSCs for alleviating the neuropathic pain in a chronic constriction nerve injury model.This neuropathic pain animal model was conducted by four 3-0 chromic gut ligatures loosely ligated around the left sciatic nerve in Sprague-Dawley rats. The intravenous administration of hAFMSCs with 5x105 cells was conducted for three consecutive days.The expression IL-1β, TNF-α and synaptophysin in dorsal root ganglion cell culture was remarkably attenuated when co-cultured with hAFMSCs. The significant decrease of PGP 9.5 in the skin after CCI was restored by administration of hAFMSCs. Remarkably increased expression of CD 68 and TNF-α and decreased S-100 and neurofilament expression in injured nerve were rescued by hAFMSCs administration. Increases in synaptophysin and TNF-α over the dorsal root ganglion were attenuated by hAFMSCs. Significant expression of TNF-α and OX-42 over the dorsal spinal cord was substantially attenuated by hAFMSCs. The increased amplitude of sensory evoked potential as well as expression of synaptophysin and TNF-α expression was alleviated by hAFMSCs. Human AFMSCs significantly improved the threshold of mechanical allodynia and thermal hyperalgesia as well as various parameters of CatWalk XT gait analysis.Human AFMSCs administration could alleviate the neuropathic pain demonstrated in histomorphological alteration and neurobehavior possibly through the modulation of the inflammatory response.

  13. 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.

  14. Effects of chronic doxepin and amitriptyline administration in naïve mice and in neuropathic pain mice model.

    Science.gov (United States)

    Mika, J; Jurga, A M; Starnowska, J; Wasylewski, M; Rojewska, E; Makuch, W; Kwiatkowski, K; Malek, N; Przewlocka, B

    2015-05-21

    Neuropathic pain is a severe clinical problem, often appearing as a co-symptom of many diseases or manifesting as a result of damage to the nervous system. Many drugs and agents are currently used for the treatment of neuropathic pain, such as tricyclic antidepressants (TCAs). The aims of this paper were to test the effects of two classic TCAs, doxepin and amitriptyline, in naïve animals and in a model of neuropathic pain and to determine the role of cytokine activation in the effects of these drugs. All experiments were carried out with Albino-Swiss mice using behavioral tests (von Frey test and the cold plate test) and biochemical analyses (qRT-PCR and Western blot). In the mice subjected to chronic constriction injury (CCI), doxepin and amitriptyline attenuated the symptoms of neuropathic pain and diminished the CCI-induced increase in the levels of spinal interleukin (IL)-6 and -1β mRNA, but not the protein levels of these cytokines, measured on day 12. Unexpectedly, chronic administration of doxepin or amitriptyline for 12 days produced allodynia and hyperalgesia in naïve mice. The treatment with these drugs did not influence the spinal levels of IL-1β and IL-6 mRNA, however, the protein levels of these pronociceptive factors were increased. The administration of ondansetron (5-HT3 receptor antagonist) significantly weakened the allodynia and hyperalgesia induced by both antidepressants in naïve mice; in contrast, yohimbine (α2-adrenergic receptors antagonist) did not influence these effects. Allodynia and hyperalgesia induced in naïve animals by amitriptyline and doxepin may be associated with an increase in the levels of pronociceptive cytokines resulting from 5-HT3-induced hypersensitivity. Our results provide new and important information about the possible side effects of antidepressants. Further investigation of these mechanisms may help to guide decisions about the use of classic TCAs for therapy.

  15. Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain.

    Science.gov (United States)

    Jhaveri, Maulik D; Richardson, Denise; Kendall, David A; Barrett, David A; Chapman, Victoria

