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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. PMID:26944242

  2. 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.

  3. Contemporary treatment neuropathic pain

    OpenAIRE

    Cvijanović Milan; Simić Svetlana; Banić-Horvat Sofija; Jovin Zita; Slankamenac Petar; Ilin Miroslav

    2011-01-01

    Introduction. Neuropathic pain, or pain associated with disease or injury to the peripheral or central nervous system, is a common symptom of a heterogeneous group of conditions, including diabetic neuropathy, trigeminal neuralgia, postherpetic neuralgia and spinal cord injury. Chronic neuropathic pain should not be thought of as a symptom. It should truly be thought of as a disease with a very complicated pathophysiology. Pathophysiology. The mechanisms involved in neuropathic pain are...

  4. Clinical use of pregabalin in the management of central neuropathic pain

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    Nanna B Finnerup

    2007-01-01

    Full Text Available Nanna B Finnerup, Troels S JensenDanish Pain Research Center, Department of Neurology, Aarhus University Hospital, Aarhus, DenmarkAbstract: Central neuropathic pain (central pain is treated with antidepressants, various anticonvulsants, opioids, and cannabinoids, but in many cases treatment is insufficient and associated with a range of side-effects. This review addresses a new treatment for neuropathic pain, the anticonvulsant pregabalin. We review the pharmacology, mode of action, pharmacokinetics, and safety of pregabalin as well as two randomized efficacy studies in central pain and a brief overview of efficacy in peripheral neuropathic pain. Pregabalin appears to have efficacy in treating central pain comparable to that in peripheral neuropathic pain as well as efficacy of other recommended drugs for central pain. Pregabalin also improves disturbed sleep and anxiety. Pregabalin is well tolerated; the most common side-effects are somnolence, dizziness, ataxia, and weight gain. Pregabalin is suitable for patients on multiple drugs although there may be additive CNS-related side-effects. Thus, pregabalin has a primary role in central pain patients.Keywords: central pain, neuropathic pain, pregabalin, pharmacology

  5. Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain

    OpenAIRE

    Jeanmonod, D.; Werner, B.; Morel, A.; Michels, L; Zadicario, E; Schiff, G.; Martin, E.

    2012-01-01

    Object Recent technological developments open the field of therapeutic application of focused ultrasound to the brain through the intact cranium. The goal of this study was to apply the new transcranial magnetic resonance imaging-guided focused ultrasound (tcMRgFUS) technology to perform noninvasive central lateral thalamotomies (CLTs) as a treatment for chronic neuropathic pain. Methods In 12 patients suffering from chronic therapy-resistant neuropathic pain, tcMRgFUS CLT was propos...

  6. Contemporary treatment neuropathic pain

    Directory of Open Access Journals (Sweden)

    Cvijanović Milan

    2011-01-01

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

  7. Ocular neuropathic pain.

    Science.gov (United States)

    Rosenthal, Perry; Borsook, David

    2016-01-01

    As the biological alarm of impending or actual tissue damage, pain is essential for our survival. However, when it is initiated and/or sustained by dysfunctional elements in the nociceptive system, it is itself a disease known as neuropathic pain. While the critical nociceptive system provides a number of protective functions, it is unique in its central role of monitoring, preserving and restoring the optical tear film in the face of evaporative attrition without which our vision would be non-functional. Meeting this existential need resulted in the evolution of the highly complex, powerful and sensitive dry eye alarm system integrated in the peripheral and central trigeminal sensory network. The clinical consequences of corneal damage to these nociceptive pathways are determined by the type and location of its pathological elements and can range from the spectrum known as dry eye disease to the centalised oculofacial neuropathic pain syndrome characterised by a striking disparity between the high intensity of symptoms and paucity of external signs. These changes parallel those observed in somatic neuropathic pain. When seen through the neuroscience lens, diseases responsible for inadequately explained chronic eye pain (including those described as dry eye) can take on new meanings that may clarify long-standing enigmas and point to new approaches for developing preventive, symptomatic and disease-modifying interventions for these currently refractory disorders. PMID:25943558

  8. [Neurorehabilitation for Neuropathic Pain].

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    Hozumi, Jun; Osumi, Michihiro; Ogata, Toru; Sumitani, Masahiko

    2015-07-01

    Deafferentation, like as in limb amputation, brachial plexus avulsion injury and spinal cord injury, is usually followed by neuropathic pain. Neuropathic pain is a debilitating condition and it impairs the quality of life profoundly. Based on recent advances in the cognitive neuroscience, we explain intimate relationships among neuropathic pain, reorganization of primary sensory and motor cortices and the sensorimotor integration of the deafferentated limb. From the standpoint of the sensorimotor integration theory for emerging phantom limb pain, we further discuss the analgesic mechanism of neurorehabilitation techniques such as mirror visual feedback treatment and its related neurorobotics advancement for neuropathic pain. PMID:26422941

  9. Meta-Analysis of Placebo Responses in Central Neuropathic Pain: Impact of Subject, Study, and Pain Characteristics

    DEFF Research Database (Denmark)

    Cragg, Jacquelyn J; Warner, Freda M; Finnerup, Nanna Brix; Jensen, Mark P; Mercier, Catherine; Richards, J Scott; Wrigley, Paul; Soler, Dolors; Kramer, John Lk

    2016-01-01

    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......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 non-invasive brain stimulation...

  10. 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  0.05). YM-58483 also inhibited the release of spinal cord IL-1β, TNF-α, and PGE2, compared with control + vehicle (n = 5, #P < 0.001). The analgesic mechanism of YM-58483 may be via inhibiting 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. PMID:26514127

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

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    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.

  12. 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.

  13. Neuropathic pain therapy: from bench to bedside.

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    Backonja, Miroslav Misha

    2012-07-01

    Neuropathic pain is a result of complex interactions between peripheral and central mechanisms with multiple potential therapeutic targets. However, the complexity of these mechanisms and relative youth of translational pain research, which is in its infancy, have prevented translation of successful basic bench research to human therapy. Most of the clinically available neuropathic pain treatments are borrowed from other therapeutic areas, such as antidepressants and antiepileptics, or involve application of older therapy, such as opioids. Exceptions are ziconotide, tapentadol, and the high-concentration capsaicin patch. Similar to all other analgesic agents, these provide only partial pain relief in subsets of patients. The standard of care for patients with chronic neuropathic pain is multimodal and multidisciplinary. For most patients to achieve and maintain satisfactory pain relief a combination of therapeutic agents is necessary, providing the empiric basis for rational polypharmacy, which has become a standard approach as well. PMID:23117951

  14. 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.

  15. 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

  16. [Non pharmacologic treatment of neuropathic pain].

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    Guastella, Virginie; Mick, Gérard; Laurent, Bernard

    2008-02-01

    Nondrug treatments of neuropathic pain should always begin at the same time as pharmacologic treatment. There are three types of nondrug treatment for neuropathic pain: physical, surgical, and "psychocorporal" and psychotherapeutic treatment. Transcutaneous electrical nerve stimulation (TENS) is a simple physical treatment that strengthens local inhibitory controls and is indicated in focal neuropathic pain when upstream stimulation is possible for a superficial sensitive nerve trunk. Destructive surgery is represented today by "DREZotomy", destruction of nociceptive fibers and their dorsal root entry zones. It is indicated essentially in intractable pain due to plexus avulsion. Functional surgery is implanted electric stimulation--either spinal or central (encephalic)--of structures that exert inhibitory control on the pain pathways. Spinal stimulation is performed at the level of the posterior spinal cord and is indicated essentially in segmental mononeuropathies refractory to drug treatment. Central stimulation is performed at the motor cortex and is indicated for refractory central pain. "Psychocorporal" techniques (relaxation, sophrology, hypnosis) are useful to reduce anxiety and neurovegetative hypertonicity, both factors that aggravate neuropathic pain. PMID:18191370

  17. 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.

  18. 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.

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

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    Walter J. Fagundes-Pereyra

    2010-12-01

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

  20. 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.

  1. Interventional therapy for neuropathic pain

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    YANG Yang

    2013-10-01

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

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

    DEFF Research Database (Denmark)

    Finnerup, Nanna Brix; Sindrup, Søren H.; Jensen, Troels Staehelin

    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...... assess various symptoms and signs in neuropathic pain and knowledge of drug mechanisms are prerequisites for pursuing this approach. The present review summarizes mechanisms of neuropathic pain, targets of currently used drugs, and measures used in neuropathic pain trials.......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...

  3. 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.

  4. Spinal Gap Junction Channels in Neuropathic Pain

    OpenAIRE

    Jeon, Young Hoon; Youn, Dong Ho

    2015-01-01

    Damage to peripheral nerves or the spinal cord is often accompanied by neuropathic pain, which is a complex, chronic pain state. Increasing evidence indicates that alterations in the expression and activity of gap junction channels in the spinal cord are involved in the development of neuropathic pain. Thus, this review briefly summarizes evidence that regulation of the expression, coupling, and activity of spinal gap junction channels modulates pain signals in neuropathic pain states induced...

  5. Prevalence of Neuropathic Pain and the Need for Treatment

    OpenAIRE

    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...

  6. Emerging Treatments for Neuropathic Pain.

    Science.gov (United States)

    Pessoa, Bruno L; Escudeiro, Gabriel; Nascimento, Osvaldo J M

    2015-12-01

    Neuropathic pain is a series of well-known conditions caused by diseases or lesions to the somatosensory system. Due to the better understanding of the pathophysiology of neuropathic pain, previously unexplored therapies have been used with encouraging results. As such, Acetyl-L-carnitine (ALC), Alpha-lipoic-acid (ALA), cannabinoids, Clonidine, EMA401, Botulinum Toxin type A, and new voltage-gated sodium channel blockers, can be cited. Furthermore, new modalities in neuromodulation such as high-frequency spinal cord stimulation, burst stimulation, dorsal root ganglion stimulation, transcranial direct current stimulation, and many others have been showing exciting results. Besides, changing paradigms may occur with the advent of optogenetics and a better understanding of epigenetic regulation. This article reviews the published literature on the treatment of NP. Despite the interesting results, randomized controlled trials are demanded for the majority of the therapies previously mentioned. PMID:26530058

  7. The endocannabinoid system and neuropathic pain.

    Science.gov (United States)

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

    2016-02-01

    The research of new therapeutic strategies for neuropathic pain represents a major current priority. Important drawbacks to advance in the development of these therapies are the limited translational value of the animal models now available and the elucidation of the complex neuronal and immune pathophysiological mechanisms underlying neuropathic pain. One of the neurotransmitter systems participating in neuropathic pain control that has recently raised a particular interest is the endocannabinoid system. This system is highly expressed in neurons and immune cells, and it plays a crucial role in the development of neuropathic pain. Preclinical studies have provided important findings, revealing the potential interest of the endocannabinoid system for the treatment of neuropathic pain. These studies have reported the analgesic effects of cannabinoid agonists in multiple neuropathic pain models, and they have identified specific targets within this system to develop more effective and safe analgesic compounds. However, further studies using more relevant neuropathic pain animal models are required to confirm these interesting results. Several clinical studies suggest that cannabinoids significantly reduced neuropathic pain, although most of these trials fail the required standards of quality. The different pain patient populations included in the systematic reviews also make it difficult to get adequate conclusions. Therefore, additional clinical trials that consider an adequate number of patients, the use active treatments as controls, and longer duration of administration are required to have an adequate profile of the effectiveness and safety of cannabinoids in neuropathic pain. PMID:26785153

  8. Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents.

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    Horváth, Gergely; Gölöncsér, Flóra; Csölle, Cecilia; Király, Kornél; Andó, Rómeó D; Baranyi, Mária; Koványi, Bence; Máté, Zoltán; Hoffmann, Kristina; Algaier, Irina; Baqi, Younis; Müller, Christa E; Von Kügelgen, Ivar; Sperlágh, Beáta

    2014-10-01

    In this study the role of P2Y12 receptors (P2Y12R) was explored in rodent models of inflammatory and neuropathic pain and in acute thermal nociception. In correlation with their activity to block the recombinant human P2Y12R, the majority of P2Y12R antagonists alleviated mechanical hyperalgesia dose-dependently, following intraplantar CFA injection, and after partial ligation of the sciatic nerve in rats. They also caused an increase in thermal nociceptive threshold in the hot plate test. Among the six P2Y12R antagonists evaluated in the pain studies, the selective P2Y12 receptor antagonist PSB-0739 was most potent upon intrathecal application. P2Y12R mRNA and IL-1β protein were time-dependently overexpressed in the rat hind paw and lumbar spinal cord following intraplantar CFA injection. This was accompanied by the upregulation of TNF-α, IL-6 and IL-10 in the hind paw. PSB-0739 (0.3mg/kg i.t.) attenuated CFA-induced expression of cytokines in the hind paw and of IL-1β in the spinal cord. Subdiaphragmatic vagotomy and the α7 nicotinic acetylcholine receptor antagonist MLA occluded the effect of PSB-0739 (i.t.) on pain behavior and peripheral cytokine induction. Denervation of sympathetic nerves by 6-OHDA pretreatment did not affect the action of PSB-0739. PSB-0739, in an analgesic dose, did not influence motor coordination and platelet aggregation. Genetic deletion of the P2Y12R in mice reproduced the effect of P2Y12R antagonists on mechanical hyperalgesia in inflammatory and neuropathic pain models, on acute thermal nociception and on the induction of spinal IL-1β. Here we report the robust involvement of the P2Y12R in inflammatory pain. The anti-hyperalgesic effect of P2Y12R antagonism could be mediated by the inhibition of both central and peripheral cytokine production and involves α7-receptor mediated efferent pathways. PMID:24971933

  9. Contribution of interleukin-1beta in neuropathic pain

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    GUO Wei

    2013-09-01

    Full Text Available Interleukin-1beta (IL-1β, a pro-inflammatory cytokine, has been implicated in the development of peripheral and central sensitization that is charactistic of neuropathic pain. Recent studies demonstrated that IL-1β is an important messenger that is interacted with glia and neurons in the central neurous system in the neuropathic pain states. Some new studies showed that IL-1β activation was regulated by several other cytokines such as CCL2, MMP-2 and MMP-9 during the neuropathic pain conditions. This review will briefly describe the key role of IL-1 β and its signaling contributes to the peripheral and central nervous system in the neuropathic pain.

  10. PHARMACOTHERAPY IN ELDERLY NEUROPATHIC PAIN

    Directory of Open Access Journals (Sweden)

    Thomas Eko P

    2013-10-01

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

  11. Burden of Illness Associated with Peripheral and Central Neuropathic Pain among Adults Seeking Treatment in the United States: A Patient-Centered Evaluation

    OpenAIRE

    Schaefer, Caroline; Mann, Rachael; Sadosky, Alesia; Daniel, Shoshana; Parsons, Bruce; Nieshoff, Edward; Tuchman, Michael; Nalamachu, Srinivas; Anschel, Alan; Stacey, Brett R.

    2014-01-01

    Objective The aim of this study was to evaluate patient-reported burden associated with peripheral and central neuropathic pain (NeP) by pain severity and NeP condition. Design Six hundred twenty-four subjects with one of six NeP conditions were recruited during routine office visits. Subjects consented to retrospective chart review and completed a one-time questionnaire (including EuroQol-5 dimensions, 12-item Short-Form Health Survey, Brief Pain Inventory-Short Form, Medical Outcomes Study ...

  12. Evidence-based pharmacological management of chronic neuropathic pain

    Directory of Open Access Journals (Sweden)

    Zarrin Ansari

    2013-06-01

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

  13. Pharmacological management of neuropathic pain following spinal cord injury.

    Science.gov (United States)

    Baastrup, Cathrine; Finnerup, Nanna B

    2008-01-01

    Spinal cord injury (SCI) has a number of severe and disabling consequences, including chronic pain, and around 40% of patients develop persistent neuropathic pain. Pain following SCI has a detrimental impact on the patient's quality of life and is a major specific healthcare problem in its own right. Thus far, there is no cure for the pain and oral pharmaceutical intervention is often inadequate, commonly resulting in a reduction of only 20-30% in pain intensity. Neuropathic pain sensations are characterized by spontaneous persistent pain and a range of abnormally evoked responses, e.g. allodynia (pain evoked by normally non-noxious stimuli) and hyperalgesia (an increased response to noxious stimuli). Neuropathic pain following SCI may be present at or below the level of injury. Oral pharmacological agents used in the treatment of neuropathic pain act either by depressing neuronal activity, by blocking sodium channels or inhibiting calcium channels, by increasing inhibition via GABA agonists, by serotonergic and noradrenergic reuptake inhibition, or by decreasing activation via glutamate receptor inhibition, especially by blocking the NMDA receptor. At present, only ten randomized, double-blind, controlled trials have been performed on oral drug treatment of pain after SCI, the results of most of which were negative. The studies included antidepressants (amitriptyline and trazodone), antiepileptics (gabapentin, pregabalin, lamotrigine and valproate) and mexiletine. Gabapentin, pregabalin and amitriptyline showed a significant reduction in neuropathic pain following SCI. Cannabinoids have been found to relieve other types of central pain, and serotonin noradrenaline reuptake inhibitors as well as opioids relieve peripheral neuropathic pain and may be used to treat patients with SCI pain. PMID:18484790

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

    DEFF Research Database (Denmark)

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

      Painful polyneuropathy is a common neuropathic pain condition with painful diabetic neuropathy being a prominent example. Numerous pathophysiological mechanisms are involved in the generation and maintenance of neuropathic pain. In spite of increasing knowledge about the mechanisms, the treatme...

  15. [Treatment of central and neuropathic facial pain by chronic stimulation of the motor cortex: value of neuronavigation guidance systems for the localization of the motor cortex].

    Science.gov (United States)

    Nguyen, J P; Lefaucheur, J P; Le Guerinel, C; Fontaine, D; Nakano, N; Sakka, L; Eizenbaum, J F; Pollin, B; Keravel, Y

    2000-11-01

    Thirty two patients with refractory central and neuropathic pain of peripheral origin were treated by chronic stimulation of the motor cortex between May 1993 and January 1997. The mean follow-up was 27. 3 months. The first 24 patients were operated according to the technique described by Tsubokawa. The last 13 cases (8 new patients and 5 reinterventions) were operated by a technique including localization by superficial CT reconstruction of the central region and neuronavigator guidance. The position of the central sulcus was confirmed by the use of intraoperative somatosensory evoked potentials. The somatotopic organisation of the motor cortex was established peroperatively by studying the motor responses at stimulation of the motor cortex through the dura. Ten of the 13 patients with central pain (77%) and nine of the 12 patients with neuropathic facial pain had experienced substantial pain relief (75%). One of the 3 patients with post-paraplegia pain was clearly improved. A satisfactory result was obtained in one patient with pain related to plexus avulsion and in one patient with pain related to intercostal herpes zoster. None of the patients developed epileptic seizures. The position of the stimulating poles effective on pain corresponded to the somatotopic representation of the motor cortex. The neuronavigator localization and guidance technique proved to be most useful identifying the appropriate portion of the motor gyrus. It also allowed the establishment of reliable correlations between electrophysiological-clinical and anatomical data which may be used to improve the clinical results and possibly to extend the indications of this technique. PMID:11084480

  16. Minimally invasive procedures for neuropathic pain.

    Science.gov (United States)

    Sdrulla, Andrei; Chen, Grace

    2016-04-01

    Neuropathic pain is "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system". The prevalence of neuropathic pain ranges from 7 to 11% of the population and minimally invasive procedures have been used to both diagnose and treat neuropathic pain. Diagnostic procedures consist of nerve blocks aimed to isolate the peripheral nerve implicated, whereas therapeutic interventions either modify or destroy nerve function. Procedures that modify how nerves function include epidural steroid injections, peripheral nerve blocks and sympathetic nerve blocks. Neuroablative procedures include radiofrequency ablation, cryoanalgesia and neurectomies. Currently, neuromodulation with peripheral nerve stimulators and spinal cord stimulators are the most evidence-based treatments of neuropathic pain. PMID:26988024

  17. P2X4 receptors and neuropathic pain

    Directory of Open Access Journals (Sweden)

    Makoto Tsuda

    2013-10-01

    Full Text Available Neuropathic pain, a debilitating pain condition, is a common consequence of damage to the nervous system. Neuropathic pain is often resistant to currently available analgesics. A growing body of evidence indicates that spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. After nerve injury, P2X4 receptors (P2X4Rs are upregulated in spinal microglia by several factors at the transcriptional and translational levels. Those include the CC chemokine CCL21 derived from damaged neurons, the extracellular matrix protein fibronectin in the spinal cord, and the transcription factor interferon regulatory factor 8 expressed in microglia. P2X4R expression in microglia is also regulated at the post-translational level by signaling from other cell-surface receptors such as CC chemokine receptor CCR2. Importantly, inhibiting the function or expression of P2X4Rs and P2X4R-regulating molecules suppresses the aberrant excitability of dorsal horn neurons and neuropathic pain. These findings indicate that P2X4R-positive microglia are a central player in mechanisms for neuropathic pain. Thus, microglial P2X4Rs are a potential target for treating the chronic pain state.

  18. Nurse’s Knowledge of Neuropathic Pain

    OpenAIRE

    Ali Yavuz Karahan; Seher Kucuksarac; Neslihan Soran; Banu Ordahan; Levent Tekin; Aynur Basaran

    2014-01-01

    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 a...

  19. Molecular hydrogen attenuates neuropathic pain in mice.

    Directory of Open Access Journals (Sweden)

    Masanori Kawaguchi

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

  20. 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.

  1. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial.

    Science.gov (United States)

    Berman, Jonathan S; Symonds, Catherine; Birch, Rolfe

    2004-12-01

    The objective was to investigate the effectiveness of cannabis-based medicines for treatment of chronic pain associated with brachial plexus root avulsion. This condition is an excellent human model of central neuropathic pain as it represents an unusually homogenous group in terms of anatomical location of injury, pain descriptions and patient demographics. Forty-eight patients with at least one avulsed root and baseline pain score of four or more on an 11-point ordinate scale participated in a randomised, double-blind, placebo-controlled, three period crossover study. All patients had intractable symptoms regardless of current analgesic therapy. Patients entered a baseline period of 2 weeks, followed by three, 2-week treatment periods during each of which they received one of three oromucosal spray preparations. These were placebo and two whole plant extracts of Cannabis sativa L.: GW-1000-02 (Sativex), containing Delta(9)tetrahydrocannabinol (THC):cannabidiol (CBD) in an approximate 1:1 ratio and GW-2000-02, containing primarily THC. The primary outcome measure was the mean pain severity score during the last 7 days of treatment. Secondary outcome measures included pain related quality of life assessments. The primary outcome measure failed to fall by the two points defined in our hypothesis. However, both this measure and measures of sleep showed statistically significant improvements. The study medications were generally well tolerated with the majority of adverse events, including intoxication type reactions, being mild to moderate in severity and resolving spontaneously. Studies of longer duration in neuropathic pain are required to confirm a clinically relevant, improvement in the treatment of this condition. PMID:15561385

  2. 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.

  3. 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...

  4. [Capsaicin in treatment of neuropathic pain].

    Science.gov (United States)

    Kamchatnov, P R; Evzelman, M A; Abusueva, B A; Volkov, A I

    2014-01-01

    Treatment of neuropathic pain (NP) is a serious medical problem. Antiepileptic drugs and antidepressants, used to relief pain, act on the central pain mechanisms and cause several side-effects, thus substantially restricting possibilities of their clinical application.At the same time, NP often has a peripheral component. Ligand-associated channels, including vanilloid receptors TRPV1, play a key role in the development of regional NP syndromes. Capsaicin, a component of chili pepper and several other plants, is a highly selective ligand of TRPV1 receptors and has long been used in treatment of pain syndromes. However, its using is limited by short-term action and relatively low efficacy. Recently it has been shown that the local use of single high doses of capsaicin during 30-60 min causes a marked stable(> 12 weeks) effect. The decrease in NP (>50%) is seen in about half of patients. Current studies will allow to single out groups of patients with the maximal treatment effect of capsaicin. PMID:25629137

  5. Ranolazine Attenuates Behavioral Signs of Neuropathic Pain

    OpenAIRE

    Gould, Harry J; Garrett, Colleen; Donahue, Renee R.; Paul, Dennis; Diamond, Ivan; Taylor, Bradley K

    2009-01-01

    Ranolazine modulates the cardiac voltage-gated sodium channel (Nav 1.5) and is FDA-approved for the treatment of ischemic heart disease. Ranolazine also targets neuronal (Nav 1.7, 1.8) isoforms that are implicated in neuropathic pain. Therefore, we determined the analgesic efficacy of ranolazine in a pre-clinical animal model of neuropathic pain. Both i.p. and oral administration of ranolazine dose-dependently inhibited the mechanical and cold allodynia associated with spared nerve injury, wi...

  6. 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.

  7. Botulinum Toxin Treatment of Neuropathic Pain.

    Science.gov (United States)

    Mittal, Shivam Om; Safarpour, Delaram; Jabbari, Bahman

    2016-02-01

    Neuropathic pain (NP), a common form of human pain, often poorly responds to analgesic medications. In this review the authors discuss the pathophysiology and conventional treatment of neuropathic pain and provide evidenced-based statements on the efficacy of botulinum neurotoxins (BoNTs) in this form of pain. The level of efficacy for BoNT treatment in each category of NP is defined according to the published guidelines of the American Academy of Neurology. The data indicate that BoNT treatment (most of the literature is with onabotulinumtoxinA) is effective (level A evidence) in postherpetic neuralgia and trigeminal neuralgia. It is probably effective (level B) in posttraumatic neuralgia and painful diabetic neuropathy. The data on complex regional pain syndrome, carpal tunnel syndrome, occipital neuralgia, and phantom limb pain are preliminary and await conduction of randomized, blinded clinical trials. Much remains to be learned about the most-effective dosage and technique of injection, optimum dilutions, and differences among BoNTs in the treatment of neuropathic pain. PMID:26866499

  8. Antidepressants in the treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Sindrup, Søren H.; Otto, Marit; Finnerup, Nanna Brix;

    2005-01-01

    neuropathic pain, serotonin noradrenaline reuptake inhibitors one in every 4-5 and selective serotonin reuptake inhibitors one in every 7 patients. Thus, based on efficacy measures such as numbers needed to treat, tricyclic antidepressants tend to work better than the anticonvulsant gabapentin and treatment...

  9. Multidimensional Neuropathic Pain Phenotypes after Spinal Cord Injury.

    Science.gov (United States)

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

    2016-03-01

    Identifying clinical neuropathic pain phenotypes is a first step to better understand the underlying pain mechanisms after spinal cord injury (SCI). The primary purpose of the present study was to characterize multidimensional neuropathic pain phenotypes based on quantitative sensory testing (QST), pain intensity, and utilization of catastrophizing coping strategies. Thermal perception, thermal pain, and vibratory perception thresholds were assessed above and below the level of injury (LOI) in 101 persons with SCI and neuropathic pain, 18 persons with SCI and no neuropathic pain, and 50 able-bodied, pain-free controls. Cluster analysis of QST z-scores below the LOI, pain intensity ratings, and the Coping Strategies Questionnaire (CSQ) catastrophizing subscale scores in subjects with neuropathic pain resulted in two phenotypes: severe neuropathic pain (SNP) with greater pain intensity (7.39 ± 1.57) and thermal and vibratory sensitivity compared with the moderate neuropathic pain (MNP; 5.40 ± 1.43). A factor analysis including all CSQ subscales, the Neuropathic Pain Symptom Inventory (NPSI) total score, and thermal pain sensitivity above and below the LOI resulted in three factors: (1) adaptive pain coping including increasing activities, diverting attention, and reinterpreting pain sensations; (2) catastrophizing, neuropathic pain, and thermal sensitivity including greater NPSI total score, thermal pain sensitivity below the LOI, and catastrophizing; and (3) general pain sensitivity including greater thermal pain sensitivity above the LOI and lower catastrophizing. Our results suggest that neuropathic pain symptom severity post-SCI is significantly associated with residual spinothalamic tract function below the LOI and catastrophizing pain coping. PMID:26414803

  10. 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.

  11. Early dexamethasone relieves trigeminal neuropathic pain.

    Science.gov (United States)

    Han, S R; Yeo, S P; Lee, M K; Bae, Y C; Ahn, D K

    2010-09-01

    The analgesic effects of dexamethasone on neuropathic pain have been controversial. The present study investigated the effects of dexamethasone on mechanical allodynia in rats with mal-positioned dental implants. Under anesthesia, the left mandibular second molar was extracted and replaced by a miniature dental implant to injure the inferior alveolar nerve. Nociceptive behavior was examined on each designated day after surgery. Mal-positioned dental implants significantly decreased air-puff thresholds both ipsilateral and contralateral to the injury site. Distinct mechanical hyperalgesia and cold and thermal hypersensitivity were also observed bilaterally. Daily administration of dexamethasone produced prolonged anti-allodynic effects (25 or 50 mg/kg, i.p.), but failed to reduce mechanical allodynia when it had already been established. Therefore, our findings provide that early treatment with dexamethasone is important in the treatment of nociceptive behavior suggestive of trigeminal neuropathic pain. PMID:20581355

  12. Neuropathic pain in the cancer patient.

    Science.gov (United States)

    Allen, R R

    1998-11-01

    Cancer presents itself in numerous ways, adding to the complexity of any pain syndrome with which it is associated. Neuropathic pain, unlike many other pain syndromes, is difficult to treat even in the absence of cancer. The combination results in a heterogeneous group of patients with a complex set of symptoms. This makes the assessment of pain, classification of syndromes, and clinical study a challenge. If the disease is nonprogressive, general principles of care are essentially the same as in those without cancer. In patients with progressive disease and more refractory painful conditions, spinal anesthetic and neurosurgical therapies must often be considered. Under such circumstances, caregivers are forced to carefully balance uncertain benefits and risks, often without the luxury of time. More careful observation and controlled trials in these patients help facilitate this challenging process. PMID:9767067

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

    OpenAIRE

    Walter J. Fagundes-Pereyra; Manoel Jacobsen Teixeira; Nicolas Reyns; Gustavo Touzet; Sérgio Dantas; Emmanuelle Laureau; Serge Blond

    2010-01-01

    OBJECTIVE: Motor cortex stimulation (MCS) is considered to be an effective treatment for chronic neuropathic pain. The aim of the present study was to assess the efficacy of MCS for treating neuropathic pain. METHOD: 27 patients with chronic neuropathic pain were operated. Electrodes were implanted with the use of an stereotactic frame. Electrophysiological evaluations (motor stimulation and somatosensory evoked potentials) were performed, with guidance by means of three-dimensional reconstru...

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

    OpenAIRE

    Ramica Sharma et al.

    2012-01-01

    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 unmyelinate...

  15. 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

    Pharmacological relief of neuropathic pain is often insufficient. Electrical neurostimulation is efficacious in chronic neuropathic pain and other neurological diseases. European Federation of Neurological Societies (EFNS) launched a Task Force to evaluate the evidence for these techniques and to...... produce relevant recommendations. We searched the literature from 1968 to 2006, looking for neurostimulation in neuropathic pain conditions, and classified the trials according to the EFNS scheme of evidence for therapeutic interventions. Spinal cord stimulation (SCS) is efficacious in failed back surgery...

  16. Treatment Considerations for Elderly and Frail Patients With Neuropathic Pain

    OpenAIRE

    Schmader, Kenneth E.; Baron, Ralf; Haanpää, Maija L.; Mayer, John; O'Connor, Alec B.; Rice, Andrew S C; Stacey, Brett

    2010-01-01

    Currently, an estimated 38 million individuals 65 years or older live in the United States, and more than 11 million of these individuals are 80 years or older. Older people are at high risk of neuropathic pain because many diseases that cause neuropathic pain increase in incidence with age. Depending on their underlying health, older adults with neuropathic pain may have to cope with multiple coexisting diseases, polypharmacy, and impaired functional ability. The objective of this article is...

  17. Spinal cord stimulation for neuropathic pain: current perspectives

    Directory of Open Access Journals (Sweden)

    Wolter T

    2014-11-01

    Full Text Available Tilman Wolter Interdisciplinary Pain Centre, University Hospital Freiburg, Freiburg, Germany Abstract: Neuropathic pain constitutes a significant portion of chronic pain. Patients with neuropathic pain are usually more heavily burdened than patients with nociceptive pain. They suffer more often from insomnia, anxiety, and depression. Moreover, analgesic medication often has an insufficient effect on neuropathic pain. Spinal cord stimulation constitutes a therapy alternative that, to date, remains underused. In the last 10 to 15 years, it has undergone constant technical advancement. This review gives an overview of the present practice of spinal cord stimulation for chronic neuropathic pain and current developments such as high-frequency stimulation and peripheral nerve field stimulation. Keywords: spinal cord stimulation, neuropathic pain, neurostimulation

  18. 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

    potentially tissue-damaging stimuli. Pain may also arise by activity generated within the nervous system without adequate stimulation of its peripheral sensory endings. For this type of pain, the International Association for the Study of Pain introduced the term neuropathic pain, defined as "pain...... initiated or caused by a primary lesion or dysfunction in the nervous system." While this definition has been useful in distinguishing some characteristics of neuropathic and nociceptive types of pain, it lacks defined boundaries. Since the sensitivity of the nociceptive system is modulated by its adequate...... affecting the somatosensory system. This revised definition fits into the nosology of neurologic disorders. The reference to the somatosensory system was derived from a wide range of neuropathic pain conditions ranging from painful neuropathy to central poststroke pain. Because of the lack of a specific...

  19. 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

  20. Neuropathic pain in hereditary coproporphyria

    OpenAIRE

    Chen, Guan-Liang; Yang, Deng-Ho; Wu, Jeng-Yuau; Kuo, Chia-Wen; Hsu, Wen-Hsiu

    2013-01-01

    Acute porphyrias are rare diseases with varying incidences worldwide. These diseases are disorders of heme biosynthesis characterized by acute attacks of neurological symptoms. Acute porphyria should be considered in patients with unexplained abdominal pain or neurological damage. Clinical manifestations of acute porphyria are nonspecific and are associated with multiple organ systems. This report examines a rare case of an uncommon type of acute porphyria in a patient with an initial present...

  1. Prevalence, Causes, and Treatment of Neuropathic Pain in Dutch Nursing Home Residents : A Retrospective Chart Review

    NARCIS (Netherlands)

    van Kollenburg, Esther G. P.; Lavrijsen, Jan C. M.; Verhagen, Stans C.; Zuidema, Sytse U.; Schalkwijk, Annelies; Vissers, Kris C. P.

    2012-01-01

    Objectives To identify the prevalence and causes of neuropathic pain in Dutch nursing home residents; to establish the prevalence of painful and nonpainful diabetic polyneuropathy in a subsample of individuals with diabetes mellitus and central poststroke pain (CPSP) in a subsample of individuals wh

  2. 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.

  3. 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

  4. Intraoral administration of botulinum toxin for trigeminal neuropathic pain.

    Science.gov (United States)

    Herrero Babiloni, Alberto; Kapos, Flavia P; Nixdorf, Donald R

    2016-06-01

    This article presents 2 cases of different neuropathic trigeminal pain conditions treated with intraoral botulinum toxin injections. There is a growing body of evidence to support the use of this substance when administered subcutaneously in the treatment of neuropathic pain, such as in extraoral injections for trigeminal neuralgia. However, reports of intraoral submucosal administration are still lacking. In the 2 cases presented here, neuropathic pain was refractory to treatment with an important intraoral peripheral component, so onabotulinum toxin A was introduced as an adjuvant therapy. The technique, doses, and dilution are discussed. The patients reported significant reductions in pain frequency and intensity, with minimal side effects of temporary mucosal dryness and smile droopiness. The analgesic benefits of botulinum toxin may be utilized to address intraoral neuropathic pain. Further studies are needed to confirm safety and effectiveness in larger samples. PMID:27181448

  5. Diagnosis and medical treatment of neuropathic pain in leprosy 1

    Science.gov (United States)

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

    2016-01-01

    ABSTRACT Objective: to identify the difficulties in diagnosing and treating neuropathic pain caused by leprosy and to understand the main characteristics of this situation. Methods: 85 patients were treated in outpatient units with reference to leprosy and the accompanying pain. We used a questionnaire known as the Douleur Neuropathic 4 test and we conducted detailed neurological exams. As a result, 42 patients were excluded from the study for not having proved their pain. Results: Out of the 37 patients that experienced pain, 22 (59.5%) had neuropathic pain (or a mixture of this pain and their existing pain) and of these 90.8% considered this pain to be moderate or severe. 81.8% of the sample suffered with this pain for more than 6 months. Only 12 (54.5%) of the patients had been diagnosed with neuropathic pain and in almost half of these cases, this pain had not been diagnosed. With reference to medical treatment (n=12) for neuropathic pain, 5 (41.6%) responded that they became better. For the other 7 (58.4%) there were no changes in relation to the pain or in some cases the pain worsened in comparison to their previous state. Statistical analysis comparing improvements in relation to the pain amongst the patients that were treated (n=12) and those that were not, showed significant differences (value p=0.020). Conclusion: we noted difficulties in diagnosing neuropathic pain for leprosy in that almost half of the patients that were studied had not had their pain diagnosed. We attributed this to some factors such as the non-adoption of the appropriate protocols which led to inadequate diagnosis and treatment that overlooked the true picture. PMID:27508904

  6. [Neuropathic pain. How to open the blackbox].

    Science.gov (United States)

    Maier, C; Baron, R; Sommer, C

    2015-10-01

    This article, without presuming to be comprehensive, gives a brief outline of the development of research on neuropathic pain in Germany. Current clinical research on this subject focusses on the validation of human models, patient phenotyping, mechanism-based classification and treatment as well as on molecular pathomechanisms. This clinical research is based to a large extent on the work of several internationally recognized basic researchers in the 1990s. In particular, findings from system physiology led to the analysis of clinical phenotypes and the underlying pathophysiology. In parallel, basic research achieved international top levels through the development of innovative methods. Close cooperation, building of consortia and European networking made major contributions to the success of this research. PMID:26264897

  7. Neuropathic pain - the case for opioid therapy.

    Science.gov (United States)

    Allen, Stephen C

    2008-01-01

    For many patients, neuropathic pain (NeP) is arguably more difficult to control than nociceptive or 'normal' pain. We also now recognise the great burden that NeP has on the lives of patients - it is not only a matter of treating pain in isolation, but managing all of the issues that affect the patient's quality of life. Until relatively recently we have had little understanding of the pathophysiology causing NeP and have relied on the secondary effects of non-analgesic drugs as the mainstays of treatment. Greater understanding of the pathophysiology of NeP has led to more appropriate therapy and an increased use of multiple drug therapy - 'rational polypharmacy'. Traditional opinions concerning the treatment of NeP have been challenged and it is because of this that the use of opioids in NeP has been re-evaluated. Opioids will never replace tricyclic antidepressants and anti-epileptic drugs as first-line therapy for NeP. However, they are now fully established as effective and useful second- or third-line drugs. Many patients in the past have been potentially undertreated as a result of our inertia to use opioids. The case for opioid therapy in NeP has been firmly established. PMID:18758203

  8. Pharmacologic management of neuropathic pain: Evidence-based recommendations

    DEFF Research Database (Denmark)

    Dworkin, Robert H.; O'Connor, Alec B.; Backonja, Miroslav;

    2007-01-01

    Patients with neuropathic pain (NP) are challenging to manage and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered...

  9. Studies on experimental and neuropathic orofacial pain, and low-dose ketamine as a probe for NMDA receptor function

    OpenAIRE

    2005-01-01

    The NMDA-receptor is known to play a central role in the development of acute andchronic pain. Ketamine is a clinically available NMDA-receptor inhibitor. We examined the role of the NMDA-receptor in acute experimental and chronic neuropathic orofacial pain in humans by using ketamine as a probe. We also examined pathophysiological mechanisms in patients suffering from orofacial neuropathic pain by use of quantitative sensory-testing. In a double-blind study we compared the effects of low...

  10. 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.

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

    OpenAIRE

    de Oliveira Rogério Adas; de Andrade Daniel; Machado André Guelman; Teixeira Manoel

    2012-01-01

    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 ...

  12. 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.

  13. 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.

  14. 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. PMID:24831263

  15. Neuropathic Pain Model of Peripheral Neuropathies Mediated by Mutations of Glycyl-tRNA Synthetase

    OpenAIRE

    Lee, Seo Jin; Seo, Ah Jung; Park, Byung Sun; Jo, Hyun Woo; Huh, Youngbuhm

    2014-01-01

    Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. Previous studies have found that, according to CMT patients, neuropathic pain is an occasional symptom of CMT. However, neuropathic pain is not considered to be a significant symptom associated with CMT and, as a result, no studies have investigated the pathophysiology underlying neuropathic pain in this disorder. Thus, the first animal model of neuropathic pain was developed by our laboratory using a...

  16. Continuous neuropathic pain secondary to endoscopic procedures: report of two cases and review of the literature.

    Science.gov (United States)

    Kalladka, Mythili; Nasri-Heir, Cibele; Eliav, Eli; Ananthan, Sowmya; Viswanath, Archana; Heir, Gary

    2016-08-01

    Neuropathic pain encompasses a spectrum of conditions that can arise from a lesion or dysfunction of the central or the peripheral nervous system, and it may develop at variable intervals after nerve injury or inflammation. Nerve injuries arising from surgical procedures commonly occur secondary to the surgical trauma, and in rare instances they are a complication of intubation during general anesthesia or endoscopic procedures. A series of 2 cases of bilateral glossopharyngeal neuropathic pain subsequent to endoscopic procedures is presented with a review of the literature concerning the mechanisms of development of neuropathic pain after these procedures. The purpose of these case reports is to make dentists aware of the occurrence, the mechanisms of nerve injuries, and the treatment of neuropathic pain after endoscopic procedures. In the first case, the patient had relief of pain with a combination therapy of clonazepam 1.0 mg in divided doses twice daily and gabapentin 300 mg in divided doses 3 times daily. In the second case, the patient had significant relief of pain with a monotherapy of gabapentin 1200 mg in divided doses 3 times daily. PMID:27422430

  17. [Pathophysiology of neuropathic pain: review of experimental models and proposed mechanisms].

    Science.gov (United States)

    Garcia-Larrea, Luis; Magnin, Michel

    2008-02-01

    Neuropathic pain can be conceptualized as the result of an "aberrant learning" process, associated with maladaptive plasticity of the nervous system. A number of modifications of the peripheral nervous system have been described in animal models of neuropathic pain, but their relation with different symptoms in humans is far from fully understood. We note in particular ectopic discharges in damaged myelinated fibers, abnormal activity in undamaged fibers, overexpression of calcium channels increasing the release of excitatory neurotransmitters, and sympathetic sprouting towards the spinal ganglia. Spinal mechanisms involve central sensitization, kindling and potentiation phenomena. Underlying these phenomena may be connectivity changes--still controversial--of non-nociceptive terminals and variations in the sensitivity of postsynaptic receptors. Also contributing to these pathophysiologic modifications are attenuation of spinal inhibition by selective neuronal loss and the development of inflammatory phenomena, including cytokine secretion by macrophages and glial cells. Changes in the dorsal horn modify the activity of projections towards the brainstem and increase spinal hyperactivity still further by feedback loops. These effects are delayed, suggesting that maintenance of spinal sensitization requires the involvement of mechanisms of descending facilitation involving the brainstem. These phenomena induce changes in the activity of thalamocortical networks, which develop autonomous processes that maintain the pain. The cortical representation of body areas change after nervous lesions, and these changes may correlate with the emergence of pain. Neuropathic allodynia and hyperalgesia are supported by cortical modifications that experimental models reproduce very incompletely. Experimental allodynia and neuropathic allodynia share the activation of the cortical pain matrix as well as the bilateralization of insular activity. However, although experimental

  18. Mechanisms and Pharmacology of Neuropathic Pain in Multiple Sclerosis

    OpenAIRE

    Iannitti, T; Kerr, B.J.; Taylor, BK

    2014-01-01

    The neuropathic pain of multiple sclerosis is quite prevalent and severely impacts quality of life. A few randomized, placebo-controlled, blinded clinical trials suggest that cannabis- and anticonvulsant-based treatments provide partial pain relief, but at the expense of adverse events. An even smaller, but emerging, number of translational studies are using rodent models of experimental autoimmune encephalomyelitis (EAE), which exhibit pain-like behaviors resembling those of MS patients. The...

  19. Stress Exacerbates Neuropathic Pain via Glucocorticoid and NMDA Receptor Activation

    OpenAIRE

    Alexander, Jessica K.; DeVries, A. Courtney; KIGERL, KRISTINA A.; Dahlman, Jason M.; G.Popovich, Phillip

    2009-01-01

    There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g. corticosterone; CORT) may interact with effectors of neuropathic pain. To test this hypothesis, mice received a spared nerve injury (SNI) after exposure to 60 min restraint stress. In stressed mice, allodynia was consistently increased. The mechanism(s) underlying the exacerbated pain response involves CORT acting via glucocorticoid receptors (GRs); RU486, ...

  20. Neuropathic Pain: Quality-of-Life Impact, Costs and Cost Effectiveness of Therapy

    OpenAIRE

    Alec B. OConnor

    2009-01-01

    A number of different diseases or injuries can damage the central or peripheral nervous system and produce neuropathic pain (NP), which seems to be more difficult to treat than many other types of chronic pain. As a group, patients with NP have greater medical co-morbidity burden than age- and sex-adjusted controls, which makes determining the humanistic and economic burden attributable to NP challenging. Health-related quality of life (HR-QOL) is substantially impaired among patients with NP...

  1. Central Pain Syndrome

    Science.gov (United States)

    ... Enhancing Diversity Find People About NINDS NINDS Central Pain Syndrome Information Page Table of Contents (click to ... being done? Clinical Trials Organizations What is Central Pain Syndrome? Central pain syndrome is a neurological condition ...

  2. Botulinum toxin - neuropathic pain: Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial.

    Science.gov (United States)

    2016-08-12

    When treated with botulinum toxin A, those patients with peripheral neuropathic pain and allodynia (triggering of pain from stimuli which do not normally provoke pain) at baseline, would appear to have a better outcome. PMID:27514345

  3. 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.

  4. EFNS guidelines on pharmacological treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Attal, Nadine; Cruccu, G; Haanpää, M;

    2006-01-01

    Neuropathic pain treatment remains unsatisfactory despite a substantial increase in the number of trials. This EFNS Task Force aimed at evaluating the existing evidence about the pharmacological treatment of neuropathic pain. Studies were identified using first the Cochrane Database then Medline....... Trials were classified according to the aetiological condition. All class I and II controlled trials (according to EFNS classification of evidence) were assessed, but lower-class studies were considered in conditions that had no top level studies. Only treatments feasible in an outpatient setting were...... 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 for...

  5. 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.

  6. Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain.