    2006-12-20

    Cannabinoid-based medicines have therapeutic potential for the treatment of pain. Augmentation of levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is analgesic in models of acute and inflammatory pain states. The aim of this study was to determine whether local inhibition of FAAH alters nociceptive responses of spinal neurons in the spinal nerve ligation model of neuropathic pain. Electrophysiological studies were performed 14-18 d after spinal nerve ligation or sham surgery, and the effects of the FAAH inhibitor cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597) on mechanically evoked responses of spinal neurons and levels of endocannabinoids were determined. Intraplantar URB597 (25 microg in 50 microl) significantly (p < 0.01) attenuated mechanically evoked responses of spinal neurons in sham-operated rats. Effects of URB597 were blocked by the cannabinoid 1 receptor (CB1) antagonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide] (30 microg in 50 microl) and the opioid receptor antagonist naloxone. URB597 treatment increased levels of anandamide, 2-arachidonyl glycerol, and oleoyl ethanolamide in the ipsilateral hindpaw of sham-operated rats. Intraplantar URB597 (25 microg in 50 microl) did not, however, alter mechanically evoked responses of spinal neurons in spinal nerve ligated (SNL) rats or hindpaw levels of endocannabinoids. Intraplantar injection of a higher dose of URB597 (100 microg in 50 microl) significantly (p < 0.05) attenuated evoked responses of spinal neurons in SNL rats but did not alter hindpaw levels of endocannabinoids. Spinal administration of URB597 attenuated evoked responses of spinal neurons and elevated levels of endocannabinoids in sham-operated and SNL rats. These data suggest that peripheral FAAH activity may be altered or that alternative pathways of metabolism have greater importance in SNL rats.

  16. Nonlinear dimension reduction and clustering by Minimum Curvilinearity unfold neuropathic pain and tissue embryological classes

    KAUST Repository

    Cannistraci, Carlo

    2010-09-01

    Motivation: Nonlinear small datasets, which are characterized by low numbers of samples and very high numbers of measures, occur frequently in computational biology, and pose problems in their investigation. Unsupervised hybrid-two-phase (H2P) procedures-specifically dimension reduction (DR), coupled with clustering-provide valuable assistance, not only for unsupervised data classification, but also for visualization of the patterns hidden in high-dimensional feature space. Methods: \\'Minimum Curvilinearity\\' (MC) is a principle that-for small datasets-suggests the approximation of curvilinear sample distances in the feature space by pair-wise distances over their minimum spanning tree (MST), and thus avoids the introduction of any tuning parameter. MC is used to design two novel forms of nonlinear machine learning (NML): Minimum Curvilinear embedding (MCE) for DR, and Minimum Curvilinear affinity propagation (MCAP) for clustering. Results: Compared with several other unsupervised and supervised algorithms, MCE and MCAP, whether individually or combined in H2P, overcome the limits of classical approaches. High performance was attained in the visualization and classification of: (i) pain patients (proteomic measurements) in peripheral neuropathy; (ii) human organ tissues (genomic transcription factor measurements) on the basis of their embryological origin. Conclusion: MC provides a valuable framework to estimate nonlinear distances in small datasets. Its extension to large datasets is prefigured for novel NMLs. Classification of neuropathic pain by proteomic profiles offers new insights for future molecular and systems biology characterization of pain. Improvements in tissue embryological classification refine results obtained in an earlier study, and suggest a possible reinterpretation of skin attribution as mesodermal. © The Author(s) 2010. Published by Oxford University Press.

  17. A large animal neuropathic pain model in sheep: a strategy for improving the predictability of preclinical models for therapeutic development

    Directory of Open Access Journals (Sweden)

    Wilkes D

    2012-10-01

    Full Text Available Denise Wilkes,1 Guangwen Li,2 Carmina F Angeles,3 Joel T Patterson,4 Li-Yen Mae Huang21Department of Anesthesiology, 2Department of Neuroscience and Cell Biology, 3Department of Neurosurgery University of Texas Medical Branch, Galveston, TX, USA; 4Neurospine Institute, Eugene, OR, USABackground: Evaluation of analgesics in large animals is a necessary step in the development of better pain medications or gene therapy prior to clinical trials. However, chronic neuropathic pain models in large animals are limited. To address this deficiency, we developed a neuropathic pain model in sheep, which shares many anatomical similarities in spine dimensions and cerebrospinal fluid volume as humans.Methods: A neuropathic pain state was induced in sheep by tight ligation and axotomy of the common peroneal nerve. The analgesic effect of intrathecal (IT morphine was investigated. Interspecies comparison was conducted by analyzing the ceiling doses of IT morphine for humans, sheep, and rats.Results: Peroneal nerve injury (PNI produced an 86% decrease in von-Frey filament-evoked withdrawal threshold on postsurgery day 3 and the decrease lasted for the 8-week test period. Compared to the pre-injury, sham, and contralateral hindlimb, the IT morphine dose that produces 50% of maximum analgesia (ED50 for injured PNI hindlimb was 1.8-fold larger and Emax, the dose that produces maximal analgesia, was 6.1-fold lower. The sheep model closely predicts human IT morphine ceiling dose by allometric scaling. This is in contrast to the approximately 10-fold lower morphine ceiling dose predicted by the rat spinal nerve ligated or spared nerve injury models.Conclusion: PNI sheep model has a fast onset and shows stable and long-lasting pain behavioral characteristics. Since the antinociceptive properties of IT morphine are similar to those observed in humans, the PNI sheep model will be a useful tool for the development of analgesics. Its large size and consistent chronic pain