    Science.gov (United States)

    Gutierrez, Tannia; Crystal, Jonathon D; Zvonok, Alexander M; Makriyannis, Alexandros; Hohmann, Andrea G

    2011-09-01

    Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB(2) agonist to attenuate a neuropathic pain state. Self-medication of the CB(2) agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal thresholds in sham-operated or naive animals. The percentage of active lever responding was similar in naive groups self-administering vehicle or (R,S)-AM1241. The CB(2) antagonist SR144528 blocked both antiallodynic effects of (R,S)-AM1241 self-medication and the percentage of active lever responding in neuropathic (but not naive) rats. Neuropathic and sham groups exhibited similar percentages of active lever responding for (R,S)-AM1241 on a fixed ratio 1 (FR1) schedule. However, neuropathic animals worked harder than shams to obtain (R,S)-AM1241 when the schedule of reinforcement was increased (to FR6). (R,S)-AM1241 self-medication on FR1, FR3, or FR6 schedules attenuated nerve injury-induced mechanical allodynia. (R,S)-AM1241 (900μg intravenously) failed to produce motor ataxia observed after administration of the mixed CB(1)/CB(2) agonist WIN55,212-2 (0.5mg/kg intravenously). Our results suggest that cannabinoid CB(2) agonists may be exploited to treat neuropathic pain with limited drug abuse liability and central nervous system side effects. These studies validate the use of drug self-administration methods for identifying nonpsychotropic analgesics possessing limited abuse potential. These methods offer potential to elucidate novel analgesics that suppress spontaneous neuropathic pain that is not measured by traditional assessments of evoked pain. PMID:21550725

  7. Voltage-Gated Ion Channels in the PNS: Novel Therapies for Neuropathic Pain?

    Science.gov (United States)

    Tibbs, Gareth R; Posson, David J; Goldstein, Peter A

    2016-07-01

    Neuropathic pain arises from injury to the nervous system. Conditions associated with neuropathic pain are diverse, and lesions and/or pathological changes in the central nervous system (CNS) or peripheral nervous system (PNS) can frequently, but not always, be identified. It is difficult to treat, with patients often on multiple, different classes of medications, all with appreciable adverse side effect profiles. Consequently, there is a pressing need for the development of new medications. The development of such therapeutics is predicated on a clear understanding of the relevant molecular and cellular processes that contribute to the development, and maintenance, of the neuropathic pain state. One proposed mechanism thought to contribute to the ontogeny of neuropathic pain is altered expression, trafficking, and functioning of ion channels expressed by primary sensory neurons. Here, we will focus on three voltage-gated ion channel families, CaV, HCN, and NaV, first reviewing the preclinical data and then the human data where it exists. PMID:27233519

  8. 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.

  9. Neuropathic changes in equine laminitis pain

    OpenAIRE

    Jones, Emma; Vinuela-Fernandez, Nacho; Eager, Rachel A; Delaney, Ada; Anderson, Heather; Patel, Anisha; Robertson, Darren C; Allchorne, Andrew; Sirinathsinghji, Eva C; Milne, Elspeth M.; MacIntyre, Neil; Darren J Shaw; Waran, Natalie K; Mayhew, Joe; Fleetwood-Walker, Susan M

    2007-01-01

    Laminitis is a common debilitating disease in horses that involves painful disruption of the lamellar dermo-epidermal junction within the hoof. This condition is often refractory to conventional anti-inflammatory analgesia and results in unremitting pain, which in severe cases requires euthanasia. The mechanisms underlying pain in laminitis were investigated using quantification of behavioural pain indicators in conjunction with histological studies of peripheral nerves innervating the hoof. ...

  10. Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside

    OpenAIRE

    Rahn, Elizabeth J; Hohmann, Andrea G.

    2009-01-01

    Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the c...

  11. 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

  12. Role of microglia in neuropathic pain, postoperative pain, and morphine tolerance

    OpenAIRE

    Wen, Yeong-Ray; Tan, Ping-Heng; Cheng, Jen-Kun; Liu, Yen-Chin; Ji, Ru-Rong

    2011-01-01

    Management of chronic pain such as nerve injury-induced neuropathic pain associated with diabetic neuropathy, viral infection, and cancer is a real clinical challenge. Major surgeries such as breast and thoracic surgery, leg amputation, and coronary artery bypass surgery also lead to chronic pain in 10–50% of individuals after acute postoperative pain, in part due to surgery-induced nerve injury. Current treatments mainly focus on blocking neurotransmission in the pain pathway and have only r...

  13. Emerging Relationships between Exercise, Sensory Nerves, and Neuropathic Pain.

    Science.gov (United States)

    Cooper, Michael A; Kluding, Patricia M; Wright, Douglas E

    2016-01-01

    The utilization of physical activity as a therapeutic tool is rapidly growing in the medical community and the role exercise may offer in the alleviation of painful disease states is an emerging research area. The development of neuropathic pain is a complex mechanism, which clinicians and researchers are continually working to better understand. The limited therapies available for alleviation of these pain states are still focused on pain abatement and as opposed to treating underlying mechanisms. The continued research into exercise and pain may address these underlying mechanisms, but the mechanisms which exercise acts through are still poorly understood. The objective of this review is to provide an overview of how the peripheral nervous system responds to exercise, the relationship of inflammation and exercise, and experimental and clinical use of exercise to treat pain. Although pain is associated with many conditions, this review highlights pain associated with diabetes as well as experimental studies on nerve damages-associated pain. Because of the global effects of exercise across multiple organ systems, exercise intervention can address multiple problems across the entire nervous system through a single intervention. This is a double-edged sword however, as the global interactions of exercise also require in depth investigations to include and identify the many changes that can occur after physical activity. A continued investment into research is necessary to advance the adoption of physical activity as a beneficial remedy for neuropathic pain. The following highlights our current understanding of how exercise alters pain, the varied pain models used to explore exercise intervention, and the molecular pathways leading to the physiological and pathological changes following exercise intervention. PMID:27601974

  14. Tetrodotoxin-resistant sodium channels in neuropathic pain

    OpenAIRE

    Fjell Hjelmström, Jenny

    2000-01-01

    Injury to the peripheral nervous system can cause neuropathic pain. Abnormal sodium channel activity has been implicated as a source of ectopic firing and changes in nociceptive threshold following nerve injury. Primary sensory neurons exhibit at least two types of sodium currents: rapidly inactivating tetrodotoxin-sensitive (TTX-S) and slowly inactivating TTX-resistant (TTX-R) sodium currents. Two TTX-R sodium channels that are expressed in primary sensory neurons have been...

  15. Duloxetine in the management of diabetic peripheral neuropathic pain

    OpenAIRE

    Boomershine, Chad

    2011-01-01

    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 tr...

  16. Effect of Sildenafil on Neuropathic Pain and Hemodynamics in Rats

    OpenAIRE

    Huang, Lan Ji; Yoon, Myung Ha; Choi, Jeong IL; Kim, Woong Mo; Lee, Hyung Gon; Kim, Yeo Ok

    2009-01-01

    Purpose The inhibition of phosphodiesterase 5 produces an antinociception through the increase of cyclic guanosine monophosphate (cGMP), and increasing cGMP levels enhance the release of γ-aminobutyric acid (GABA). Furthermore, this phosphodiesterase 5 plays a pivotal role in the regulation of the vasodilatation associated to cGMP. In this work, we examined the contribution of GABA receptors to the effect of sildenafil, a phosphodiesterase 5 inhibitor, in a neuropathic pain rat, and assessed ...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    In neuropathic pain with irritable nociceptor phenotype, up-regulation of sodium channels on nociceptors is supposed to be an important pain mechanism that may be targeted by topical sodium channel blockade. This randomised, double-blind, phenotype-panel, cross-over study with 4-week treatment...... patients with irritable nociceptor and 25 patients with non-irritable nociceptor. In the total sample, lidocaine reduced pain by 0.3 NRS points (95% CI 0.1;0.5) and pain-related sleep disturbance by 0.6 points (95% CI 0.4;0.8) more than placebo (p=0.007 and p<0.001), and relieved pain by 0.4 verbal score...

  18. Pharmacoresistant neuropathic pain: Role of proper assessment in the understanding and tactics of correction

    Directory of Open Access Journals (Sweden)

    Maksim Valeryevich Churyukanov

    2013-11-01

    Full Text Available The paper gives information on the state-of-the-art of pharmacoresistant neuropathic pain (PNP. It presents the definitions of PNP, which make it possible to accurately identify such patients and to plan tactics for their treatment. Similarities and differences in scales and questionnaires for the valid identification of a neuropathic pain component are discussed. General information is given on international guidelines for the treatment of neuropathic pain, the use of stepwise therapy, and indications for neurostimulation.

  19. Are Spinal GABAergic Elements Related to the Manifestation of Neuropathic Pain in Rat?

    OpenAIRE

    Lee, Jaehee; Back, Seung Keun; Lim, Eun Jeong; Cho, Gyu Chong; Kim, Myung Ah; Kim, Hee Jin; Lee, Min Hee; Na, Heung Sik

    2010-01-01

    Impairment in spinal inhibition caused by quantitative alteration of GABAergic elements following peripheral nerve injury has been postulated to mediate neuropathic pain. In the present study, we tested whether neuropathic pain could be induced or reversed by pharmacologically modulating spinal GABAergic activity, and whether quantitative alteration of spinal GABAergic elements after peripheral nerve injury was related to the impairment of GABAergic inhibition or neuropathic pain. To these ai...

  20. 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.

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

    Science.gov (United States)

    Intiso, Domenico; Basciani, Mario; Santamato, Andrea; Intiso, Marta; Di Rienzo, Filomena

    2015-01-01

    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 including post

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

    Science.gov (United States)

    Intiso, Domenico; Basciani, Mario; Santamato, Andrea; Intiso, Marta; Di Rienzo, Filomena

    2015-07-01

    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 including post

  3. 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

  4. A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain

    Science.gov (United States)

    Wilsey, Barth; Marcotte, Thomas; Tsodikov, Alexander; Millman, Jeanna; Bentley, Heather; Gouaux, Ben; Fishman, Scott

    2016-01-01

    The Food and Drug Administration (FDA), Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute for Drug Abuse (NIDA) report that no sound scientific studies support the medicinal use of cannabis. Despite this lack of scientific validation, many patients routinely use “medical marijuana,” and in many cases this use is for pain related to nerve injury. We conducted a double-blinded, placebo-controlled, crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain. Thirty-eight patients with central and peripheral neuropathic pain underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis. In addition to the primary outcome of pain intensity, secondary outcome measures included evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance. A mixed linear model demonstrated an analgesic response to smoking cannabis. No effect on evoked pain was seen. Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly with memory, at higher doses. PMID:18403272

  5. Mechanisms and pharmacology of neuropathic pain in multiple sclerosis.

    Science.gov (United States)

    Iannitti, T; Kerr, B J; Taylor, B K

    2014-01-01

    The neuropathic pain of multiple sclerosis is quite prevalent and severely impacts quality of life. A few randomized, placebo-controlled, blinded clinical trials suggest that cannabis- and anticonvulsant-based treatments provide partial pain relief, but at the expense of adverse events. An even smaller, but emerging, number of translational studies are using rodent models of experimental autoimmune encephalomyelitis (EAE), which exhibit pain-like behaviors resembling those of Multiple sclerosis (MS) patients. These studies not only support the possible effectiveness of anticonvulsants, but also compel further clinical trials with serotonin-norepinephrine reuptake inhibitors, the immunosuppressant drug rapamycin, or drugs which interfere with glutamatergic neurotransmission. Future behavioral studies in EAE models are essential toward a new pharmacotherapy of multiple sclerosis pain. PMID:24590824

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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

  8. Classification of neuropathic pain in cancer patients

    DEFF Research Database (Denmark)

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

    2014-01-01

    and on the relevance of patient-reported outcome (PRO) descriptors for the screening of NP in this population. An international group of 42 experts was invited to participate in a consensus process through a modified 2-round Internet-based Delphi survey. Relevant topics investigated were...... good agreement was found on the statement "the pathophysiology of NP due to cancer can be different from non-cancer NP" (MED=9, IQR=2). Satisfactory consensus was reached for the first 3 NeuPSIG criteria (pain distribution, history, and sensory findings; MEDs⩾8, IQRs⩽3), but not for the fourth one...

  9. 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

  10. 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

    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 and......, it is presently illegal to drive when using Sativex, which impedes the inclusion of patients....

  11. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside.

    Science.gov (United States)

    Rahn, Elizabeth J; Hohmann, Andrea G

    2009-10-01

    Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the clinical and preclinical literature. Neuropathic pain associated with nerve injury, diabetes, chemotherapeutic treatment, human immunodeficiency virus, multiple sclerosis, and herpes zoster infection is considered. In animals, cannabinoids attenuate neuropathic nociception produced by traumatic nerve injury, disease, and toxic insults. Effects of mixed cannabinoid CB(1)/CB(2) agonists, CB(2) selective agonists, and modulators of the endocannabinoid system (i.e., inhibitors of transport or degradation) are compared. Effects of genetic disruption of cannabinoid receptors or enzymes controlling endocannabinoid degradation on neuropathic nociception are described. Specific forms of allodynia and hyperalgesia modulated by cannabinoids are also considered. In humans, effects of smoked marijuana, synthetic Delta(9)-THC analogs (e.g., Marinol, Cesamet) and medicinal cannabis preparations containing both Delta(9)-THC and cannabidiol (e.g., Sativex, Cannador) in neuropathic pain states are reviewed. Clinical studies largely affirm that neuropathic pain patients derive benefits from cannabinoid treatment. Subjective (i.e., rating scales) and objective (i.e., stimulus-evoked) measures of pain and quality of life are considered. Finally, limitations of cannabinoid pharmacotherapies are discussed together with directions for future research. PMID:19789075

  12. 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.

  13. Alpha lipoic acid : a new treatment for neuropathic pain in patients with diabetes?

    NARCIS (Netherlands)

    Mijnhout, G. S.; Alkhalaf, A.; Kleefstra, N.; Bibo, H. J. G.

    2010-01-01

    Background: Neuropathic pain is difficult to treat. We identified those studies in the literature in which the effectiveness of alpha lipoic acid as a treatment for neuropathic pain was evaluated. Methods: Systematic literature review. The databases MEDLINE and EMBASE were searched using the keyword

  14. 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 formulat...

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

    Directory of Open Access Journals (Sweden)

    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 .

  16. Lysophosphatidic acid (LPA) signaling in neuropathic pain development and Schwann cell biology

    OpenAIRE

    Lin, Mu-En

    2012-01-01

    Neuropathic pain is a chonic pain state caused by lesions or diseases in the nervous system. Unlike acute pain, neuropathic pain persists without obvious injury or stimuli and can severely interfere with normal daily life for those who suffer from it. Despite numerous efforts on studying its mechanism and possible treatments, there is no effective treatment currently available to remove or alleviate this symptom. This dissertation aims to provide further understanding into the relationship be...

  17. Are the emergence of affective disturbances in neuropathic pain states contingent on supraspinal neuroinflammation?

    Science.gov (United States)

    Fiore, Nathan T; Austin, Paul J

    2016-08-01

    Neuro-immune interactions contribute to the pathogenesis of neuropathic pain due to peripheral nerve injury. A large body of preclinical evidence supports the idea that the immune system acts to modulate the sensory symptoms of neuropathy at both peripheral and central nervous system sites. The potential involvement of neuro-immune interactions in the highly debilitating affective disturbances of neuropathic pain, such as depression, anhedonia, impaired cognition and reduced motivation has received little attention. This is surprising given the widely accepted view that sickness behaviour, depression, cognitive impairment and other neuropsychiatric conditions can arise from inflammatory mechanisms. Moreover, there is a set of well-described immune-to-brain transmission mechanisms that explain how peripheral inflammation can lead to supraspinal neuroinflammation. In the last 5years increasing evidence has emerged that peripheral nerve injury induces supraspinal changes in cytokine or chemokine expression and alters glial cell activity. In this systematic review, based on strong preclinical evidence, we advance the argument that the emergence of affective disturbances in neuropathic pain states are contingent on pro-inflammatory mediators in the interconnected hippocampal-medial prefrontal circuitry that subserve affective behaviours. We explore how dysregulation of inflammatory mediators in these networks may result in affective disturbances through a wide variety of neuromodulatory mechanisms. There are also promising results from clinical trials showing that anti-inflammatory agents have efficacy in the treatment of a variety of neuropsychiatric conditions including depression and appear suited to sub-groups of patients with elevated pro-inflammatory profiles. Thus, although further research is required, aggressively targeting supraspinal pro-inflammatory mediators at critical time-points in appropriate clinical populations is likely to be a novel avenue to treat

  18. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis.

    Science.gov (United States)

    Langford, R M; Mares, J; Novotna, A; Vachova, M; Novakova, I; Notcutt, W; Ratcliffe, S

    2013-04-01

    Central neuropathic pain (CNP) occurs in many multiple sclerosis (MS) patients. The provision of adequate pain relief to these patients can very difficult. Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP. Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment, in a double-blind manner, for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain. This parallel-group phase of the study was then followed by an 18-week randomized-withdrawal study (14-week open-label treatment period plus a double-blind 4-week randomized-withdrawal phase) to investigate time to treatment failure and show maintenance of efficacy. A total of 339 patients were randomized to phase A (167 received THC/CBD spray and 172 received placebo). Of those who completed phase A, 58 entered the randomized-withdrawal phase. The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met, with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo (p = 0.234). However, an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point (p = 0.046). During the randomized-withdrawal phase, the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray, with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group (p = 0.04). The mean change from baseline in Pain Numerical Rating Scale (NRS) (p = 0.028) and sleep quality NRS (p = 0.015) scores, both secondary endpoints in phase B, were also statistically

  19. Methylcobalamin ameliorates neuropathic pain induced by vincristine in rats

    Science.gov (United States)

    Xu, Jing; Wang, Wei; Zhong, Xiong-Xiong; Feng, Yi-Wei; Liu, Xian-Guo

    2016-01-01

    Background Vincristine, a widely used chemotherapeutic agent, often induces painful peripheral neuropathy and there are currently no effective drugs to prevent or treat this side effect. Previous studies have shown that methylcobalamin has potential analgesic effect in diabetic and chronic compression of dorsal root ganglion model; however, whether methylcobalamin has effect on vincristine-induced painful peripheral neuropathy is still unknown. Results We found that vincristine-induced mechanical allodynia and thermal hyperalgesia, accompanied by a significant loss of intraepidermal nerve fibers in the plantar hind paw skin and an increase in the incidence of atypical mitochondria in the sciatic nerve. Moreover, in the spinal dorsal horn, the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the protein expression of p-p65 as well as tumor necrosis factor α was increased, whereas the protein expression of IL-10 was decreased following vincristine treatment. Furthermore, intraperitoneal injection of methylcobalamin could dose dependently attenuate vincristine-induced mechanical allodynia and thermal hyperalgesia, which was associated with intraepidermal nerve fibers rescue, and atypical mitochondria prevalence decrease in the sciatic nerve. Moreover, methylcobalamin inhibited the activation of NADPH oxidase and the downstream NF-κB pathway. Production of tumor necrosis factor α was also decreased and production of IL-10 was increased in the spinal dorsal horn following methylcobalamin treatment. Intrathecal injection of Phorbol-12-Myristate-13-Acetate, a NADPH oxidase activator, could completely block the analgesic effect of methylcobalamin. Conclusions Methylcobalamin attenuated vincrinstine-induced neuropathic pain, which was accompanied by inhibition of intraepidermal nerve fibers loss and mitochondria impairment. Inhibiting the activation of NADPH oxidase and the downstream NF-κB pathway, resulting in the rebalancing of

  20. Pain treatment with ziconotide and baclofen in a case of spasticity associated with neuropathic pain

    OpenAIRE

    Danilo G. Quarta; Allegra Cionini Ciardi; Daniela Clerici; Patrizia Spina; Luigi Parigi

    2009-01-01

    This study presents the clinical case of a patient with paraparesis, subjected for a long period of time to treatment with intrathecal baclofen and morphine to control spasticity and neuropathic pain, resulting from spinal cord injury due to road trauma. After several years of treatment the pain was not controlled with high doses of intrathecal morphine combined with transmucosal fentanyl that were given when needed. It was therefore decided to switch to intrathecal ziconotide. Starting with ...

  1. Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society

    OpenAIRE

    Moulin, DE; Boulanger, A; AJ Clark; Clarke, H.; Dao, T; GA Finley; Furlan, A.; Gilron, I; Gordon, A.; PK Morley-Forster; BJ Sessle; Squire, P; Stinson, J; Taenzer, P.; Velly, A

    2014-01-01

    BACKGROUND: Neuropathic pain (NeP), redefined as pain caused by a lesion or a disease of the somatosensory system, is a disabling condition that affects approximately two million Canadians. OBJECTIVE: To review the randomized controlled trials (RCTs) and systematic reviews related to the pharmacological management of NeP to develop a revised evidence-based consensus statement on its management. METHODS: RCTs, systematic reviews and existing guidelines on the pharmacological management of NeP ...

  2. 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

  3. Forced-exercise delays neuropathic pain in experimental diabetes: effects on voltage-activated calcium channels.

    Science.gov (United States)

    Shankarappa, Sahadev A; Piedras-Rentería, Erika S; Stubbs, Evan B

    2011-07-01

    Physical exercise produces a variety of psychophysical effects, including altered pain perception. Elevated levels of centrally produced endorphins or endocannabinoids are implicated as mediators of exercise-induced analgesia. The effect of exercise on the development and persistence of disease-associated acute/chronic pain remains unclear. In this study, we quantified the physiological consequence of forced-exercise on the development of diabetes-associated neuropathic pain. Euglycemic control or streptozotocin (STZ)-induced diabetic adult male rats were subdivided into sedentary or forced-exercised (2-10 weeks, treadmill) subgroups and assessed for changes in tactile responsiveness. Two weeks following STZ-treatment, sedentary rats developed a marked and sustained hypersensitivity to von Frey tactile stimulation. By comparison, STZ-treated diabetic rats undergoing forced-exercise exhibited a 4-week delay in the onset of tactile hypersensitivity that was independent of glucose control. Exercise-facilitated analgesia in diabetic rats was reversed, in a dose-dependent manner, by naloxone. Small-diameter (exercise attenuated diabetes-associated changes in HVA Ca(2+) current density while preventing the depolarizing shift in steady-state inactivation of LVA Ca(2+) currents. Forced-exercise markedly delays the onset of diabetes-associated neuropathic pain, in part, by attenuating associated changes in HVA and LVA Ca(2+) channel function within small-diameter DRG neurons possibly by altering opioidergic tone. PMID:21554321

  4. Duloxetine in the management of diabetic peripheral neuropathic pain

    Directory of Open Access Journals (Sweden)

    Boomershine CS

    2011-07-01

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

  5. Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain.

    Science.gov (United States)

    Kim, Sun Kwang; Hayashi, Hideaki; Ishikawa, Tatsuya; Shibata, Keisuke; Shigetomi, Eiji; Shinozaki, Youichi; Inada, Hiroyuki; Roh, Seung Eon; Kim, Sang Jeong; Lee, Gihyun; Bae, Hyunsu; Moorhouse, Andrew J; Mikoshiba, Katsuhiko; Fukazawa, Yugo; Koizumi, Schuichi; Nabekura, Junichi

    2016-05-01

    Long-term treatments to ameliorate peripheral neuropathic pain that includes mechanical allodynia are limited. While glial activation and altered nociceptive transmission within the spinal cord are associated with the pathogenesis of mechanical allodynia, changes in cortical circuits also accompany peripheral nerve injury and may represent additional therapeutic targets. Dendritic spine plasticity in the S1 cortex appears within days following nerve injury; however, the underlying cellular mechanisms of this plasticity and whether it has a causal relationship to allodynia remain unsolved. Furthermore, it is not known whether glial activation occurs within the S1 cortex following injury or whether it contributes to this S1 synaptic plasticity. Using in vivo 2-photon imaging with genetic and pharmacological manipulations of murine models, we have shown that sciatic nerve ligation induces a re-emergence of immature metabotropic glutamate receptor 5 (mGluR5) signaling in S1 astroglia, which elicits spontaneous somatic Ca2+ transients, synaptogenic thrombospondin 1 (TSP-1) release, and synapse formation. This S1 astrocyte reactivation was evident only during the first week after injury and correlated with the temporal changes in S1 extracellular glutamate levels and dendritic spine turnover. Blocking the astrocytic mGluR5-signaling pathway suppressed mechanical allodynia, while activating this pathway in the absence of any peripheral injury induced long-lasting (>1 month) allodynia. We conclude that reawakened astrocytes are a key trigger for S1 circuit rewiring and that this contributes to neuropathic mechanical allodynia. PMID:27064281

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

    Directory of Open Access Journals (Sweden)

    Estrella Lasry-Levy

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

  7. Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction.

    Science.gov (United States)

    Chen, Jeremy Tsung-chieh; Guo, Da; Campanelli, Dario; Frattini, Flavia; Mayer, Florian; Zhou, Luming; Kuner, Rohini; Heppenstall, Paul A; Knipper, Marlies; Hu, Jing

    2014-01-01

    The gate control theory proposes the importance of both pre- and post-synaptic inhibition in processing pain signal in the spinal cord. However, although postsynaptic disinhibition caused by brain-derived neurotrophic factor (BDNF) has been proved as a crucial mechanism underlying neuropathic pain, the function of presynaptic inhibition in acute and neuropathic pain remains elusive. Here we show that a transient shift in the reversal potential (EGABA) together with a decline in the conductance of presynaptic GABAA receptor result in a reduction of presynaptic inhibition after nerve injury. BDNF mimics, whereas blockade of BDNF signalling reverses, the alteration in GABAA receptor function and the neuropathic pain syndrome. Finally, genetic disruption of presynaptic inhibition leads to spontaneous development of behavioural hypersensitivity, which cannot be further sensitized by nerve lesions or BDNF. Our results reveal a novel effect of BDNF on presynaptic GABAergic inhibition after nerve injury and may represent new strategy for treating neuropathic pain. PMID:25354791

  8. TMEM16F Regulates Spinal Microglial Function in Neuropathic Pain States

    Directory of Open Access Journals (Sweden)

    Laura Batti

    2016-06-01

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

  9. Dental impaction pain model as a potential tool to evaluate drugs with efficacy in neuropathic pain.

    Science.gov (United States)

    Malmstrom, Kerstin; Kotey, Paul; McGratty, Megan; Ramakrishnan, Rohini; Gottesdiener, Keith; Reicin, Alise; Wagner, John A

    2006-08-01

    Intravenous lidocaine, a nonspecific Na-channel blocker, was used to assess the dental impaction model for evaluation of neuropathic pain drugs. Sixty patients, experiencing moderate or severe pain after removal of > or = 2 third molars, were randomized (2:2:1:1) to lidocaine (4 mg/kg; maximal dose 300 mg), oxycodone/acetaminophen (10/650 mg), placebo, and active placebo (diphenhydramine, 50 mg). Lidocaine provided a modest degree of pain relief. Predefined endpoints of total pain relief and sum of pain intensity at 2, 4, and 6 hours showed numerically, not statistically significantly, greater pain relief versus placebo. A significantly greater effect over placebo was observed in peak effect and at shorter time points (30 minutes and 1 hour), consistent with the pharmacokinetic profile (plasma concentration of approximately 2 mug/mL). Oxycodone/acetaminophen provided significantly greater analgesia versus placebo, validating study conduct, and significantly greater pain relief was observed versus lidocaine, which is consistent with a smaller portion of dental extraction pain being of neuropathic origin. PMID:16855076

  10. The effects of spinal cord stimulation on the neuronal activity of the brain in patients with chronic neuropathic pain

    International Nuclear Information System (INIS)

    The effects of spinal cord stimulation (SCS) on the neuronal activity of the brain were examined by single photon emission computed tomography (SPECT) in patients with chronic neuropathic pain. Regional cerebral blood flow (CBF) in each cortical area and the thalamus decreased in several patients without SCS. Patients with central pain due to thalamic hemorrhage showed a decrease in rCBF in the thalamus contralateral to the painful side. During the stimulation period in SCS, parietal rCBF decreased on the side contralateral to the pain. In contrast, rCBF increased in the bilateral frontal and anterior cingulate cortex and in the contralateral temporal lobe in half of the patients in whom SCS was effective in relieving pain. The decrease in thalamic rCBF in two patients with central pain was improved by the SCS therapy; however, pain was relieved in only one of them. In the majority of patients in whom SCS was not effective, there was no change in rCBF in various cortical areas, even after SCS. These results suggest that, in patients with chronic neuropathic pain, SCS modulates the neuronal activities of several brain areas that are believed to be associated with pain processing. (author)

  11. A burden of illness study for neuropathic pain in Europe

    Directory of Open Access Journals (Sweden)

    Liedgens H

    2016-04-01

    Full Text Available Hiltrud Liedgens,1 Marko Obradovic,1 Jonathan De Courcy,2 Timothy Holbrook,2 Rafal Jakubanis2 1Grunenthal, Aachen, Germany; 2Adelphi Real World, Bollington, Cheshire, UK Purpose: Neuropathic pain (NP is often severe and represents a major humanistic and economic burden. This study aimed at providing insight on this burden across France, Germany, Italy, Spain, and the UK, considering direct and indirect costs, productivity loss, and humanistic impact on patients and their families. Methods: Physician questionnaires provided data on patients presenting with NP covering demographics, sick leave and retirement, number of consultations, drug treatments, and surgical procedures. Patients provided further demographic and disease-related data and completed the Work Productivity and Activity Impairment (WPAI, the EuroQol 5-Dimension (EQ-5D, and the Brief Pain Inventory (BPI questionnaires. All health-related direct unitary costs were collected from relevant country-specific sources and adjusted to 2012 prices (€ where necessary. A subgroup analysis of costs based on diabetic peripheral neuropathy (n=894, fibromyalgia (n=300, and low back pain (n=963 was performed. Findings: About 413 physicians completed a total of 3,956 patient records forms. Total annual direct health-care costs per patient ranged from €1,939 (Italy to €3,131 (Spain. Annual professional caregiver costs ranged from €393 (France to €1,242 (UK, but this only represented a small proportion of total care because much care is provided by family or friends. Sick leave costs ranged from €5,492 (UK to €7,098 (France, with 10%–32% patients prevented from working at some point by NP. Total cost (including direct and indirect costs of NP per patient was €10,313 in France (69% of the total cost, €14,446 in Germany (78%, €9,305 in Italy (69%, €10,597 in Spain (67%, and €9,685 in the UK (57%. Indirect costs (ie, sick leave constituted the majority of costs in all five

  12. Frequency, character, intensity and impact of neuropathic pain in a cohort of spinal cord injury patients

    International Nuclear Information System (INIS)

    The purpose of this study was to determine frequency, character, approximate location and intensity of neuropathic pain in spinal cord injury and its impact on the quality of life. Study Design: A cross-sectional survey Place and Duration of Study: Armed Forces Institute of Rehabilitation Medicine (AFIRM), Rawalpindi from Feb 2009 to Feb 2010. Material and Methods: Through non-probability convenience sampling 87 patients of both genders diagnosed with spinal cord injury based on American Spinal Injury Association criteria and admitted within a year of injury were included. Those in spinal shock, having poor cognition, inability to communicate, concurrent brain injury and history of chronic pain before injury were excluded. The history, localization and characteristics of the pain and interference with life activities were recorded. Neuropathic pain of patients was evaluated with Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale. Visual analogue scale was used to measure the severity of pain. Results: Out of 87 patients (mean age 36.9 years) seventy four were male and 13 were female. Seventy patients (80%) were AIS-A, 6 (7%) were AIS-B and 11 (13%) were AIS-C. Neuropathic pain was present in 57.5% (n=50). Most of the patients localized their pain below the neurological level of injury (78%) and rated pain intensity as moderate pain (54%). Majority (48%) described the pain as burning followed by electric shock like (42%), stabbing (8%) and pricking (2%). 48% patients reported that their quality of life was affected due to pain. 52% required two analgesics of different groups to relieve pain followed by 40% requiring three analgesics and 8% requiring one analgesic. Conclusion: Neuropathic pain is prevalent in people with spinal cord injury and adversely affects life quality. Neuropathic pain is primarily described as a burning sensation of moderate intensity mostly referred to below the neurological level of injury. (author)

  13. Carbon Monoxide Reduces Neuropathic Pain and Spinal Microglial Activation by Inhibiting Nitric Oxide Synthesis in Mice

    OpenAIRE

    Hervera, Arnau; Leánez, Sergi; Negrete, Roger; Motterlini, Roberto; Pol, Olga

    2012-01-01

    BACKGROUND: Carbon monoxide (CO) synthesized by heme oxygenase 1 (HO-1) exerts antinociceptive effects during inflammation but its role during neuropathic pain remains unknown. Our objective is to investigate the exact contribution of CO derived from HO-1 in the modulation of neuropathic pain and the mechanisms implicated. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the antiallodynic and antihyperalgesic effects of CO following sciatic nerve injury in wild type (WT) or inducible nitric oxide...

  14. Suppression of microRNA-155 attenuates neuropathic pain by regulating SOCS1 signalling pathway.

    Science.gov (United States)

    Tan, Yi; Yang, Jun; Xiang, Kai; Tan, Qindong; Guo, Qulian

    2015-03-01

    Chronic neuropathic pain is an unfavourable pathological pain characterised by allodynia and hyperalgesia which has brought considerable trouble to people's physical and mental health, but effective therapeutics are still lacking. MicroRNAs (miRNAs) have been widely studied in the development of neuropathic pain and neuronal inflammation. Among various miRNAs, miR-155 has been widely studied. It is intensively involved in regulating inflammation-associated diseases. However, the role of miR-155 in regulating neuropathic pain development is poorly understood. In the present study, we aimed to investigate whether miR-155 is associated with neuropathic pain and delineate the underlying mechanism. Using a neuropathic pain model of chronic constriction injury (CCI), miR-155 expression levels were markedly increased in the spinal cord. Inhibition of miR-155 significantly attenuated mechanical allodynia, thermal hyperalgesia and proinflammatory cytokine expression. We also demonstrated that miR-155 directly bound with the 3'-untranslated region of the suppressor of cytokine signalling 1 (SOCS1). The expression of SOCS1 significantly decreased in the CCI rat model, but this effect could be reversed by miR-155 inhibition. Furthermore, knockdown of SOCS1 abrogated the inhibitory effects of miR-155 inhibition on neuropathic development and neuronal inflammation. Finally, we demonstrated that inhibition of miR-155 resulted in the suppression of nuclear factor-κB and p38 mitogen-activated protein kinase activation by mediating SOCS1. Our data demonstrate the critical role of miR-155 in regulating neuropathic pain through SOCS1, and suggest that miR-155 may be an important and potential target in preventing neuropathic pain development. PMID:25488154

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

    OpenAIRE

    Swetha Kanyadhara; Sujatha Dodoala; Sunitha Sampathi; Priyanka Punuru; Gopichand Chinta

    2014-01-01

    Background: Aloe vera is being used since ages by human kind for treating various ailments including various inflammatory conditions, but scientific validation has not been done for analgesic activity against neuropathic pain. Objective: The current study was designed to systematically evaluate the therapeutic potential of the ethanolic extract of A. vera (EEAV) against sciatic nerve ligation (SCNL) induced neuropathic pain. Materials and Methods: Nociceptive threshold of EEAV against...

  16. N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases.

    Science.gov (United States)

    Li, Jiajie; Xu, Lujie; Deng, Xueting; Jiang, Chunyi; Pan, Cailong; Chen, Lu; Han, Yuan; Dai, Wenling; Hu, Liang; Zhang, Guangqin; Cheng, Zhixiang; Liu, Wentao

    2016-08-01

    The treatment of neuropathic pain remains a clinical challenge because of its unclear mechanisms and broad clinical morbidity. Matrix metalloproteinase (MMP)-9 and MMP-2 have previously been described as key components in neuropathic pain because of their facilitation of inflammatory cytokine maturation and induction of neural inflammation. Therefore, the inhibition of MMPs may represent a novel therapeutic approach to the treatment of neuropathic pain. In this study, we report that N-acetyl-cysteine (NAC), which is a broadly used respiratory drug, significantly attenuates neuropathic pain through a unique mechanism of MMP inhibition. Both the in vitro (0.1 mM) and in vivo application of NAC significantly suppressed the activity of MMP-9/2. Orally administered NAC (50, 100, and 200 mg/kg) not only postponed the occurrence but also inhibited the maintenance of chronic constrictive injury (CCI)-induced neuropathic pain in rats. The administration of NAC blocked the maturation of interleukin-1β, which is a critical substrate of MMPs, and markedly suppressed the neuronal activation induced by CCI, including inhibiting the phosphorylation of protein kinase Cγ, NMDAR1, and mitogen-activated protein kinases. Finally, NAC significantly inhibited CCI-induced microglia activation but elicited no notable effects on astrocytes. These results demonstrate an effective and safe approach that has been used clinically to alleviate neuropathic pain through the powerful inhibition of the activation of MMPs. PMID:27075430

  17. Duloxetine in the management of diabetic peripheral neuropathic pain.

    Science.gov (United States)

    Ormseth, Michelle J; Scholz, Beth A; Boomershine, Chad S

    2011-01-01

    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. PMID:21845034

  18. Duloxetine in the management of diabetic peripheral neuropathic pain

    Science.gov (United States)

    Ormseth, Michelle J; Scholz, Beth A; Boomershine, Chad S

    2011-01-01

    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. PMID:21845034

  19. Prevalence of Neuropathic Pain in Radiotherapy Oncology Units

    International Nuclear Information System (INIS)

    Purpose: Neuropathic pain (NP) in cancer patients severely impacts quality of life. Radiotherapy (RT) may cause NP, and at the same time, cancer patients visit RT units for pain relief. NP prevalence at these sites and current analgesic treatment should be assessed to improve management. Methods and Materials: This epidemiological, prospective, multicenter study was undertaken to assess NP prevalence, according to Douleur Neuropathique 4 questions questtionaire (DN4) test results, and analgesic management in cancer pain patients visiting RT oncologic units. Secondary analyses assessed NP etiology and pain intensity (using the Brief Pain Inventory-Short Form) and impact (using the Hospital Anxiety and Depression Scale (HADS), Medical Outcomes Study [MOS] for Sleep, and the Health Survey Short Form-12). Results: A total of 1,098 patients with any kind of pain were registered. NP prevalence was 31.1% (95% confidence interval, 28.4%--33.9%); 291 NP patients (mean age, 62.2 ±12.5 years and 57.7% men) were eligible for study; 49% of patients were overweight. The most frequent tumors were those of breast and lung, and stage IIIB was the most common cancer stage. The tumors caused 75% of NP cases. Anxiety, sleepiness, and depression were common. At 8 weeks, pain intensity and interference with daily activities decreased significantly for 50.8% of responders. Depression and anxiety (p < 0.0001) scores on the Physical Component Summary and Mental Component Summary measures (p < 0.0001) and all MOS-Sleep subscales, except for snoring, improved significantly. The percentage of satisfied patients increased from 13.8% to 87.4% (p < 0.0001) with the current analgesic treatment, which meant a 1.2- and 6-fold increase (p < 0.0001) in narcotic analgesics and anticonvulsants, respectively, compared to previous treatment. Conclusions: NP is highly prevalent at RT oncology units, with sleepiness, anxiety, and depression as frequent comorbidities. There is a need to improve management

  20. Neuropathic pain in patients with spinal cord injury: report of 213 patients

    Directory of Open Access Journals (Sweden)

    Manoel Jacobsen Teixeira

    2013-09-01

    Full Text Available Objective Management of neuropathic pain following spinal cord injury (SCI can be a frustrating experience for patients since it poses a therapeutic challenge. In this article the authors describe the clinical characteristics of a group of patients with pain after spinal cord injury. Methods In this retrospective study, 213 patients with SCI and neuropathic pain were assessed. We analyzed clinical characteristics, treatment options, and pain intensity for these patients. Results The main cause of SCI was spine trauma, which occurred in 169 patients, followed by tumors and infection. Complete lesions were verified in 144 patients. In our study, patients with traumatic SCI and partial lesions seem to be presented with more intense pain; however, this was not statistically significant. Conclusions Neuropathic pain is a common complaint in patients with SCI and presents a treatment challenge. Knowledge of the clinical characteristics of this group of patients may help determine the best approach to intervention.

  1. 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...... 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...... pain correlated positively with the Post-traumatic Stress Disorder Checklist-Civilian score (rho = 0.469, P < 0.001) and Hospital Anxiety and Depression Scale subscale for anxiety score (rho = 0.357, P = 0.009), and inversely with the EuroQOL Visual Analogue Scale score (rho = -0.361, P = 0.008). In...

  2. The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats

    Science.gov (United States)

    Gris, Georgia; Portillo-Salido, Enrique; Aubel, Bertrand; Darbaky, Yassine; Deseure, Kristof; Vela, José Miguel; Merlos, Manuel; Zamanillo, Daniel

    2016-01-01

    E-52862 is a selective σ1R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several neuropathic pain models in rats: mechanical allodynia in cephalic (trigeminal) neuropathic pain following chronic constriction injury of the infraorbital nerve (IoN), mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic polyneuropathy, and cold allodynia in oxaliplatin (OX)-induced polyneuropathy. Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolerance but an increased antinociceptive effect in all three models. Additionally, as shown in the STZ and OX models, repeated daily treatment with E-52862 attenuated baseline pain behaviours, which supports a sustained modifying effect on underlying pain-generating mechanisms. These preclinical findings support a role for σ1R in neuropathic pain and extend the potential for the use of selective σ1R antagonists (e.g., E-52862) to the chronic treatment of cephalic and extra-cephalic neuropathic pain. PMID:27087602

  3. 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.

  4. Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain.

    Science.gov (United States)

    Seltzman, Herbert H; Shiner, Craig; Hirt, Erin E; Gilliam, Anne F; Thomas, Brian F; Maitra, Rangan; Snyder, Rod; Black, Sherry L; Patel, Purvi R; Mulpuri, Yatendra; Spigelman, Igor

    2016-08-25

    Alleviation of neuropathic pain by cannabinoids is limited by their central nervous system (CNS) side effects. Indole and indene compounds were engineered for high hCB1R affinity, peripheral selectivity, metabolic stability, and in vivo efficacy. An epithelial cell line assay identified candidates with <1% blood-brain barrier penetration for testing in a rat neuropathy induced by unilateral sciatic nerve entrapment (SNE). The SNE-induced mechanical allodynia was reversibly suppressed, partially or completely, after intraperitoneal or oral administration of several indenes. At doses that relieve neuropathy symptoms, the indenes completely lacked, while the brain-permeant CB1R agonist HU-210 (1) exhibited strong CNS side effects, in catalepsy, hypothermia, and motor incoordination assays. Pharmacokinetic findings of ∼0.001 cerebrospinal fluid:plasma ratio further supported limited CNS penetration. Pretreatment with selective CB1R or CB2R blockers suggested mainly CB1R contribution to an indene's antiallodynic effects. Therefore, this class of CB1R agonists holds promise as a viable treatment for neuropathic pain. PMID:27482723

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

    Directory of Open Access Journals (Sweden)

    Fifteen A. Fajrin

    2015-12-01

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

  6. 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.

  7. Neuropathic Pain in Dogs and Cats: Current Evaluation and Treatment Perspectives: Review

    Directory of Open Access Journals (Sweden)

    A. Jiménez-Yedra

    2014-02-01

    Full Text Available During the past decade, the number of scientific papers on the recognition and multimodal management of pain in small animals increased exponentially. However, the variable of neuropathic pain, or adaptive disorder, has not yet been characterized completely. Its genesis is related to several diseases and injuries of the nervous system that change the neuroanatomical structures that participate in pain processing. Finding novel neurobiological mechanisms and the development of techniques for diagnosis and treatment in Human Medicine, are opening great opportunities for research and the understanding of neuropathic pain in pets.

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

    Science.gov (United States)

    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, Pnerve 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

  9. An inhibitor of neuronal exocytosis (DD04107) displays long-lasting in vivo activity against chronic inflammatory and neuropathic pain.

    Science.gov (United States)

    Ponsati, Berta; Carreño, Cristina; Curto-Reyes, Verdad; Valenzuela, Belen; Duart, María José; Van den Nest, Wim; Cauli, Omar; Beltran, Beatriz; Fernandez, Jimena; Borsini, Franco; Caprioli, Antonio; Di Serio, Stefano; Veretchy, Mario; Baamonde, Ana; Menendez, Luis; Barros, Francisco; de la Pena, Pilar; Borges, Ricardo; Felipo, Vicente; Planells-Cases, Rosa; Ferrer-Montiel, Antonio

    2012-06-01

    Small peptides patterned after the N terminus of the synaptosomal protein of 25 kDa, a member of the protein complex implicated in Ca(2+)-dependent neuronal exocytosis, inhibit in vitro the release of neuromodulators involved in pain signaling, suggesting an in vivo analgesic activity. Here, we report that compound DD04107 (palmitoyl-EEMQRR-NH(2)), a 6-mer palmitoylated peptide that blocks the inflammatory recruitment of ion channels to the plasma membrane of nociceptors and the release of calcitonin gene-related peptide from primary sensory neurons, displays potent and long-lasting in vivo antihyperalgesia and antiallodynia in chronic models of inflammatory and neuropathic pain, such as the complete Freund's adjuvant, osteosarcoma, chemotherapy, and diabetic neuropathic models. Subcutaneous administration of the peptide produced a dose-dependent antihyperalgesic and antiallodynic activity that lasted ≥24 h. The compound showed a systemic distribution, characterized by a bicompartmental pharmacokinetic profile. Safety pharmacology studies indicated that the peptide is largely devoid of side effects and substantiated that the in vivo activity is not caused by locomotor impairment. Therefore, DD04107 is a potent and long-lasting antinociceptive compound that displays a safe pharmacological profile. These findings support the notion that neuronal exocytosis of receptors and neuronal algogens pivotally contribute to chronic inflammatory and neuropathic pain and imply a central role of peptidergic nociceptor sensitization to the pathogenesis of pain. PMID:22393248

  10. 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.

  11. A burden of illness study for neuropathic pain in Europe

    Science.gov (United States)

    Liedgens, Hiltrud; Obradovic, Marko; De Courcy, Jonathan; Holbrook, Timothy; Jakubanis, Rafal

    2016-01-01

    Purpose Neuropathic pain (NP) is often severe and represents a major humanistic and economic burden. This study aimed at providing insight on this burden across France, Germany, Italy, Spain, and the UK, considering direct and indirect costs, productivity loss, and humanistic impact on patients and their families. Methods Physician questionnaires provided data on patients presenting with NP covering demographics, sick leave and retirement, number of consultations, drug treatments, and surgical procedures. Patients provided further demographic and disease-related data and completed the Work Productivity and Activity Impairment (WPAI), the EuroQol 5-Dimension (EQ-5D), and the Brief Pain Inventory (BPI) questionnaires. All health-related direct unitary costs were collected from relevant country-specific sources and adjusted to 2012 prices (€) where necessary. A subgroup analysis of costs based on diabetic peripheral neuropathy (n=894), fibromyalgia (n=300), and low back pain (n=963) was performed. Findings About 413 physicians completed a total of 3,956 patient records forms. Total annual direct health-care costs per patient ranged from €1,939 (Italy) to €3,131 (Spain). Annual professional caregiver costs ranged from €393 (France) to €1,242 (UK), but this only represented a small proportion of total care because much care is provided by family or friends. Sick leave costs ranged from €5,492 (UK) to €7,098 (France), with 10%–32% patients prevented from working at some point by NP. Total cost (including direct and indirect costs) of NP per patient was €10,313 in France (69% of the total cost), €14,446 in Germany (78%), €9,305 in Italy (69%), €10,597 in Spain (67%), and €9,685 in the UK (57%). Indirect costs (ie, sick leave) constituted the majority of costs in all five countries: €7,098 in France, €11,232 in Germany, €6,382 in Italy, €7,066 in Spain, and €5,492 in the UK. In the subgroup analysis, total annual direct costs per patient

  12. Effect of minocycline on lumbar radicular neuropathic pain: a randomized, placebo-controlled, double-blind clinical trial with amitriptyline as a comparator

    NARCIS (Netherlands)

    Vanelderen, P.; Zundert, J. Van; Kozicz, L.T.; Puylaert, M.; Vooght, P. De; Mestrum, R.; Heylen, R.; Roubos, E.; Vissers, K.C.P.