  18. Capsaicina tópica en el tratamiento del dolor neuropático Topical capsaicin for the management of neuropathic pain

    Directory of Open Access Journals (Sweden)

    M. A. Vidal

    2004-07-01

    sensación de quemazón en la zona de aplicación, que tiende a desaparecer después de la primera semana. Esta sensación de quemazón constituye, junto con la limitada efectividad clínica, la principal limitación de la aplicación tópica de capsaicina. La principal indicación del uso de la capsaicina tópica es la de coadyuvante de los antidepresivos y anticonvulsivantes en el tratamiento de los diversos cuadros de dolor neuropático, ya que como terapia única parece ser insuficiente. Es una opción a tener en cuenta en los pacientes añosos afectos de dolor neuropático, con lo que disminuiremos la incidencia de efectos secundarios sistémicos y de interacciones medicamentosas.Neuropathic pain is one of the most complex painful syndromes and one of the most difficult to treat. It is a symptom resulting from neurological damage (peripheral, central or both affecting the pain nervous transmission system. Several drugs have been used, but none of them has resulted effective enough and their side effects frequently deter the continuation of the treatment. It can show up in different situations, all of which are more frequent in aged patients. A powerful analgesic with as little number ofside effects as possible is needed. This paper is a bibliographic review performed through the Medline data base of the treatment with topical capsaicin in different cases of neuropathic pain: postherpetic neuralgia, diabetic neuropathy, neuropathic pain associated to AIDS, trigeminal neuralgia, post-mastectomy painful syndromes and regional complex pain. The topical administration of capsaicin 0.075%, has shown to be effective for the management of dysesthesic pain and hence it is a therapeutic alternative for this type of pain. Its mechanism of action appears to be based on the selective stimulation of the neurons of amyelinic fibers C, causing the release of substance P and perhaps of other neurotransmitters; and finally, a depletion of substance P, which would disturb pain

  19. Investigation of Central Pain Processing in Post-Operative Shoulder Pain and Disability

    OpenAIRE

    Valencia, Carolina; Fillingim, Roger B.; Bishop, Mark; Wu, Samuel S.; Wright, Thomas W.; Moser, Michael; Farmer, Kevin; George, Steven Z.

    2014-01-01

    Measures of central pain processing like conditioned pain modulation (CPM), and suprathreshold heat pain response (SHPR) have been described to assess different components of central pain modulatory mechanisms. Central pain processing potentially play a role in the development of postsurgical pain, however, the role of CPM and SHPR in explaining postoperative clinical pain and disability is still unclear.

  20. The antinociceptive effects of the tetracyclic triterpene euphol in inflammatory and neuropathic pain models: The potential role of PKCε.

    Science.gov (United States)

    Dutra, R C; Bicca, M A; Segat, G C; Silva, K A B S; Motta, E M; Pianowski, L F; Costa, R; Calixto, J B

    2015-09-10

    Evidences suggest protein kinase C epsilon (PKCε) activation is involved in both inflammatory and neuropathic pains. We have previously shown that tetracyclic triterpene euphol produces antinociception in different models of persistent pain, an action associated with its anti-inflammatory properties. Among these properties are the cannabinoid system activation and different PKC isozymes modulation. Herein, we sought to explore the potential role of PKCε modulation on euphol antinociceptive effect, in inflammatory and neuropathic pain models, in rodents. Also, we investigated further mechanisms associated with euphol effects. Oral treatment with euphol (30 mg/kg) prevented the putative effect of PGE2-induced acute and persistent mechanical hypersensitivity in mice and rats, respectively. In the PGE2-induced acute mechanical hypersensitivity euphol promoted an inhibitory effect similar to a PKCε inhibitor peptide. Likewise, in rats it prevented the mechanical hypersensitivity induced by a PKCε activator. Conversely, euphol effectiveness was not observed in a cAMP/PKA-induced mechanical hypersensitivity in mice. Single (1h prior) or repeated (twice daily during 3 or 13 days) treatments with euphol ameliorated painful peripheral neuropathy induced by paclitaxel and also the mechanical hypersensitivity induced by B16F10 melanoma cells injection, in mice. Additionally, in both inflammatory and neuropathic pain models, euphol consistently prevented PKCε up-regulation, as well as, inhibited the up-regulation of PKCε-activated intracellular pathways; namely nuclear factor-κB (NF-κB), cyclic AMP response element binding protein (CREB) and cyclo-oxygenase-2 (COX-2). The present results suggest the antinociceptive effect on persistent pain caused by euphol is likely dependent on the inhibition of pro-inflammatory mediators modulated by PKCε.