    2015-01-01

    BACKGROUND: Less than 50% of patients experience sufficient pain relief with current drug therapy for neuropathic pain. Minocycline shows promising results in rodent models of neuropathic pain but was not studied in humans with regard to the treatment of neuropathic pain. METHODS: In this randomized

  13. Use of naturally occurring peptides for neuropathic spinal cord injury pain.

    Science.gov (United States)

    Hama, Aldric; Sagen, Jacqueline

    2013-05-01

    Spinal cord injury (SCI) is accompanied by intractable pain as well as loss of motor and visceral control. As part of an overall strategy in patient rehabilitation and improvement in quality of life, pain management is crucial. Interestingly, SCI patients report pain below the level of injury that has characteristics of neuropathic-type pain. Preclinical studies suggest that a key substrate that underlies the symptoms of neuropathic pain such as spontaneous pain and below-level cutaneous hypersensitivity is aberrant activity of spinal dorsal horn neurons. While pharmacotherapies for peripheral neuropathic pain exist, these treatments may lead to adverse side effects in SCI patients, such as muscle weakness and constipation, which may exacerbate existing dysfunctions. Thus, novel therapeutic strategies are needed. One way to limit the adverse effects associated with systemically administered drugs is intrathecal delivery. Intrathecal delivery also directs drug to dorsal horn neurons. Another way to reduce the severity of side effects and to potentially enhance drug efficacy is to utilize combination drug therapy. While the conopeptide ziconotide has demonstrated clinical efficacy for severe chronic pain, a limitation of this drug is its potential for significant side effects. Combinations of conopeptides with currently available drugs as well as with other conopeptides could be an effective means of reducing neuropathic SCI pain. PMID:23721309

  14. The painDETECT project - far more than a screening tool on neuropathic pain.

    Science.gov (United States)

    Freynhagen, Rainer; Tölle, Thomas R; Gockel, Ulrich; Baron, Ralf

    2016-06-01

    Background and objectives The painDETECT questionnaire (PD-Q), a simple and reliable screening questionnaire of neuropathic pain, was developed in 2004 in cooperation with the German Research Network on Neuropathic Pain. The initial aim was to implement quality management and to improve the situation of neuropathic pain (NeP) patients in Germany. The PD-Q proved immediately successful and was translated into and validated in multiple languages. Subsequently a comprehensive electronic system (PD) comprising various validated questionnaires with regard to pain typical comorbidities, such as function, sleep, mood or anxiety, was implemented Germany wide. We aimed to provide a comprehensive overview about the development and validation as well as the application of the PD-Q in various clinical conditions. Methods This overview is based on a literature search on English full-text papers using the term 'painDETECT' in Medline and PubMed covering the time period from 2006 to September 2015, amended with further publications cited in the retrieved publications or provided by the questionnaire developers. Results PD-Q as screening tool for NeP described in patients with lower back pain (8 studies), rheumatoid arthritis and osteoarthritis (10), thoracotomy (2 studies), tumor diseases (4 studies), fibromyalgia (4 studies), diverse musculoskeletal conditions (12 studies) and diverse other conditions (10 studies). In addition, the PD-Q was used in 9 studies that investigated the effect of drugs for the treatment of patients with a NeP component. Conclusion To date more than 300,000 patients were assessed, providing the basis for one of the world's largest datasets for chronic pain. Among others the extensive pool of PD-Q data triggered the idea of subgrouping patients on the basis of their individual sensory profiles which might in the future lead to a stratified treatment approach and ultimately to personalized therapy. Started as a healthcare utilization project in Germany

  15. Neuropathic itch.

    Science.gov (United States)

    Oaklander, Anne Louise

    2011-06-01

    Chronic itch can be caused by dysfunctions of itch-sensing neurons that produce sensory hallucinations of pruritogenic stimuli. The cellular and molecular mechanisms are still unknown. All neurological disease categories have been implicated, and neurological causes should be considered for patients with otherwise-unexplained itch. The same neurological illnesses that cause neuropathic pain can also or instead cause itch. These include shingles (particularly of the head or neck), small-fiber polyneuropathies, radiculopathies (eg, notalgia paresthetica and brachioradial pruritis), and diverse lesions of the trigeminal nerve, root, and central tracts. Central nervous system lesions affecting sensory pathways, including strokes, multiple sclerosis, and cavernous hemangiomas, can cause central itch. Neuropathic itch is a potent trigger of reflex and volitional scratching although this provides only fleeting relief. Rare patients whose lesion causes sensory loss as well as neuropathic itch can scratch deeply enough to cause painless self-injury. The most common location is on the face (trigeminal trophic syndrome). Treating neuropathic itch is difficult; antihistamines, corticosteroids, and most pain medications are largely ineffective. Current treatment recommendations include local or systemic administration of inhibitors of neuronal excitability (especially local anesthetics) and barriers to reduce scratching. PMID:21767768

  16. Neuropathic and psychogenic itch.

    Science.gov (United States)

    Yosipovitch, Gil; Samuel, Lena S

    2008-01-01

    Neuropathic and psychogenic itch are two entities that have not been well studied. Neuropathic itch is related to pathology located at any point along the afferent pathway of the nervous system. It could be related to damage to the peripheral nervous system, such as in postherpetic neuropathy, brachioradial pruritus, notalgia paresthetica, and in central nervous system damage as a result of spinal cord tumors and demyelinization diseases such as multiple sclerosis. It has many clinical features similar to neuropathic pain. Patients complain of itch, which coincides with burning sensation, aching, and stinging. Psychogenic itch is related to psychologic abnormalities e.g., itch in obsessive compulsive disorders, depression, and delusions of parasitosis. Although no controlled studies have been conducted for treatment of neuropathic and psychogenic itch, medications that are part of the treatment armentarium for neuropathic pain, depression, and anxiety seem to be effective. PMID:18318883

  17. Non-invasive Brain Stimulation, a Tool to Revert Maladaptive Plasticity in Neuropathic Pain.

    Science.gov (United States)

    Naro, Antonino; Milardi, Demetrio; Russo, Margherita; Terranova, Carmen; Rizzo, Vincenzo; Cacciola, Alberto; Marino, Silvia; Calabro, Rocco S; Quartarone, Angelo

    2016-01-01

    Neuromodulatory effects of non-invasive brain stimulation (NIBS) have been extensively studied in chronic pain. A hypothetic mechanism of action would be to prevent or revert the ongoing maladaptive plasticity within the pain matrix. In this review, the authors discuss the mechanisms underlying the development of maladaptive plasticity in patients with chronic pain and the putative mechanisms of NIBS in modulating synaptic plasticity in neuropathic pain conditions. PMID:27512368

  18. Successful use of flupirtine in refractory neuropathic pain due to small fiber neuropathy.

    Science.gov (United States)

    Mishra, Seema; Choudhary, Prakash; Joshi, Saurabh; Bhatnagar, Sushma

    2013-02-01

    Small fiber neuropathy typically involves the small diameter nerve fibers, is usually idiopathic, and presents with peripheral pain. It can be excruciatingly painful at times despite the best of treatments. We present the case of a 22-year-old postoperative case of right frontoparietal oligodendroglioma who received multiple drugs for his severe neuropathic pain without significant relief. However, the pain almost completely subsided once flupirtine was added and substituted for some of the currently recommended first-line drugs. PMID:22495792

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Introduction: Neuropathic pain and spasticity after spinal cord injury (SCI) represent still a significant, unresolved problem causing suffering and re¬duced quality of life in patients with SCI. Treatment of neuropathic pain is a complex and difficult task, and many patients have incom...... neuropathic pain, and sec¬ondary to study the effect of Normast on spas¬ticity and psychological functioning in patients with spinal cord injury. Population characteristics: Gender, male/female, n 43/15 Age since inclusion, years, mean (SD) 55.3 (9.5) Time since injury, years, mean (SD) 8.8 (8.9) Present......¬plete relief from present available and recom¬mended treatment. Palmitoylethanolamide (PEA) is a fatty acid which is produced in many cells in the body. It suggested to potentiate the body’s own canna¬bis-like substances (endocannabinoids) and to reduce pain and inflammation. Clinical trials support the use of...

  20. Depletion of vesicular zinc in dorsal horn of spinal cord causes increased neuropathic pain in mice

    DEFF Research Database (Denmark)

    Jo, Seung; Danscher, Gorm; Schrøder, Henrik;

    2008-01-01

    neuropathic pain we applied Chung's rodent pain model on BALB/c mice, and traced zinc transporter 3 (ZnT3) proteins and zinc ions with immunohistochemistry and autometallography (AMG), respectively. Under anesthesia the left fifth lumbar spinal nerve was ligated in male mice in order to produced neuropathic...... pain. The animals were then sacrificed 5 days later. The ZnT3 immunoreactivity was found to have decreased significantly in dorsal horn of fourth, fifth, and sixth lumbar segments. In parallel with the depressed ZnT3 immunoreactivity the amount of vesicular zinc decreased perceptibly in superficial...

  1. Ultramicronized Palmitoylethanolamide (PEA) in spinal cord injury neuropathic pain: a randomized controlled trial

    DEFF Research Database (Denmark)

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

    2015-01-01

    Introduction  Neuropathic pain and spasticity after spinal cord injury (SCI) represent significant problems. Palmitoylethanolamide (PEA) is a fatty acid that isproduced in many cells in the body, and it is thought to potentiate endocannabinoids. PEA is suggested to reduce pain and inflammation but....... Methods  A randomized, double-blind, placebo-controlled parallel multicenter study. Study population of at least 66 patients must complete the 12 week trial.Questionnaires regarding neuropathic pain, spasticity, insomnia, anxiety and depression are completed before and after treatment. A numeric...

  2. What can rats tell us about neuropathic pain? Critical evaluation of behavioral tests used in rodent pain models

    OpenAIRE

    Sapunar, Damir; Puljak, Livia

    2009-01-01

    Background and Purpose: Animal models are a necessity in the study of neuropathic pain, and much of what we know about pain comes from studies in mice and rats. However, very few basic discoveries have been translated so far from rodent models into effective pain therapy. This review presents the most important rat models used in basic pain research, discusses their limitations and recommends better use of these models in future studies. Materials and Methods: A critical review of existin...

  3. Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients.

    Directory of Open Access Journals (Sweden)

    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

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

    Science.gov (United States)

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

    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 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. PMID:26761032

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Neuronal-derived Ccl7 drives neuropathic pain by promoting astrocyte proliferation.

    Science.gov (United States)

    Ke, Bin Chang; Huang, Xia Xiao; Li, Yang; Li, Li Ya; Xu, Qin Xue; Gao, Yan; Liu, Yingju; Luo, Jie

    2016-08-01

    Recent studies suggest that peripheral nerve injury converts resting spinal cord astroglial cells into an activated state, which is required for the development and maintenance of neuropathic pain. However, the underlying mechanisms of how resting astrocytes are activated after nerve injury remain largely unknown. Astroglial cell proliferation and activation could be affected by endogenous factors including chemokines, growth factors, and neurotropic factor. Chemokine (C-C motif) ligand 7 (Ccl7) is essential in facilitating the development of neuropathic pain; however, the mechanism is unknown. In the present study, we found that Ccl7 promoted astrocyte proliferation and thus contributed toward neuropathic pain. Spinal nerve ligation increased the expression in the spinal cord of neuronal Ccl7. Behavioral analyses showed that knockdown of Ccl7 alleviated spinal nerve ligation-induced neuropathic pain. Further in-vitro study showed that neuronal-derived Ccl7 was sufficient for the proliferation and activation of astroglial cells. We found a novel mechanism of Ccl7 stimulating the proliferation and activation of spinal cord astrocytes that contributes toward neuropathic pain. PMID:27295026

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

    Directory of Open Access Journals (Sweden)

    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.

  8. Antidepressants inhibit P2X4 receptor function: a possible involvement in neuropathic pain relief

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    Tozaki-Saitoh Hidetoshi

    2009-04-01

    Full Text Available Abstract Background Neuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X4 receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X4 receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X4 receptors and analysed their analgesic mechanism using an animal model of neuropathic pain. Results Antidepressants strongly inhibited ATP-mediated Ca2+ responses in P2X4 receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X4 receptors, with IC50 values of 2.45 μM and 1.87 μM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine. Conclusion These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part

  9. 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...... 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...

  10. [Experience in treatment of patients with neuropathic facial pain using ziconotide].

    Science.gov (United States)

    Lux, E A; Rasche, D

    2011-08-01

    We report on the intrathecal use of ziconotide in three patients with idiopathic facial pain after surgery of the mouth, jaw or face and one patient with neuropathic pain after damage of the lingual nerve. The therapy was successful in three patients but one patient with idiopathic facial pain had pain relief only during the test phase of ziconotide with an external pump and not after implanting the Synchromed® pump. With intrathecal morphine therapy this patient achieved good pain relief. We recommend that patients with neuropathic facial pain should be treated with ziconotide after implementation of guideline-based therapy. In the test phase the ziconotide dose should be increased by 0.6 µg/day per week after an initial dose of 0.6-1.2 µg/day to avoid side-effects. PMID:21818721

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

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    Jurairat Khongrum

    2012-01-01

    Full Text Available Problem statement: Neuropathic pain, a challenge of this decade, has been reported to be associated with the diversity conditions including diabetes. At present, there are no conventional analgesics that can effectively treat neuropathic pain with a satisfactory outcome. Due to the limitation of therapeutic efficacy, the searching for novel effective remedies in the management of neuropathic pain is required. Approach: Male Wistar rats, weighing 180-220 g were induced diabetes mellitus by Streptozotocin (STZ (single injection, 65 mg kg-1 BW, i.p. Diabetic rats were induced neuropathic pain by Constricting the right sciatic nerve (CCI at permanently. Then, all rats were administered the extract of M. oleifera leaves at doses of 100, 200 and 300 mg kg-1 BW once daily in a period of 21 days. The analgesic effect of the plant extract was evaluated using Von Frey filament and hot plate tests every 3 days after CCI throughout 21-day experimental period. In addition, at the end of the experiment, the alteration of oxidative damage markers including MDA level and the activities of SOD, CAT and GSH-PX in the injured sciatic nerve were also evaluated. Results: The current results showed that rats subjected to M.oleifera leaves extract at doses of 100 and 200 mg kg-1 BW significantly reversed the decreased withdrawal threshold intensity and withdrawal latency in Von Frey filament and hot plate tests respectively. In addition, rats subjected to the medium dose extract also reversed the decreased activities of SOD and GSH-Px and the elevation of MDA level in the injured nerve. Taken all together, our data suggest that M. oleifera leaves extract can attenuate neuropathic pain in diabetic condition. The possible underlying mechanism may occur partly via the decreased oxidative stress. However, other mechanisms may also involve. Conclusion: Our results suggest that M. oleifera leaves may be the potential novel adjuvant therapy for neuropathic pain management.

  12. Therapeutic Strategies for Neuropathic Pain: Potential Application of Pharmacosynthetics and Optogenetics.

    Science.gov (United States)

    Lee, Gum Hwa; Kim, Sang Seong

    2016-01-01

    Chronic pain originating from neuronal damage remains an incurable symptom debilitating patients. Proposed molecular modalities in neuropathic pain include ion channel expressions, immune reactions, and inflammatory substrate diffusions. Recent advances in RNA sequence analysis have discovered specific ion channel expressions in nociceptors such as transient receptor potential (TRP) channels, voltage-gated potassium, and sodium channels. G protein-coupled receptors (GPCRs) also play an important role in triggering surrounding immune cells. The multiple protein expressions complicate therapeutic development for neuropathic pain. Recent progress in optogenetics and pharmacogenetics may herald the development of novel therapeutics for the incurable pain. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) facilitate the artificial manipulation of intracellular signaling through excitatory or inhibitory G protein subunits activated by biologically inert synthetic ligands. Expression of excitatory channelrhodopsins and inhibitory halorhodopsins on injured neurons or surrounding cells can attenuate neuropathic pain precisely controlled by light stimulation. To achieve the discrete treatment of injured neurons, we can exploit the transcriptome database obtained by RNA sequence analysis in specific neuropathies. This can recommend the suitable promoter information to target the injury sites circumventing intact neurons. Therefore, novel strategies benefiting from pharmacogenetics, optogenetics, and RNA sequencing might be promising for neuropathic pain treatment in future. PMID:26884648

  13. Characterization of two Runx1-dependent nociceptor differentiation programs necessary for inflammatory versus neuropathic pain

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    Arber Silvia

    2010-07-01

    Full Text Available Abstract Background The cellular and molecular programs that control specific types of pain are poorly understood. We reported previously that the runt domain transcription factor Runx1 is initially expressed in most nociceptors and controls sensory neuron phenotypes necessary for inflammatory and neuropathic pain. Results Here we show that expression of Runx1-dependent ion channels and receptors is distributed into two nociceptor populations that are distinguished by persistent or transient Runx1 expression. Conditional mutation of Runx1 at perinatal stages leads to preferential impairment of Runx1-persistent nociceptors and a selective defect in inflammatory pain. Conversely, constitutive Runx1 expression in Runx1-transient nociceptors leads to an impairment of Runx1-transient nociceptors and a selective deficit in neuropathic pain. Notably, the subdivision of Runx1-persistent and Runx1-transient nociceptors does not follow the classical nociceptor subdivision into IB4+ nonpeptidergic and IB4- peptidergic populations. Conclusion Altogether, we have uncovered two distinct Runx1-dependent nociceptor differentiation programs that are permissive for inflammatory versus neuropathic pain. These studies lend support to a transcription factor-based distinction of neuronal classes necessary for inflammatory versus neuropathic pain.

  14. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice

    OpenAIRE

    Woojin Kim; Min Joon Kim; Donghyun Go; Byung-Il Min; Heung Sik Na; Sun Kwang Kim

    2016-01-01

    Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechan...

  15. Involvement of phosphatase and tensin homolog deleted from chromosome 10 in rodent model of neuropathic pain

    OpenAIRE

    Huang, Shi-Ying; Sung, Chun-Sung; Chen, Wu-Fu; Chen, Chun-Hong; Feng, Chien-Wei; Yang, San-Nan; Hung, Han-Chun; Chen, Nan-Fu; Lin, Pey-Ru; Chen, San-Cher; Wang, Hui-Min David; Chu, Tian-Huei; Tai, Ming-Hong; Wen, Zhi-Hong

    2015-01-01

    Background Many cancer research studies have extensively examined the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) pathway. There are only few reports that suggest that PTEN might affect pain; however, there is still a lack of evidence to show the role of PTEN for modulating pain. Here, we report a role for PTEN in a rodent model of neuropathic pain. Results We found that chronic constriction injury (CCI) surgery in rats could elicit downregulation of spinal PTEN as well a...

  16. Trigeminal neuropathic pain as a complication of anterior temporal lobectomy: report of 2 cases.

    Science.gov (United States)

    Gill, Impreet; Parrent, Andrew G; Steven, David A

    2016-04-01

    Cranial nerve (CN) deficits following anterior temporal lobectomy (ATL) are an uncommon but well-recognized complication. The usual CNs implicated in post-ATL complications include the oculomotor, trochlear, and facial nerves. To the authors' knowledge, injury to the trigeminal nerve leading to neuropathic pain has not been previously described in the literature. This paper presents 2 cases of trigeminal neuropathic pain following temporal lobe resections for pharmacoresistant epilepsy. The possible pathophysiological mechanisms are discussed and the microsurgical anatomy of surgically relevant structures is reviewed. PMID:26517768

  17. 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

    accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations...... for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30...

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

    Directory of Open Access Journals (Sweden)

    Selvaraj Deepitha

    2010-03-01

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

  19. Increased autophagic activity in dorsal root ganglion attenuates neuropathic pain following peripheral nerve injury.

    Science.gov (United States)

    Guo, Jian-Shuang; Jing, Peng-Bo; Wang, Ji-An; Zhang, Rui; Jiang, Bao-Chun; Gao, Yong-Jing; Zhang, Zhi-Jun

    2015-07-10

    Autophagy is a process of cellular self-cannibalization, and provides an adaptive mechanism to protect cells against diverse pathological settings. Following peripheral nerve injury, autophagic process was changed in Schwann cells and spinal neurons and glial cells, implicating a vital role of autophagy in chronic pain. However, little is known about the role of autophagy in dorsal root ganglion (DRG) in neuropathic pain. In the present study, we investigated the autophagic process in DRG and its effect on neuropathic pain induced by L5 spinal nerve ligation (SNL). The level of microtubule associated protein 1 light chain 3 (LC3)-II, a general marker for autophagy, was increased in L5 DRG after SNL. Immunofluorescence staining showed that LC3-II puncta were observed in DRG neurons after SNL. Injection of autophagy inducer rapamycin into L5 DRG before or after SNL dose-dependently attenuated neuropathic pain. The expression of LC3 was enhanced in L5 DRG by rapamycin. These data suggest that the autophagy in L5 DRG neurons is a defensive reaction to L5 spinal nerve injury, and pharmacological enhancement of autophagy may be a potential treatment to prevent the onset and chronification of neuropathic pain. PMID:26021876

  20. Dynamics of circadian thalamocortical flow of information during a peripheral neuropathic pain condition

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    Helder Cardoso-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. Pain treatment with ziconotide and baclofen in a case of spasticity associated with neuropathic pain

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    Danilo G. Quarta

    2009-03-01

    Full Text Available This study presents the clinical case of a patient with paraparesis, subjected for a long period of time to treatment with intrathecal baclofen and morphine to control spasticity and neuropathic pain, resulting from spinal cord injury due to road trauma. After several years of treatment the pain was not controlled with high doses of intrathecal morphine combined with transmucosal fentanyl that were given when needed. It was therefore decided to switch to intrathecal ziconotide. Starting with high levels of intrathecal morphine, the patient was referred first to weaning from morphine to a gradual titration of ziconotide doses of up to 7.4 mcg/die associated with 680 mcg/die of baclofen. A technical problem related to the infusion pump has led to the abrupt interruption of the administration of ziconotide and baclofen, which did not cause side effects, except for a poorly controlled pain. The spasticity, however, did not recur. After replacing the intrathecal pump and restarting the gradual titration of ziconotide alone, the patient has once again regained a good pain control with no recurrence to date of spasticity.

  2. 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

  3. Orofacial Pain Operant Analysis with Concomitant Investigation of Peripherally Restricted Cannabinoids and Nav1.8 Axonal Accumulation for the Potential Treatment of Neuropathic Pain

    OpenAIRE

    Mulpuri, Yatendra

    2015-01-01

    The primary emphasis of this dissertation project was to study the pathogenesis of neuropathic pain, and to develop new treatment strategies targeting primary sensory neurons of the pain pathway. Chronic neuropathic pain is debilitating and is maladaptive. Current treatment options are moderately effective with serious side-effects. Translational progress of novel drugs is impeded by side-effects, which is partly due to reliance on inaccurate methods of pain evaluation in animals. Our first s...

  4. The christchurch earthquake: crush injury, neuropathic pain, and posttraumatic stress disorder.

    Science.gov (United States)

    Cammack, Frances; Shipton, Edward A

    2013-01-01

    On February 22, 2011, an earthquake of magnitude 6.3 struck Christchurch, New Zealand. The peak ground acceleration, a measure of the shaking or intensity of an earthquake, was one of the highest ever recorded worldwide. One hundred and eighty-five people lost their lives; many others were injured. Two cases both involving young women are presented; they sustained crush injuries to limbs after being trapped by falling debris and went on to develop severe neuropathic pain. This report examines the mechanisms of neuropathic pain in the setting of crush injury, the treatment modalities, and the association between chronic pain and posttraumatic stress disorder. These case reports highlight the fact that crush injury is relatively common during major earthquakes and that neuropathic pain is an important sequel of this. Post-traumatic stress disorder is common in earthquake survivors with a recognised association with chronic pain. Pain-related disability may increase as well. Issues such as chronic pain and physical disability should not be overlooked as attention focuses on disaster management and the treatment of life-threatening injuries. PMID:23956754

  5. Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain.

    Science.gov (United States)

    Barnes, Michael Philip

    2006-04-01

    Sativex is one of the first cannabis-based medicines to undergo conventional clinical development and to be approved as a prescription medicine. It is an oromucosal spray that allows flexible, individualised dosing. Patients self titrate their overall dose and pattern of dosing according to their response to and tolerance of the medicine. This usually results in the administration of approximately 8-12 sprays/day. Each spray delivers tetrahydrocannabinol 2.7 mg and cannabidiol 2.5 mg, giving an approximate average dose of tetrahydrocannabinol 22-32 mg/day and cannabidiol 20-30 mg/day. Development has concentrated on the treatment of symptoms of multiple sclerosis, notably spasticity and neuropathic pain, as well as the treatment of neuropathic pain of other aetiologies. Positive results in placebo-controlled trials of the use of Sativex as an add-on therapy in these indications demonstrate that Sativex is efficacious and well tolerated in the treatment of these symptoms. Sativex has been approved for use in neuropathic pain due to multiple sclerosis in Canada. If ongoing studies replicate the results already observed, further approvals for the treatment of spasticity in multiple sclerosis and for neuropathic pain are likely. PMID:16553576

  6. Silencing of Id2 Alleviates Chronic Neuropathic Pain Following Chronic Constriction Injury.

    Science.gov (United States)

    Jiang, Liuming; Wu, Qun; Yang, Tao

    2016-05-01

    Inhibitor of DNA binding/differentiation 2 (Id2) belongs to a helix-loop-helix family of proteins. Recent studies have showed that Id2 plays a pivotal role in neuronal survival and neuroprotection. However, under neuropathic pain conditions, the role of Id2 is still unclear. In this study, we investigated the effect of Id2 on neuropathic pain in a rat chronic constriction injury (CCI) model. Our results demonstrated that Id2 was upregulated in the dorsal root ganglion (DRG) in a CCI rat in a time-dependent manner. Intrathecal short-hairpin RNA (shRNA)-Id2 attenuates mechanical allodynia and thermal hyperalgesia in CCI rats, and inhibits the expression of TNF-α and IL-1β in the DRG in CCI rats. Furthermore, knockdown of Id2 reduces the expression of NF-κB p65 in the DRG of CCI rats. Taken together, our findings suggest that knockdown of Id2 may alleviate neuropathic pain by inhibiting the NF-κB activation to inhibit the production of pro-inflammatory mediators. Therefore, Id2 may provide an important target of neuropathic pain treatment. PMID:26768262

  7. 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.

  8. 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.

  9. Long term clinical outcome of peripheral nerve stimulation in patients with chronic peripheral neuropathic pain

    DEFF Research Database (Denmark)

    Calenbergh, F. Van; Gybels, J.; Laere, K. Van;

    2009-01-01

    BACKGROUND: Chronic neuropathic pain after injury to a peripheral nerve is known to be resistant to treatment. Peripheral nerve stimulation is one of the possible treatment options, which is, however, not performed frequently. In recent years we have witnessed a renewed interest for PNS. The aim ...

  10. Electroacupuncture relieves neuropathic pain via upregulation of glutamate transporters in the spinal cord of rats.

    Science.gov (United States)

    Zeng, Jie; Cui, Lu-Ying; Feng, Yan; Ding, Ming-Xing

    2016-05-01

    Glutamate transports (GTs), the only vehicle for removal of glutamate from the extracellular fluid, is reported to be related to chronic pain. To investigate whether the glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) participate in electroacupuncture (EA) analgesia, the EA effect was observed with paw withdraw threshold in a rat model of spared nerve injury. The expression levels of GLAST and GLT-1 were determined with Western Blot and RT-PCR. The results showed significantly upregulated GLAST and GLT-1, along with the relieved pain behaviors after EA treatment. In addition, intrathecal injection of GTs inhibitor, l-trans-pyrrolidine-2-4-dicarboxylate, attenuated the EA-induced analgesic effect. The experiment demonstrates that EA can increase the GTs of neuropathic pain rats, which might be one of the mechanisms underlying its effectiveness in the neuropathic pain. PMID:27026488

  11. 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

  12. 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

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

    Directory of Open Access Journals (Sweden)

    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

  14. Recomendaciones para el tratamiento del dolor neuropático Recommendations for the treatment of neuropathic pain

    Directory of Open Access Journals (Sweden)

    J.R. González-Escalada

    2009-12-01

    estas recomendaciones se han tenido en cuenta los tratamientos que se deben administrar inicialmente, denominados de primera elección y, posteriormente, se enumeran las alternativas de primer orden y consecutivas siguiendo la experiencia que dicta la práctica diaria según el consenso de los especialistas en dolor.The introduction and development of new products with demonstrated efficacy in neuropathic pain has generated a clear need for an evidence based algorithm to treat the different types of neuropathic pain. The present article aims to provide recommendations on the treatment of neuropathic pain supported by the scientific evidence and agreed on by consensus by a multidisciplinary group of experts in methodology and pain management. The evidence was obtained from meta-analyses including the greatest amount of information available for each type of neuropathic pain. The literature search was performed by 5 reviewers, who focussed individually on the distinct forms of presentation of neuropathic pain. The databases consulted were the Cochrane Library, EMBASE (from 2000 onwards, and PUBMED (from 2000 onwards. Meta-analyses and randomized, controlled clinical trials were selected. Finally, retrieved articles were evaluated and clinical recommendations for the treatment of neuropathic pain were designed by the pain specialists. For some types of neuropathic pain, there is insufficient information. In these types of pain, recommendations based on scientific publications without evidence were included to provide the greatest possible amount of information on their treatment. Studies of safety and efficacy in postherpetic neuralgia (PHN, painful diabetic neuropathy (PDN, and trigeminal neuralgia (TN were reviewed as paradigms of peripheral neuropathic pain. The scarce available information on central neuropathic pain (CNP and sympathetic pain (SP was also gathered. Based on the results obtained with this literature review and the evidence extracted, a decision

  15. 17beta-estradiol counteracts neuropathic pain: a behavioural, immunohistochemical, and proteomic investigation on sex-related differences in mice

    OpenAIRE

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

    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 neuro...

  16. Cannabinoid receptor-mediated antinociception with acetaminophen drug combinations in rats with neuropathic spinal cord injury pain

    OpenAIRE

    Hama, Aldric T; Sagen, Jacqueline

    2009-01-01

    Pre-clinical evidence demonstrates that neuropathic spinal cord injury (SCI) pain is maintained by a number of neurobiological mechanisms, suggesting that treatments directed at several pain-related targets may be more advantageous compared to a treatment focused on a single target. The current study evaluated the efficacy of the non-opiate analgesic acetaminophen, which has several putative analgesic mechanisms, combined with analgesic drugs used to treat neuropathic pain in a rat model of b...

  17. Motor cortex stimulation for neuropathic pain syndromes: a case series experience.

    Science.gov (United States)

    Buchanan, Robert J; Darrow, David; Monsivais, Daniel; Nadasdy, Zoltan; Gjini, Klevest

    2014-06-18

    Neuropathic pain is a chronic condition lacking effective management and responding poorly to standard treatment protocols. Motor cortex stimulation has emerged as a new and promising therapeutic tool with outcomes potentially affected by the specific causes and location. In this study we report a series of eight cases in the neurosurgery practice of one of the authors (R.J.B.), including neuropathic pain syndromes of trigeminal or thalamic origin with or without anesthesia dolorosa. Pain relief was evaluated on the basis of comparison of Visual Analog scores at baseline and at 3 months after surgery. In addition, we assessed differences in pain relief outcomes between cases with trigeminal neuralgia and thalamic stroke, as well as cases with or without anesthesia dolorosa (i.e. pain with numbness of the affected area). Visual Analog Scale scores showed a statistically significant decrease of 4.19 (P=0.002) at 3 months follow-up compared with baseline. Pain relief levels in four of five patients in the subgroup with facial pain were higher than 50%, and none of the patients in the subgroup with thalamic and phantom limb pain showed such a good outcome. Furthermore, we found larger pain relief levels in facial pain conditions with versus without anesthesia dolorosa. These results point to utility of motor cortex stimulation in relieving neuropathic pain, as well as better outcomes for patients with facial pain and anesthesia dolorosa. Future studies should incorporate methods to noninvasively trial those patients who may benefit from surgical implantation to predict the outcomes and maximize their negative predictive value. PMID:24780896

  18. Primary care incidence and treatment of four neuropathic pain conditions: A descriptive study, 2002–2005

    OpenAIRE

    Carroll Dawn; Hall Gillian C; McQuay Henry J

    2008-01-01

    Abstract Background Between 1992 and 2001 the UK general practice incidence of post-herpetic neuralgia and trigeminal neuralgia declined, whilst the incidence of painful diabetic neuropathy increased. The most common first line treatments were compound analgesics. As therapeutic options have subsequently changed, this study presents updated data on incidence and prescribing patterns in neuropathic pain. Methods A descriptive analysis of the epidemiology and prescription treatment at diagnosis...

  19. Transforming growth factor-β1 impairs neuropathic pain through pleiotropic effects

    OpenAIRE

    Liu Hong; Haw Alexandra; Shi Xiang; Echeverry Stefania; Zhang Zhong-wei; Zhang Ji

    2009-01-01

    Abstract Background Understanding the underlying mechanisms of neuropathic pain caused by damage to the peripheral nervous system remains challenging and could lead to significantly improved therapies. Disturbance of homeostasis not only occurs at the site of injury but also extends to the spinal cord and brain involving various types of cells. Emerging data implicate neuroimmune interaction in the initiation and maintenance of chronic pain hypersensitivity. Results In this study, we sought t...

  20. Behavioral testing in rodent models of orofacial neuropathic and inflammatory pain

    OpenAIRE

    Krzyzanowska, Agnieszka; Avendaño, Carlos

    2012-01-01

    Orofacial pain conditions are often very debilitating to the patient and difficult to treat. While clinical interest is high, the proportion of studies performed in the orofacial region in laboratory animals is relatively low, compared with other body regions. This is partly due to difficulties in testing freely moving animals and therefore lack of reliable testing methods. Here we present a comprehensive review of the currently used rodent models of inflammatory and neuropathic pain adapted ...

  1. Population Analyses of Efficacy and Safety of ABT-594 in Subjects with Diabetic Peripheral Neuropathic Pain

    OpenAIRE

    Dutta, Sandeep; Hosmane, Balakrishna S.; Awni, Walid M.

    2012-01-01

    ABT-594, a neuronal nicotinic acetylcholine receptor ligand, is 30- to 100-fold more potent than morphine in animal models of nociceptive and neuropathic pain. Efficacy and safety of ABT-594 in subjects with painful diabetic polyneuropathy was evaluated in a phase 2 study. The objective of this work was to use a nonlinear mixed effects model-based approach for characterizing the relationship between dose and response (efficacy and safety) of ABT-594. Subjects (N = 266) were randomized into fo...

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

    OpenAIRE

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

    2012-01-01

    Rudolf Likar,1 Ingo Kager,1 Michael Obmann,1 Wolfgang Pipam,1 Reinhard Sittl21Department of Anesthesiology and Intensive Care, Klagenfurt Hospital, Klagenfurt, Austria; 2Department of Anesthesiology, Interdisciplinary Pain Center, University Hospital Erlangen, Erlangen, GermanyObjective: To assess treatment with the 5% lidocaine medicated plaster for peripheral neuropathic pain after disk herniation.Study design: Case series, single center, retrospective data.Patients and methods: Data of 23 ...

  3. Increased miR-132-3p expression is associated with chronic neuropathic pain.

    Science.gov (United States)

    Leinders, M; Üçeyler, N; Pritchard, R A; Sommer, C; Sorkin, L S

    2016-09-01

    Alterations in the neuro-immune balance play a major role in the pathophysiology of chronic neuropathic pain. MicroRNAs (miRNA) can regulate both immune and neuronal processes and may function as master switches in chronic pain development and maintenance. We set out to analyze the role of miR-132-3p, first in patients with peripheral neuropathies and second in an animal model of neuropathic pain. We initially determined miR-132-3p expression by measuring its levels in white blood cells (WBC) of 30 patients and 30 healthy controls and next in sural nerve biopsies of 81 patients with painful or painless inflammatory or non-inflammatory neuropathies based on clinical diagnosis. We found a 2.6 fold increase in miR-132-3p expression in WBC of neuropathy patients compared to healthy controls (panimal model of neuropathic pain, the spared nerve injury model (SNI). For this purpose miR-132-3p expression levels were measured in dorsal root ganglia and spinal cord of rats. Subsequently, miR-132-3p expression was pharmacologically modulated with miRNA antagonists or mimetics, and evoked pain and pain aversion were assessed. Spinal miR-132-3p levels were highest 10days after SNI, a time when persistent allodynia was established (pbehavior in the place escape avoidance paradigm (pbehavior in naïve rats (p<0.001). Taken together these results indicate a pro-nociceptive effect of miR-132-3p in chronic neuropathic pain. PMID:27349406

  4. Effect of Ethyl Pyruvate on Paclitaxel-Induced Neuropathic Pain in Rats

    OpenAIRE

    Choi, Seong Soo; Koh, Won Uk; Nam, Jae Sik; Shin, Jin Woo; Leem, Jeong Gill; Suh, Jeong Hun

    2013-01-01

    Background Although paclitaxel is a widely used chemotherapeutic agent for the treatment of solid cancers, side effects such as neuropathic pain lead to poor compliance and discontinuation of the therapy. Ethyl pyruvate (EP) is known to have analgesic effects in several pain models and may inhibit apoptosis. The present study was designed to investigate the analgesic effects of EP on mechanical allodynia and apoptosis in dorsal root ganglion (DRG) cells after paclitaxel administration. Method...

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

    OpenAIRE

    Domenico Intiso; Mario Basciani; Andrea Santamato; Marta Intiso; Filomena Di Rienzo

    2015-01-01

    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 pro...

  6. Euphol, a tetracyclic triterpene produces antinociceptive effects in inflammatory and neuropathic pain: the involvement of cannabinoid system.

    Science.gov (United States)

    Dutra, Rafael Cypriano; Simão da Silva, Kathryn Ana Bortolini; Bento, Allisson Freire; Marcon, Rodrigo; Paszcuk, Ana Flávia; Meotti, Flávia Carla; Pianowski, Luiz Francisco; Calixto, João B

    2012-09-01

    Persistent pains associated with inflammatory and neuropathic states are prevalent and debilitating diseases, which still remain without a safe and adequate treatment. Euphol, an alcohol tetracyclic triterpene, has a wide range of pharmacological properties and is considered to have anti-inflammatory action. Here, we assessed the effects and the underlying mechanisms of action of euphol in preventing inflammatory and neuropathic pain. Oral treatment with euphol (30 and 100 mg/kg) reduced carrageenan-induced mechanical hyperalgesia. Likewise, euphol given through the spinal and intracerebroventricular routes prevented mechanical hyperalgesia induced by carrageenan. Euphol consistently blocked the mechanical hyperalgesia induced by complete Freund's adjuvant, keratinocyte-derived chemokine, interleukin-1β, interleukin-6 and tumor necrosis factor-alpha associated with the suppression of myeloperoxidase activity in the mouse paw. Oral treatment with euphol was also effective in preventing the mechanical nociceptive response induced by ligation of the sciatic nerve and also significantly reduced the levels and mRNA of cytokines/chemokines in both paw and spinal cord tissues following i.pl. injection of complete Freund's adjuvant. In addition, the pre-treatment with either CB₁R or CB₂R antagonists, as well as the knockdown gene of the CB₁R and CB₂R, significantly reversed the antinociceptive effect of euphol. Interestingly, even in higher doses, euphol did not cause any relevant action in the central nervous system. Considering that few drugs are currently available for the treatment of chronic pain states, the present results provided evidence that euphol constitutes a promising molecule for the management of inflammatory and neuropathic pain states. PMID:22613837

  7. The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: screening and diagnosis recommendations

    DEFF Research Database (Denmark)

    Mehta, S; Guy, S D; Bryce, T N;

    2016-01-01

    in Canada. METHODS: The CanPainSCI Working Group reviewed evidence to address clinical questions regarding screening and diagnosis of neuropathic pain after SCI. A consensus process was followed to achieve agreement on recommendations and clinical considerations. RESULTS: Twelve recommendations......, based on expert consensus, were developed for the screening and diagnosis of neuropathic pain after SCI. The recommendations address methods for assessment, documentation tools, team member accountability, frequency of screening and considerations for diagnostic investigation. Important clinical...... considerations accompany each recommendation. CONCLUSIONS: The expert Working Group developed recommendations for the screening and diagnosis of neuropathic pain after SCI that should be used to inform practice....

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

    Directory of Open Access Journals (Sweden)

    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

  9. TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress.

    Science.gov (United States)

    Trevisan, Gabriela; Benemei, Silvia; Materazzi, Serena; De Logu, Francesco; De Siena, Gaetano; Fusi, Camilla; Fortes Rossato, Mateus; Coppi, Elisabetta; Marone, Ilaria Maddalena; Ferreira, Juliano; Geppetti, Pierangelo; Nassini, Romina

    2016-05-01

    Despite intense investigation, the mechanisms of the different forms of trigeminal neuropathic pain remain substantially unidentified. The transient receptor potential ankyrin 1 channel (encoded by TRPA1) has been reported to contribute to allodynia or hyperalgesia in some neuropathic pain models, including those produced by sciatic nerve constriction. However, the role of TRPA1 and the processes that cause trigeminal pain-like behaviours from nerve insult are poorly understood. The role of TRPA1, monocytes and macrophages, and oxidative stress in pain-like behaviour evoked by the constriction of the infraorbital nerve in mice were explored. C57BL/6 and wild-type (Trpa1(+/+)) mice that underwent constriction of the infraorbital nerve exhibited prolonged (20 days) non-evoked nociceptive behaviour and mechanical, cold and chemical hypersensitivity in comparison to sham-operated mice (P trigeminal neuropathic pain, pain-like behaviours are entirely mediated by the TRPA1 channel, targeted by increased oxidative stress by-products released from monocytes and macrophages clumping at the site of nerve injury. PMID:26984186

  10. Neuropathic pain: quality-of-life impact, costs and cost effectiveness of therapy.

    Science.gov (United States)

    O'Connor, Alec B

    2009-01-01

    A number of different diseases or injuries can damage the central or peripheral nervous system and produce neuropathic pain (NP), which seems to be more difficult to treat than many other types of chronic pain. As a group, patients with NP have greater medical co-morbidity burden than age- and sex-adjusted controls, which makes determining the humanistic and economic burden attributable to NP challenging. Health-related quality of life (HR-QOL) is substantially impaired among patients with NP. Patients describe pain-related interference in multiple HR-QOL and functional domains, as well as reduced ability to work and reduced mobility due to their pain. In addition, the spouses of NP patients have been shown to experience adverse social consequences related to NP. In randomized controlled trials, several medications have been shown to improve various measures of HR-QOL. Changes in HR-QOL appear to be tightly linked to pain relief, but not to the development of adverse effects. However, in cross-sectional studies, many patients continue to have moderate or severe pain and markedly impaired HR-QOL, despite taking medications prescribed for NP. The quality of NP treatment appears to be poor, with few patients receiving recommended medications in efficacious dosages. The substantial costs to society of NP derive from direct medical costs, loss of the ability to work, loss of caregivers' ability to work and possibly greater need for institutionalization or other living assistance. No single study has measured all of these costs to society for chronic NP. The cost effectiveness of various interventions for the treatment or prevention of different types of NP has been assessed in several different studies. The most-studied diseases are post-herpetic neuralgia and painful diabetic neuropathy, for which tricyclic antidepressants (both amitriptyline and desipramine) have been found to be either cost effective or dominant relative to other strategies. Increasing the use of

  11. 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

    above the level 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...

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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

  15. Pain relief induces dopamine release in the rat nucleus accumbens during the early but not late phase of neuropathic pain.

    Science.gov (United States)

    Kato, Takahiro; Ide, Soichiro; Minami, Masabumi

    2016-08-26

    Comorbidity of chronic pain and depression has long been recognized in the clinic, and preclinical studies have reported depression-like behaviors in animal models of chronic pain. These findings suggest a common neuronal basis for chronic pain and depression. The neuronal pathway from the ventral tegmental area to the nucleus accumbens (NAc) is critical in the mesolimbic dopamine (DA) reward circuit, and dysfunction of this pathway has been implicated in depression. Although time-dependent development of depression-related behaviors has been reported in chronic pain animals, time-dependent functional changes in this pathway remain to be examined. To address this issue, we examined the effects of two types of rewards, pain relief by intrathecal injection of pregabalin (100μg in 10μL phosphate buffered saline) and 30% sucrose solution intake, on intra-NAc DA release in rats subjected to spinal nerve ligation (SNL). Specifically, the effects were investigated during the early (17-20days after ligation) and late (31-34days after ligation) phases of neuropathic pain. Pain relief increased the intra-NAc DA levels in the SNL rats during the early but not late phase of neuropathic pain. Intake of the sucrose solution increased the intra-NAc DA levels both in the SNL and sham animals during the early phase of neuropathic pain, while it induced DA release in the sham but not SNL animals during the late phase. These results suggest that dysfunction of the mesolimbic DA reward circuit develops in a time-dependent manner. Mesolimbic DA reward circuit dysfunction might be a common neuronal mechanism underlying chronic pain and depression, and a potential target for novel analgesic and antidepressant medications. PMID:27369326

  16. 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

  17. Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations

    DEFF Research Database (Denmark)

    van Hecke, Oliver; Kamerman, Peter R; Attal, Nadine; Baron, Ralf; Bjornsdottir, Gyda; Bennett, David L H; Bennett, Michael I; Bouhassira, Didier; Diatchenko, Luda; Freeman, Roy; Freynhagen, Rainer; Haanpää, Maija; Jensen, Troels S; Raja, Srinivasa N; Rice, Andrew S C; Seltzer, Zeʼev; Thorgeirsson, Thorgeir E; Yarnitsky, David; Smith, Blair H

    2015-01-01

    phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity......" neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration...