  1. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study.

    Science.gov (United States)

    Demant, Dyveke T; Lund, Karen; Vollert, Jan; Maier, Christoph; Segerdahl, Märtha; Finnerup, Nanna B; Jensen, Troels S; Sindrup, Søren H

    2014-11-01

    In neuropathic pain it has been suggested that pain phenotype based on putative pain mechanisms may predict response to treatment. This was a randomised, double-blind, placebo-controlled, and phenotype-stratified study with 2 6-week treatment periods of oxcarbazepine (1800-2400mg) and placebo. The primary efficacy measure was change in median pain intensity between baseline and the last week of treatment measured on an 11-point numeric rating scale, and the primary objective was to compare the effect of oxcarbazepine in patients with and without the irritable nociceptor phenotype as defined by hypersensitivity and preserved small nerve fibre function determined by detailed quantitative sensory testing. Ninety-seven patients with peripheral neuropathic pain due to polyneuropathy, surgical or traumatic nerve injury, or postherpetic neuralgia were randomised. The intention-to-treat population comprised 83 patients: 31 with the irritable and 52 with the nonirritable nociceptor phenotype. In the total sample, oxcarbazepine relieved pain of 0.7 points (on a numeric rating scale 0-10; 95% confidence interval [CI] 0.4-1.4) more than placebo (P=0.015) and there was a significant interaction between treatment and phenotype of 0.7 (95% CI 0.01-1.4, P=0.047). The number needed to treat to obtain one patient with more than 50% pain relief was 6.9 (95% CI 4.2-22) in the total sample, 3.9 (95% CI 2.3-12) in the irritable, and 13 (95% CI 5.3-∞) in the nonirritable nociceptor phenotype. In conclusion, oxcarbazepine is more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs the nonirritable nociceptor phenotype.

  2. A multidisciplinary cognitive behavioural programme for coping with chronic neuropathic pain following spinal cord injury: the protocol of the CONECSI trial

    Directory of Open Access Journals (Sweden)

    Dijkstra Catja A

    2010-10-01

    Full Text Available Abstract Background Most people with a spinal cord injury rate neuropathic pain as one of the most difficult problems to manage and there are no medical treatments that provide satisfactory pain relief in most people. Furthermore, psychosocial factors have been considered in the maintenance and aggravation of neuropathic spinal cord injury pain. Psychological interventions to support people with spinal cord injury to deal with neuropathic pain, however, are sparse. The primary aim of the CONECSI (COping with NEuropathiC Spinal cord Injury pain trial is to evaluate the effects of a multidisciplinary cognitive behavioural treatment programme on pain intensity and pain-related disability, and secondary on mood, participation in activities, and life satisfaction. Methods/Design CONECSI is a multicentre randomised controlled trial. A sample of 60 persons with chronic neuropathic spinal cord injury pain will be recruited from four rehabilitation centres and randomised to an intervention group or a waiting list control group. The control group will be invited for the programme six months after the intervention group. Main inclusion criteria are: having chronic (> 6 months neuropathic spinal cord injury pain as the worst pain complaint and rating the pain intensity in the last week as 40 or more on a 0-100 scale. The intervention consists of educational, cognitive, and behavioural elements and encompasses 11 sessions over a 3-month period. Each meeting will be supervised by a local psychologist and physical therapist. Measurements will be perfomed before starting the programme/entering the control group, and at 3, 6, 9, and 12 months. Primary outcomes are pain intensity and pain-related disability (Chronic Pain Grade questionnaire. Secondary outcomes are mood (Hospital Anxiety and Depression Scale, participation in activities (Utrecht Activities List, and life satisfaction (Life Satisfaction Questionnaire. Pain coping and pain cognitions will be

  3. 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-op