  18. A preconditioning nerve lesion inhibits mechanical pain hypersensitivity following subsequent neuropathic injury

    Directory of Open Access Journals (Sweden)

    Wu Ann

    2011-01-01

    Full Text Available Abstract Background A preconditioning stimulus can trigger a neuroprotective phenotype in the nervous system - a preconditioning nerve lesion causes a significant increase in axonal regeneration, and cerebral preconditioning protects against subsequent ischemia. We hypothesized that a preconditioning nerve lesion induces gene/protein modifications, neuronal changes, and immune activation that may affect pain sensation following subsequent nerve injury. We examined whether a preconditioning lesion affects neuropathic pain and neuroinflammation after peripheral nerve injury. Results We found that a preconditioning crush injury to a terminal branch of the sciatic nerve seven days before partial ligation of the sciatic nerve (PSNL; a model of neuropathic pain induced a significant attenuation of pain hypersensitivity, particularly mechanical allodynia. A preconditioning lesion of the tibial nerve induced a long-term significant increase in paw-withdrawal threshold to mechanical stimuli and paw-withdrawal latency to thermal stimuli, after PSNL. A preconditioning lesion of the common peroneal induced a smaller but significant short-term increase in paw-withdrawal threshold to mechanical stimuli, after PSNL. There was no difference between preconditioned and unconditioned animals in neuronal damage and macrophage and T-cell infiltration into the dorsal root ganglia (DRGs or in astrocyte and microglia activation in the spinal dorsal and ventral horns. Conclusions These results suggest that prior exposure to a mild nerve lesion protects against adverse effects of subsequent neuropathic injury, and that this conditioning-induced inhibition of pain hypersensitivity is not dependent on neuroinflammation in DRGs and spinal cord. Identifying the underlying mechanisms may have important implications for the understanding of neuropathic pain due to nerve injury.

  19. 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

    Patients suffering from chronic pain may benefit from learning adaptive coping strategies. Consensus on efficient strategies for this group of patients is, however, lacking, and previous studies have shown inconsistent results. The present study has examined coping strategies in two distinctly...... 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...... did not cope differently with pain. The only difference between the groups was that FM patients felt more in control of their pain than NP patients. Both patient groups used more maladaptive/passive coping strategies, but surprisingly also more adaptive/active coping strategies than healthy controls...

  20. Botulinum toxin type A for neuropathic pain in patients with spinal cord injury

    Science.gov (United States)

    Han, Zee‐A; Song, Dae Heon; Oh, Hyun‐Mi

    2016-01-01

    Objective To evaluate the analgesic effect of botulinum toxin type A (BTX‐A) on patients with spinal cord injury‐associated neuropathic pain. Methods The effect of BTX‐A on 40 patients with spinal cord injury‐associated neuropathic pain was investigated using a randomized, double‐blind, placebo‐controlled design. A 1‐time subcutaneous BTX‐A (200U) injection was administered to the painful area. Visual analogue scale (VAS) scores (0–100mm), the Korean version of the short‐form McGill Pain Questionnaire, and the World Health Organization WHOQOL‐BREF quality of life assessment were evaluated prior to treatment and at 4 and 8 weeks after the injection. Results At 4 and 8 weeks after injection, the VAS score for pain was significantly reduced by 18.6 ± 16.8 and 21.3 ± 26.8, respectively, in the BTX‐A group, whereas it was reduced by 2.6 ± 14.6 and 0.3 ± 19.5, respectively, in the placebo group. The pain relief was associated with preservation of motor or sensory function below the neurological level of injury. Among the responders in the BTX‐A group, 55% and 45% reported pain relief of 20% or greater at 4 and 8 weeks, respectively, after the injection, whereas only 15% and 10% of the responders in the placebo group reported a similar level of pain relief. Improvements in the score for the physical health domain of the WHOQOL‐BREF in the BTX‐A group showed a marginal trend toward significance (p = 0.0521) at 4 weeks after the injection. Interpretation These results indicate that BTX‐A may reduce intractable chronic neuropathic pain in patients with spinal cord injury. Ann Neurol 2016;79:569–578 PMID:26814620

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

    OpenAIRE

    Dijkstra Catja A; Pfennings Lilian EMA; Luthart Peter; Post Marcel WM; Heutink Matagne; Lindeman Eline

    2010-01-01

    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 CONE...

  2. (+)-Naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats

    OpenAIRE

    Lewis, Susannah S.; Loram, Lisa C.; Hutchinson, Mark R; Li, Chien-Ming; Zhang, Yingning; Maier, Steven F.; Huang, Yong; Rice, Kenner C.; Watkins, Linda R.

    2012-01-01

    Previous work demonstrated that both the opioid antagonist (−)-naloxone and the nonopioid (+)-naloxone inhibit toll-like receptor 4 (TLR4) signaling and reverse neuropathic pain expressed shortly after chronic constriction injury. The present studies reveal that the TLR4 contributes to neuropathic pain in another major model (spinal nerve ligation) and to long established (2–4 mon) neuropathic pain, not just to pain shortly after nerve damage. Additionally, analyses of plasma levels of (+)-na...

  3. 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...... consensus 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...

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

    Directory of Open Access Journals (Sweden)

    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

  5. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)

    OpenAIRE

    Hutchinson, Mark R; Zhang, Yingning; Brown, Kimberley; Coats, Benjamen D.; Shridhar, Mitesh; Sholar, Paige W.; Patel, Sonica J.; Crysdale, Nicole Y.; Harrison, Jacqueline A.; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R.

    2008-01-01

    Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (...

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

    Directory of Open Access Journals (Sweden)

    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. Optogenetic Silencing of Nav1.8-Positive Afferents Alleviates Inflammatory and Neuropathic Pain.

    Science.gov (United States)

    Daou, Ihab; Beaudry, Hélène; Ase, Ariel R; Wieskopf, Jeffrey S; Ribeiro-da-Silva, Alfredo; Mogil, Jeffrey S; Séguéla, Philippe

    2016-01-01

    We report a novel transgenic mouse model in which the terminals of peripheral nociceptors can be silenced optogenetically with high spatiotemporal precision, leading to the alleviation of inflammatory and neuropathic pain. Inhibitory archaerhodopsin-3 (Arch) proton pumps were delivered to Nav1.8(+) primary afferents using the Nav1.8-Cre driver line. Arch expression covered both peptidergic and nonpeptidergic nociceptors and yellow light stimulation reliably blocked electrically induced action potentials in DRG neurons. Acute transdermal illumination of the hindpaws of Nav1.8-Arch(+) mice significantly reduced mechanical allodynia under inflammatory conditions, while basal mechanical sensitivity was not affected by the optical stimulation. Arch-driven hyperpolarization of nociceptive terminals was sufficient to prevent channelrhodopsin-2 (ChR2)-mediated mechanical and thermal hypersensitivity in double-transgenic Nav1.8-ChR2(+)-Arch(+) mice. Furthermore, prolonged optical silencing of peripheral afferents in anesthetized Nav1.8-Arch(+) mice led to poststimulation analgesia with a significant decrease in mechanical and thermal hypersensitivity under inflammatory and neuropathic conditions. These findings highlight the role of peripheral neuronal inputs in the onset and maintenance of pain hypersensitivity, demonstrate the plasticity of pain pathways even after sensitization has occurred, and support the involvement of Nav1.8(+) afferents in both inflammatory and neuropathic pain. Together, we present a selective analgesic approach in which genetically identified subsets of peripheral sensory fibers can be remotely and optically inhibited with high temporal resolution, overcoming the compensatory limitations of genetic ablations. PMID:27022626

  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. PMID:26524415

  9. Exercise therapy normalizes BDNF upregulation and glial hyperactivity in a mouse model of neuropathic pain.

    Science.gov (United States)

    Almeida, Cayo; DeMaman, Aline; Kusuda, Ricardo; Cadetti, Flaviane; Ravanelli, Maria Ida; Queiroz, André L; Sousa, Thais A; Zanon, Sonia; Silveira, Leonardo R; Lucas, Guilherme

    2015-03-01

    Treatment of neuropathic pain is a clinical challenge likely because of the time-dependent changes in many neurotransmitter systems, growth factors, ionic channels, membrane receptors, transcription factors, and recruitment of different cell types. Conversely, an increasing number of reports have shown the ability of extended and regular physical exercise in alleviating neuropathic pain throughout a wide range of mechanisms. In this study, we investigate the effect of swim exercise on molecules associated with initiation and maintenance of nerve injury-induced neuropathic pain. BALB/c mice were submitted to partial ligation of the sciatic nerve followed by a 5-week aerobic exercise program. Physical training reversed mechanical hypersensitivity, which lasted for an additional 4 weeks after exercise interruption. Swim exercise normalized nerve injury-induced nerve growth factor, and brain-derived neurotrophic factor (BDNF) enhanced expression in the dorsal root ganglion, but had no effect on the glial-derived neurotrophic factor. However, only BDNF remained at low levels after exercise interruption. In addition, exercise training significantly reduced the phosphorylation status of PLCγ-1, but not CREB, in the spinal cord dorsal horn in response to nerve injury. Finally, prolonged swim exercise reversed astrocyte and microglia hyperactivity in the dorsal horn after nerve lesion, which remained normalized after training cessation. Together, these results demonstrate that exercise therapy induces long-lasting analgesia through various mechanisms associated with the onset and advanced stages of neuropathy. Moreover, the data support further studies to clarify whether appropriate exercise intensity, volume, and duration can also cause long-lasting pain relief in patients with neuropathic pain. PMID:25687543

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

    Directory of Open Access Journals (Sweden)

    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

  11. [Mirror feed-back - a new method for the treatment of neuropathic pain].

    Science.gov (United States)

    Schwarzer, A; Glaudo, S; Zenz, M; Maier, C

    2007-10-01

    The mirror feedback therapy is a method for treatment of neuropathic pain syndromes that are associated with a missing or disordered afferent sensory input. That concerns especially the phantom limb pain, the pain after plexus or spinal nerve root injury and the complex regional pain syndrome. This therapeutic method has been increasingly implemented in the past few years. Its theoretical background rest upon recent pain research findings that refer to changes in the cortical organization and the influence of sensory and motor training effects on the pain experience. During the therapy the patients are instructed to use the mirror in a way that the image of the mirrored healthy limb seems to appear in the place of the missing or affected extremity. The mirror image produces an illusion of two "healthy" limbs. An ergotherapeutic training program with sensory and motor training elements based on the visual impressions is performed additionally. PMID:17924298

  12. Virtual reality hypnosis in the treatment of chronic neuropathic pain: a case report.

    Science.gov (United States)

    Oneal, Brent J; Patterson, David R; Soltani, Maryam; Teeley, Aubriana; Jensen, Mark P

    2008-10-01

    This case report evaluates virtual reality hypnosis (VRH) in treating chronic neuropathic pain in a patient with a 5-year history of failed treatments. The patient participated in a 6-month trial of VRH, and her pain ratings of intensity and unpleasantness dropped on average 36% and 33%, respectively, over the course of 33 sessions. In addition, she reported both no pain and a reduction of pain for an average of 3.86 and 12.21 hours, respectively, after treatment sessions throughout the course of the VRH treatment. These reductions and the duration of treatment effects following VRH treatment were superior to those following a trial of standard hypnosis (non-VR) treatment. However, the pain reductions with VRH did not persist over long periods of time. The findings support the potential of VRH treatment for helping individuals with refractory chronic pain conditions. PMID:18726807

  13. EFFECTS OF CAPSAICIN ON RAT SCIATIC NERVE IN VINCRISTINE-INDUCED NEUROPATHIC PAIN MODEL

    Directory of Open Access Journals (Sweden)

    Thanaa A. El-Masry *, Magda E. El Sayaad , Ibrahim A. Gaaboub and Wafaa M. Fouda

    2013-02-01

    Full Text Available Capsaicin, the pungent ingredient of red pepper, is used topically to treat different types of neuropathic pain, in rat model of vincristine induced neuropathic pain we tried to investigate the effect of capsaicin on sciatic nerve through electrophysiological and histopathological studies. We found that treatment of animals with vincristine results in significant decrease in sciatic nerve conduction velocity and degeneration of the nerve fibers, where combined treatment of vincristine and capsaicin showed highly significant decrease in sciatic nerve conduction velocity and degeneration of the nerve fibers compared with that treated with vincristine only. In new trial, we tried to investigate the effect of direct capsaicin titration on sciatic nerve fibers that results in nearly abolishment of nerve conduction velocity. All of these findings may illustrate the mechanism of capsaicin effect through afferent nerves degeneration.

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

    Directory of Open Access Journals (Sweden)

    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

  15. Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential.

    Science.gov (United States)

    Xie, Jennifer Y; Chew, Lindsey A; Yang, Xiaofang; Wang, Yuying; Qu, Chaoling; Wang, Yue; Federici, Lauren M; Fitz, Stephanie D; Ripsch, Matthew S; Due, Michael R; Moutal, Aubin; Khanna, May; White, Fletcher A; Vanderah, Todd W; Johnson, Philip L; Porreca, Frank; Khanna, Rajesh

    2016-09-01

    Uncoupling the protein-protein interaction between collapsin response mediator protein 2 (CRMP2) and N-type voltage-gated calcium channel (CaV2.2) with an allosteric CRMP2-derived peptide (CBD3) is antinociceptive in rodent models of inflammatory and neuropathic pain. We investigated the efficacy, duration of action, abuse potential, and neurobehavioral toxicity of an improved mutant CRMP2 peptide. A homopolyarginine (R9)-conjugated CBD3-A6K (R9-CBD3-A6K) peptide inhibited the CaV2.2-CRMP2 interaction in a concentration-dependent fashion and diminished surface expression of CaV2.2 and depolarization-evoked Ca influx in rat dorsal root ganglia neurons. In vitro studies demonstrated suppression of excitability of small-to-medium diameter dorsal root ganglion and inhibition of subtypes of voltage-gated Ca channels. Sprague-Dawley rats with tibial nerve injury had profound and long-lasting tactile allodynia and ongoing pain. Immediate administration of R9-CBD3-A6K produced enhanced dopamine release from the nucleus accumbens shell selectively in injured animals, consistent with relief of ongoing pain. R9-CBD3-A6K, when administered repeatedly into the central nervous system ventricles of naive rats, did not result in a positive conditioned place preference demonstrating a lack of abusive liability. Continuous subcutaneous infusion of R9-CBD3-A6K over a 24- to 72-hour period reversed tactile allodynia and ongoing pain, demonstrating a lack of tolerance over this time course. Importantly, continuous infusion of R9-CBD3-A6K did not affect motor activity, anxiety, depression, or memory and learning. Collectively, these results validate the potential therapeutic significance of targeting the CaV-CRMP2 axis for treatment of neuropathic pain. PMID:27537210

  16. Improving the translation of analgesic drugs to the clinic: animal models of neuropathic pain

    OpenAIRE

    Percie du Sert, N; Rice, A. S. C.

    2014-01-01

    Neuropathic pain remains an area of considerable unmet clinical need. Research based on preclinical animal models has failed to deliver truly novel treatment options, questioning the predictive value of these models. This review addresses the shortcomings of rodent in vivo models commonly used in the field and highlights approaches which could increase their predictivity, including more clinically relevant assays, outcome measures and animal characteristics. The methodological quality of anim...

  17. GluA1 Phosphorylation Contributes to Postsynaptic Amplification of Neuropathic Pain in the Insular Cortex

    OpenAIRE

    Qiu, Shuang; Zhang, Ming; Yan LIU; Guo, Yanyan; Zhao, Huan; Song, Qian; Zhao, Minggao; Huganir, Richard L.; Luo, Jianhong; Xu, Hui; Zhuo, Min

    2014-01-01

    Long-term potentiation of glutamatergic transmission has been observed after physiological learning or pathological injuries in different brain regions, including the spinal cord, hippocampus, amygdala, and cortices. The insular cortex is a key cortical region that plays important roles in aversive learning and neuropathic pain. However, little is known about whether excitatory transmission in the insular cortex undergoes plastic changes after peripheral nerve injury. Here, we found that peri...

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

    OpenAIRE

    Reza Heidari; Samad Zare; Farrin Babaei-Balderlou; Farah Farrokhi

    2010-01-01

    Objective(s)Previous 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 w...

  19. Efficacy of antiepileptic isomers of valproic acid and valpromide in a rat model of neuropathic pain

    OpenAIRE

    Winkler, Ilan; Blotnik, Simcha; Shimshoni, Jakob; Yagen, Boris; Devor, Marshall; Bialer, Meir

    2005-01-01

    Antiepileptic drugs (AEDs) are often utilized in the treatment of neuropathic pain. The major AED valproic acid (VPA) is of particular interest as it is thought to engage a variety of different neural mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but life-threatening side effects: teratogenicity and hepatotoxicity.We synthesized VPA's corresponding amide: valpromide (VPD), two of VPAs isomers and their corresponding amides; valnoctic acid (VCA), valnoctami...

  20. Eligibility audits for the randomized neuropathic bone pain trial (TROG 96.05)

    International Nuclear Information System (INIS)

    In February 1996 the Trans-Tasman Radiation Oncology Group (TROG) initiated a two-arm, multicentre, prospective randomized trial on radiotherapy for neuropathic pain due to bone metastases (TROG 96.05). This trial compares the response to a single 8-Gy fraction with 20 Gy in five fractions. The accrual target is 270 patients. In order to evaluate compliance with eligibility criteria after approximately 1 year of accrual, an independent audit of the first 42 randomized patients was commissioned. This found that only one of these patients did not have genuine neuropathic pain, but that this patient and seven others (19%) had infringements of other eligibility/exclusion criteria for the trial. Accordingly it was decided to continue the full audit up to 90 patients. This detected no further patients without genuine neuropathic pain, and found only one other eligibility infringement (1/48; 2%). It is concluded that this quality assurance (QA) measure undertaken early in the trial led to significantly improved clinician awareness of, and compliance with, eligibility/exclusion criteria. It also enabled an accurate comparison of outcome data for all randomized versus all eligible patients at the time of the preplanned first interim analysis at 90 patients. In view of the excellent compliance demonstrated in the second audit, a one-in-five sampling is proposed for future audits from centres that have already accrued at least five consecutive eligible patients. This is consistent with TROG QA guidelines now operational. Copyright (2000) Blackwell Science Pty Ltd

  1. Analgesic activity of catalpol in rodent models of neuropathic pain, and its spinal mechanism.

    Science.gov (United States)

    Wang, Yingbin; Zhang, Rongzhi; Xie, Jianqin; Lu, Jianzhong; Yue, Zhongjin

    2014-12-01

    Neuropathic pain is a major health issue that represents considerable social and economic burden worldwidely. In this study, we investigated the potential of catalpol, an iridoid glucoside of Rehmannia glutinosa Steud, to alleviate neuropathic pain. The potential analgesic effects of catalpol were evaluated by chronic constriction injury (CCI) and lumbar 5 spinal nerve ligation (L5 SNL) model. In addition, we explored whether catalpol altered the degree of microglia activation and neuroinflammation in rat spinal cord after CCI induction. Repeated administration of catalpol (1, 5, 25, and 125 mg/kg) reversed mechanical allodynia induced by CCI and L5 SNL in a dose-dependent manner in rats. Levels of activated microglia, activated NF-κB, and proinflammatory cytokines (IL-1β, IL-6, TNF-α) in lumber spinal cord were elevated in rats following CCI induction, and catalpol significantly inhibited these effects. Our results demonstrated that catalpol produces significant antinociceptive action in rodent behavioral models of neuropathic pain and that this effect is associated with modulation of neuroinflammation in spinal cord. PMID:24980862

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

    Science.gov (United States)

    Kaur, Gurpreet; Bali, Anjana; Singh, Nirmal; Jaggi, Amteshwar S

    2015-03-01

    The present study was designed to investigate the ameliorative potential of Ocimum sanctum 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 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 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. PMID:25673470

  3. Calcium-Permeable AMPA Receptors in the Nucleus Accumbens Regulate Depression-Like Behaviors in the Chronic Neuropathic Pain State

    OpenAIRE

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

    2013-01-01

    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 ...

  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. PMID:27302204

  5. Management of neuropathic pain following treatment for breast cancer in the absence of recurrence: a challenge for the radiation oncologist

    International Nuclear Information System (INIS)

    This report reviews various management options for treatment-induced neuropathic pain in breast cancer. First-line options include tricyclic antidepressants and anticonvulsant drugs. Opioids should be prescribed according to published guidelines. Second-line treatments include lignocaine, mexiletine and ketamine. Sympatholytic therapies are available to patients with features of chronic regional pain syndrome. Anti-inflammatory agents are used for neurogenic inflammation. Surgical interventions are considered for refractory neuropathic pain. Interdisciplinary management is appropriate when persisting pain causes physical and psychosocial disabilities. Copyright (2004) Blackwell Science Pty Ltd

  6. L-Tetrahydropalmatine alleviates mechanical hyperalgesia in models of chronic inflammatory and neuropathic pain in mice.

    Science.gov (United States)

    Zhou, Hai-Hui; Wu, Dan-Lian; Gao, Li-Yan; Fang, Yun; Ge, Wei-Hong

    2016-05-01

    Chronic pain is categorized as inflammatory and neuropathic, and there are common mechanisms underlying the generation of each pain state. Such pain is difficult to treat and the treatment at present is inadequate. Corydalis yanhusuo is a traditional Chinese medicine with demonstrated analgesic efficacy in humans. The potential antihyperalgesic effect of its active component is L-tetrahydropalmatine (L-THP). L-THP has been used for the treatment of headache and other mild pain. However, little is known about its analgesic effect on chronic pain and its mechanism. Here, we report that L-THP exerts remarkable antihyperalgesic effects on neuropathic and inflammatory pain in animal models. Neuropathic hypersensitivity was induced by segmental spinal nerve ligation and inflammatory hypersensitivity was induced by an intraplantar injection of complete Freund's adjuvant. To determine the receptor mechanism underlying the antihyperalgesic actions of L-THP, we used SCH23390, an antagonist of a dopamine D1 receptor, in an attempt to block the antihyperalgesic effects of L-THP. We found that L-THP (1-4 mg/kg, i.p.) produced a dose-dependent antihyperalgesic effect in spinal nerve ligation and complete Freund's adjuvant models. The antihyperalgesic effects of L-THP were abolished by a dopamine D1 receptor antagonist SCH23390 (0.02 mg/kg). Furthermore, L-THP (4 mg/kg, i.p.) did not influence motor function. These findings suggest that L-THP may ameliorate mechanical hyperalgesia by enhancing dopamine D1 receptor-mediated dopaminergic transmission. PMID:26981712

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Introduction: Neuropathic pain and spasticity after spinal cord injury represent significant problems. Palmitoylethanolamide (PEA) is a fatty acid that is produced in many cells in the body, and it is thought to potentiate the body's own cannabis-like substances (endocannabinoids). PEA is suggested...... and depression are completed before and after treatment with either placebo or Normast. A numeric rating scale for pain intensity (0-10 point) is used to measure primary outcome. Results: Presently, 66 patients (74% male) are included of which 55 have completed the trial. Of those included, 5% have...

  8. 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.

  9. 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

  10. Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.

    Science.gov (United States)

    Grace, Peter M; Strand, Keith A; Galer, Erika L; Urban, Daniel J; Wang, Xiaohui; Baratta, Michael V; Fabisiak, Timothy J; Anderson, Nathan D; Cheng, Kejun; Greene, Lisa I; Berkelhammer, Debra; Zhang, Yingning; Ellis, Amanda L; Yin, Hang Hubert; Campeau, Serge; Rice, Kenner C; Roth, Bryan L; Maier, Steven F; Watkins, Linda R

    2016-06-14

    Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain. PMID:27247388

  11. D-Aspartate drinking solution alleviates pain and cognitive impairment in neuropathic mice.

    Science.gov (United States)

    Palazzo, Enza; Luongo, Livio; Guida, Francesca; Marabese, Ida; Romano, Rosaria; Iannotta, Monica; Rossi, Francesca; D'Aniello, Antimo; Stella, Luigi; Marmo, Federica; Usiello, Alessandro; de Bartolomeis, Andrea; Maione, Sabatino; de Novellis, Vito

    2016-07-01

    D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechanical allodynia, improved cognition and motor coordination and increased social interaction. D-Asp also restored the levels of extracellular D-Asp, Homer 1a and NR2B subunit of the NMDA receptor to physiological levels and reduced Shank1 and PSD-95 protein levels in the mPFC. Amitriptyline, a tricyclic antidepressant used also to alleviate neuropathic pain in humans, reverted mechanical allodynia and cognitive impairment, and unlike D-Asp, was effective in reducing depression and anxiety-like behaviour in the SNI mice and increased PSD protein level. Altogether these findings demonstrate that D-Asp improves sensorial, motor and cognitive-like symptoms related to chronic pain possibly through glutamate neurotransmission normalization in neuropathic mice. PMID:27115160

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

    Science.gov (United States)

    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 neuropathic pain and small fibers neuropathy and the mechanism of the reversal. Results We demonstrate that GM3 synthase knockout and the resultant GM3 depletion rescues the denervation in mouse footpad skin and fully reverses the neuropathic pain in diet-induced obese diabetic mice. In cultured dorsal root ganglia from diet-induced diabetic mice, GM3 depletion protects against increased intracellular calcium influx in vitro. Conclusions These studies establish ganglioside GM3 as a new candidate responsible for neuropathic pain and small fiber neuropathy in diabetes. Moreover, these observations indicate that systemic or topically applied interventions aimed at depleting GM3 may improve both the painful neuropathy and the wound healing impairment in diabetes by protecting against nerve end terminal degeneration, providing a disease-modifying approach to this common, currently intractable medical issue. PMID:27590073

  13. Intrathecal Ziconotide and Morphine for Pain Relief: A Case Series of Eight Patients with Refractory Cancer Pain, Including Five Cases of Neuropathic Pain

    OpenAIRE

    de la Calle Gil, Ana Bella; Peña Vergara, Isaac; Cormane Bornacelly, María Auxiliadora; Pajuelo Gallego, Antonio

    2015-01-01

    Introduction Studies have shown that, at low doses and with careful titration, combination therapy with intrathecal ziconotide and morphine results in rapid control of opioid-refractory cancer pain. However, there is a lack of published data regarding the efficacy and safety of intrathecal ziconotide specifically for the treatment of neuropathic cancer pain. Case series Case reports of ziconotide intrathecal infusion in eight patients (age 45–71 years; 75% male) with chronic, uncontrolled can...

  14. An observational descriptive study of the epidemiology and treatment of neuropathic pain in a UK general population

    OpenAIRE

    Hall, Gillian C.; Morant, Steve V; Carroll, Dawn; Gabriel, Zahava L; McQuay, Henry J

    2013-01-01

    Background This study updated our knowledge of UK primary care neuropathic pain incidence rates and prescribing practices. Methods Patients with a first diagnosis of post-herpetic neuralgia (PHN), painful diabetic neuropathy (PDN) or phantom limb pain (PLP) were identified from the General Practice Research Database (2006 – 2010) and incidence rates were calculated. Prescription records were searched for pain treatments from diagnosis of these conditions and the duration and daily dose estima...

  15. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain.

    Science.gov (United States)

    Kostich, Walter; Hamman, Brian D; Li, Yu-Wen; Naidu, Sreenivasulu; Dandapani, Kumaran; Feng, Jianlin; Easton, Amy; Bourin, Clotilde; Baker, Kevin; Allen, Jason; Savelieva, Katerina; Louis, Justin V; Dokania, Manoj; Elavazhagan, Saravanan; Vattikundala, Pradeep; Sharma, Vivek; Das, Manish Lal; Shankar, Ganesh; Kumar, Anoop; Holenarsipur, Vinay K; Gulianello, Michael; Molski, Ted; Brown, Jeffrey M; Lewis, Martin; Huang, Yanling; Lu, Yifeng; Pieschl, Rick; O'Malley, Kevin; Lippy, Jonathan; Nouraldeen, Amr; Lanthorn, Thomas H; Ye, Guilan; Wilson, Alan; Balakrishnan, Anand; Denton, Rex; Grace, James E; Lentz, Kimberley A; Santone, Kenneth S; Bi, Yingzhi; Main, Alan; Swaffield, Jon; Carson, Ken; Mandlekar, Sandhya; Vikramadithyan, Reeba K; Nara, Susheel J; Dzierba, Carolyn; Bronson, Joanne; Macor, John E; Zaczek, Robert; Westphal, Ryan; Kiss, Laszlo; Bristow, Linda; Conway, Charles M; Zambrowicz, Brian; Albright, Charles F

    2016-09-01

    To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2

  16. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

    Science.gov (United States)

    Kostich, Walter; Hamman, Brian D.; Li, Yu-Wen; Naidu, Sreenivasulu; Dandapani, Kumaran; Feng, Jianlin; Easton, Amy; Bourin, Clotilde; Baker, Kevin; Allen, Jason; Savelieva, Katerina; Louis, Justin V.; Dokania, Manoj; Elavazhagan, Saravanan; Vattikundala, Pradeep; Sharma, Vivek; Das, Manish Lal; Shankar, Ganesh; Kumar, Anoop; Holenarsipur, Vinay K.; Gulianello, Michael; Molski, Ted; Brown, Jeffrey M.; Lewis, Martin; Huang, Yanling; Lu, Yifeng; Pieschl, Rick; O’Malley, Kevin; Lippy, Jonathan; Nouraldeen, Amr; Lanthorn, Thomas H.; Ye, Guilan; Wilson, Alan; Balakrishnan, Anand; Denton, Rex; Grace, James E.; Lentz, Kimberley A.; Santone, Kenneth S.; Bi, Yingzhi; Main, Alan; Swaffield, Jon; Carson, Ken; Mandlekar, Sandhya; Vikramadithyan, Reeba K.; Nara, Susheel J.; Dzierba, Carolyn; Bronson, Joanne; Macor, John E.; Zaczek, Robert; Westphal, Ryan; Kiss, Laszlo; Bristow, Linda; Conway, Charles M.

    2016-01-01

    To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2

  17. 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

    This randomized controlled trial found no effect of ultramicronized palmitoylethanolamide as add-on-therapy on neuropathic pain after spinal cord injury.Neuropathic pain and spasticity after spinal cord injury (SCI) represent significant problems. Palmitoylethanolamide (PEA), a fatty acid amide t...... in pain scores 0.4 (-0.1 to 0.9) vs 0.7 (0.2 to 1.2); difference of means 0.3 (-0.4 to 0.9)). There was also no effect of PEA-um as add-on therapy on spasticity, insomnia, or psychological functioning. PEA was not associated with more adverse effects than placebo....

  18. 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

  19. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice

    Directory of Open Access Journals (Sweden)

    Woojin Kim

    2016-01-01

    Full Text Available Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.. BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36 or morphine (0.5, 2, and 5 mg/kg, i.p. alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg or 5-HT3 (MDL-72222, 15 μg receptor antagonist, but not with α2-adrenergic (idazoxan, 10 μg receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain.

  20. Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice.

    Science.gov (United States)

    Kim, Woojin; Kim, Min Joon; Go, Donghyun; Min, Byung-Il; Na, Heung Sik; Kim, Sun Kwang

    2016-02-01

    Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg) or 5-HT3 (MDL-72222, 15 μg) receptor antagonist, but not with α2 adrenergic (idazoxan, 10 μg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain. PMID:26805884

  1. Update on neuropathic pain treatment for trigeminal neuralgia

    OpenAIRE

    Al-Quliti, Khalid W.

    2015-01-01

    Trigeminal neuralgia is a syndrome of unilateral, paroxysmal, stabbing facial pain, originating from the trigeminal nerve. Careful history of typical symptoms is crucial for diagnosis. Most cases are caused by vascular compression of the trigeminal root adjacent to the pons leading to focal demyelination and ephaptic axonal transmission. Brain imaging is required to exclude secondary causes. Many medical and surgical treatments are available. Most patients respond well to pharmacotherapy; car...

  2. Optogenetic Silencing of Nav1.8-Positive Afferents Alleviates Inflammatory and Neuropathic Pain123

    Science.gov (United States)

    Daou, Ihab; Beaudry, Hélène; Ase, Ariel R.; Wieskopf, Jeffrey S.; Ribeiro-da-Silva, Alfredo; Mogil, Jeffrey S.

    2016-01-01

    Abstract We report a novel transgenic mouse model in which the terminals of peripheral nociceptors can be silenced optogenetically with high spatiotemporal precision, leading to the alleviation of inflammatory and neuropathic pain. Inhibitory archaerhodopsin-3 (Arch) proton pumps were delivered to Nav1.8+ primary afferents using the Nav1.8-Cre driver line. Arch expression covered both peptidergic and nonpeptidergic nociceptors and yellow light stimulation reliably blocked electrically induced action potentials in DRG neurons. Acute transdermal illumination of the hindpaws of Nav1.8-Arch+ mice significantly reduced mechanical allodynia under inflammatory conditions, while basal mechanical sensitivity was not affected by the optical stimulation. Arch-driven hyperpolarization of nociceptive terminals was sufficient to prevent channelrhodopsin-2 (ChR2)-mediated mechanical and thermal hypersensitivity in double-transgenic Nav1.8-ChR2+-Arch+mice. Furthermore, prolonged optical silencing of peripheral afferents in anesthetized Nav1.8-Arch+ mice led to poststimulation analgesia with a significant decrease in mechanical and thermal hypersensitivity under inflammatory and neuropathic conditions. These findings highlight the role of peripheral neuronal inputs in the onset and maintenance of pain hypersensitivity, demonstrate the plasticity of pain pathways even after sensitization has occurred, and support the involvement of Nav1.8+ afferents in both inflammatory and neuropathic pain. Together, we present a selective analgesic approach in which genetically identified subsets of peripheral sensory fibers can be remotely and optically inhibited with high temporal resolution, overcoming the compensatory limitations of genetic ablations. PMID:27022626

  3. Neuropathic pain develops normally in mice lacking both Nav1.7 and Nav1.8

    Directory of Open Access Journals (Sweden)

    Stirling L Caroline

    2005-08-01

    Full Text Available Abstract Two voltage gated sodium channel α-subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain. Mis-expression of voltage-gated sodium channels by damaged sensory neurons has also been implicated in the development of neuropathic pain, but the role of Nav1.7 and Nav1.8 is uncertain. Here we show that deleting Nav1.7 has no effect on the development of neuropathic pain. Double knockouts of both Nav1.7 and Nav1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds. These studies demonstrate that, in contrast to the highly significant role for Nav1.7 in determining inflammatory pain thresholds, the development of neuropathic pain does not require the presence of either Nav1.7 or Nav1.8 alone or in combination.

  4. 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

  5. JAB1 is Involved in Neuropathic Pain by Regulating JNK and NF-κB Activation After Chronic Constriction Injury.

    Science.gov (United States)

    Chen, Yan; Chen, Xiangdong; Yu, Jiang; Xu, Xingguo; Wei, Xiaojia; Gu, Xiaoling; Liu, Chun; Zhang, Dongmei; Xu, Zhongling

    2016-05-01

    Neuropathic pain, caused by a lesion or dysfunction of the somatosensory nervous system, is a severe debilitating condition with which clinical treatment remains challenging. Jun activation domain-binding protein (JAB1) is a multifunctional protein that participates in several signaling pathways, controlling cell proliferation and apoptosis. However, the expression and possible function of JAB1 in the pathogenesis of neuropathic pain has not been elucidated. This study aimed to investigate the possible involvement of JAB1. Here, employing a neuropathic pain model induced by chronic constriction injury (CCI) on rats, we reported the role of JAB1 in the maintenance of neuropathic pain. By western blot, we found that CCI markedly up-regulated JAB1 expression in the dorsal root ganglion (DRG) and spinal cord. Immunofluorescent assay demonstrated that JAB1 was extensively localized in IB4-, CGRP- and NF200-positive neurons in the injured L5 DRG, and mainly co-localized with NeuN in spinal cord. In addition, we showed that CCI induced phosphorylation of p65 and JNK in vivo. Intrathecal injection of JAB1 siRNA significantly attenuated the CCI-induced JNK and p65 phosphorylation and alleviated both mechanical allodynia and heat hyperalgesia in rats. Taken together, these results suggested that JAB1 promotes neuropathic pain via positively regulating JNK and NF-κB activation. PMID:26700435

  6. Somatosensory Rehabilitation for Neuropathic Pain in Burn Survivors: A Case Series.

    Science.gov (United States)

    Nedelec, Bernadette; Calva, Valerie; Chouinard, Annick; Couture, Marie-Andrée; Godbout, Elisabeth; de Oliveira, Ana; LaSalle, Léo

    2016-01-01

    Neuropathic pain is an enormous rehabilitation challenge that has a substantial negative effect on patient function and quality of life. Somatosensory rehabilitation is a novel, nonpharmacological intervention described by Spicher based on the neuroplasticity of the somatosensory system. The rationale for somatosensory rehabilitation is that treating hypoesthesia will decrease neuropathic pain. Particularly for those with established neuropathic pain, the hypoesthesia may be masked by mechanical allodynia, which must be treated before treating the underlying hyposensitive zone. This case series describes the outcome of 17 burn survivors treated with somatosensory rehabilitation for their neuropathic pain. Before initiating treatment a modified version of the McGill Pain Questionnaire-short form (Questionnaire de la douleur St. Antoine, QDSA) was completed with the patients. The total score (×/64) was converted to percentage. The mechanical allodynia was assessed with the Rainbow Pain Scale that uses touch with the 15-g Semmes Weinstein Monofilaments (SWMs) and that was rated as painful on the visual analog scale (3/10 or resting pain + 1/10), as the criteria for mechanical allodynia. The severity level was assessed using seven predetermined SWMs to identify the smallest that elicited pain. The treatment consisted of avoiding all touch in the allodynic zone while concurrently providing proximal sensory and vibratory counter stimulation. Once the mechanical allodynia was eliminated, the underlying hypoesthesia was treated. Hypoesthesia was evaluated with the SWMs, and the percent improvement from baseline was calculated. The sensory reeducation treatment for hypoesthesia consisted of touch discrimination, texture perception, and vibratory stimulation. Seventeen patients (71/29% male/female, 21 ± 25% TBSA burned, 486 ± 596 days postburn) were evaluated and treated. Of these 15 initially presented with mechanical allodynia. The SWM scores had improved by 27 ± 21

  7. The importance of catastrophizing for successful pharmacological treatment of peripheral neuropathic pain

    Directory of Open Access Journals (Sweden)

    Toth C

    2014-06-01

    Full Text Available Cory Toth, Shauna Brady, Melinda Hatfield Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada Objective: Catastrophizing may be a negative predictor of pain-related outcomes. We evaluated the impact of catastrophizing upon success of first-line pharmacotherapy in the management of neuropathic pain (NeP due to peripheral polyneuropathy. Methods: Patients with confirmed NeP with NeP Visual Analog Scale (VAS pain severity score ≥4 (0–10 scale completed the Coping Strategies Questionnaire (CSQ catastrophizing subscale at baseline. Pharmacological therapy consisting of first-line agents gabapentin, pregabalin, or a tricyclic antidepressant was initiated. Other measures examined included the Karnofsky Performance Scale, Beck Depression Inventory, EuroQol Quality of Life Health Questionnaire, and Modified Brief Pain Inventory. At 3 and 6 months, questionnaires were repeated and adverse effect reporting was completed. Outcome measures assessed were pharmacotherapy success (≥30% relief of NeP and tolerability over 6 months of follow-up. Bivariate relationships using Pearson product-moment correlations were examined for baseline CSQ catastrophizing subscale score and the change in the NeP VAS scores and medication discontinuation. Results: Sixty-six patients were screened, 62 subjects participated, and 58 subjects (94% completed the final follow-up visit. Greater catastrophizing was associated with poor pain relief response and greater likelihood of discontinuation of pharmacotherapy, reports of greater disability, and impaired quality of life. Duration of pain was negatively associated with likelihood of pharmacotherapy success. Conclusion: Catastrophizing exerts maladaptive effects on outcomes with pharmacotherapy in NeP patients. Detection of catastrophizing during clinical visits when pharmacological therapy is being considered can be a predictive factor for patient outcomes. Keywords: neuropathic pain

  8. Involvement of the melanocortin-1 receptor in acute pain and pain of inflammatory but not neuropathic origin.

    Directory of Open Access Journals (Sweden)

    Ada Delaney

    Full Text Available BACKGROUND: Response to painful stimuli is susceptible to genetic variation. Numerous loci have been identified which contribute to this variation, one of which, MC1R, is better known as a gene involved in mammalian hair colour. MC1R is a G protein-coupled receptor expressed in melanocytes and elsewhere and mice lacking MC1R have yellow hair, whilst humans with variant MC1R protein have red hair. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R. METHODOLOGY AND PRINCIPAL FINDINGS: We have tested responses to noxious and non-noxious stimuli in mutant mice which lack MC1R, or which overexpress an endogenous antagonist of the receptor, as well as controls. We have also examined the response of these mice to inflammatory pain, assessing the hyperalgesia and allodynia associated with persistent inflammation, and their response to neuropathic pain. Finally we tested by a paired preference paradigm their aversion to oral administration of capsaicin, which activates the noxious heat receptor TRPV1. Female mice lacking MC1R showed increased tolerance to noxious heat and no alteration in their response to non-noxious mechanical stimuli. MC1R mutant females, and females overexpressing the endogenous MC1R antagonist, agouti signalling protein, had a reduced formalin-induced inflammatory pain response, and a delayed development of inflammation-induced hyperalgesia and allodynia. In addition they had a decreased aversion to capsaicin at moderate concentrations. Male mutant mice showed no difference from their respective controls. Mice of either sex did not show any effect of mutant genotype on neuropathic pain. CONCLUSIONS: We demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin.

  9. Opioid and noradrenergic contributions of tapentadol in experimental neuropathic pain

    OpenAIRE

    Meske, Diana S.; Xie, Jennifer Y.; Oyarzo, Janice; Badghisi, Hamid; Ossipov, Michael H.; Porreca, Frank

    2013-01-01

    Tapentadol is a dual action molecule with mu opioid agonist and norepinephrine (NE) reuptake blocking activity that has recently been introduced for the treatment of moderate to severe pain. The effects of intraperitoneal (i.p.) morphine (10 mg/kg), tapentadol (10 or 30 mg/kg) or duloxetine (30 mg/kg), a norepinephrine/serotonin (NE/5HT) reuptake inhibitor, were evaluated in male, Sprague-Dawley rats with spinal nerve ligation (SNL) or sham surgery. Additionally, the effects of these drugs on...

  10. 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\\

  11. 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

  12. 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.

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

    Science.gov (United States)

    Hadid, Vicky; Dahan, Michael Haim

    2015-01-01

    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. PMID:26137334

  14. 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

  15. Neuropathic pain induced by spinal cord injury: Role of endothelin ETA and ETB receptors.

    Science.gov (United States)

    Forner, S; Martini, A C; de Andrade, E L; Rae, G A

    2016-03-23

    Spinal cord injury (SCI) is a devastating neurologic disorder that often inflicts neuropathic pain, which further impacts negatively on the patient's quality of life. Endothelin peptides, which exert their effects via endothelin A (ETAR) and endothelin B (ETBR) receptors, can contribute to sensory changes associated with inflammatory and neuropathic pain, but their role in nociception following SCI is unknown. At different time points after subjecting male Wistar rats to surgery for compression-induced T10 level SCI, the spinal cord levels of ETAR and ETBR were assessed by Western blot and immunohistochemistry, and the corresponding mRNAs by real-time PCR, alongside recordings of behavioural responses to mechanical stimulation of the hind paws with von Frey hairs. SCI was associated with development of hind paw mechanical allodynia from day 14 onwards, and up-regulation of ETAR and ETBR mRNA in the spinal cord and dorsal root ganglia, and of ETAR protein in the spinal cord. SCI increased ETAR protein expression in spinal grey matter. Treatment on day 21 after surgery with the ETAR selective antagonist BQ-123 (40 and 90pmol, intrathecally) or the dual ETAR/ETBR antagonist bosentan (30 and 100mg/kg, orally) transiently reduced SCI-induced mechanical allodynia, but the ETBR antagonist BQ-788 was ineffective. Altogether, these data show that SCI upregulates ETAR expression in the spinal cord, which appears to contribute to the hind paw mechanical allodynia associated with this condition. Therapies directed towards blockade of spinal ETAR may hold potential to limit SCI-induced neuropathic pain. PMID:26861196

  16. 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.

  17. Primary care incidence and treatment of four neuropathic pain conditions: A descriptive study, 2002–2005

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    Carroll Dawn

    2008-05-01

    Full Text Available Abstract Background Between 1992 and 2001 the UK general practice incidence of post-herpetic neuralgia and trigeminal neuralgia declined, whilst the incidence of painful diabetic neuropathy increased. The most common first line treatments were compound analgesics. As therapeutic options have subsequently changed, this study presents updated data on incidence and prescribing patterns in neuropathic pain. Methods A descriptive analysis of the epidemiology and prescription treatment at diagnosis of incident post-herpetic neuralgia (n = 1,923; trigeminal neuralgia (1,862; phantom limb pain (57 and painful diabetic neuropathy (1,444 using computerised UK general practice records (THIN: May 2002 to July 2005. Results Primary care incidences per 100,000 person years observation of 28 (95% confidence interval (CI 27–30 for post-herpetic neuralgia, 27 (95%CI 26–29 for trigeminal neuralgia, 0.8 (95%CI 0.6–1.1 for phantom limb pain and 21 (95%CI 20–22 for painful diabetic neuropathy are reported. The most common initial treatments were tricyclic antidepressants (post-herpetic neuralgia or antiepileptics (trigeminal neuralgia and painful diabetic neuropathy and opioid analgesics (phantom limb pain. The mean number of changes before a stable drug regimen was 1.2 to 1.5 for trigeminal neuralgia, painful diabetic neuropathy and post-herpetic neuralgia, and 2.4 for phantom limb pain. Conclusion The incidence of phantom limb pain and post-herpetic neuralgia are decreasing whilst painful diabetic neuropathy plateaued and trigeminal neuralgia remained constant. Despite more frequent use of antidepressants and antiepileptics for first line treatment, as opposed to conventional non-opioid analgesics, changes to therapy are common before a stable regimen is reached.

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

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    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

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

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2010-04-01

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

  20. Relationships between changes in pain severity and other patient-reported outcomes: an analysis in patients with posttraumatic peripheral neuropathic pain

    OpenAIRE

    Zlateva Gergana; Morlion Bart; Bach Flemming W; Serpell Michael; van Seventer Robert; Bushmakin Andrew G; Cappelleri Joseph C; Nimour Meryem

    2011-01-01

    Abstract Background The objective of this study is to use the pain numeric rating scale (NRS) to evaluate associations between change in pain severity and changes in sleep, function, and mood assessed via patient-reported outcomes (PROs) in patients with posttraumatic pain. Methods This is a secondary analysis of a clinical trial evaluating pregabalin in patients with posttraumatic peripheral neuropathic pain (N = 254). Regression models were used to determine associations between changes in ...

  1. Self-medication of a cannabinoid CB2 agonist in an animal model of neuropathic pain

    OpenAIRE

    Gutierrez, Tannia; Crystal, Jonathon D.; Zvonok, Alexander M.; Makriyannis, Alexandros; Hohmann, Andrea G.

    2011-01-01

    Drug self-administration methods were used to test the hypothesis that rats would self-medicate with a cannabinoid CB2 agonist to attenuate a neuropathic pain state. Self-medication of the CB2 agonist (R,S)-AM1241, but not vehicle, attenuated mechanical hypersensitivity produced by spared nerve injury. Switching rats from (R,S)-AM1241 to vehicle self-administration also decreased lever responding in an extinction paradigm. (R,S)-AM1241 self-administration did not alter paw withdrawal threshol...

  2. Evaluation of Lercanidipine in Paclitaxel-Induced Neuropathic Pain Model in Rat: A Preliminary Study

    OpenAIRE

    Lekha Saha; Debasish Hota; Amitava Chakrabarti

    2012-01-01

    Objective. To demonstrate the antinociceptive effect of lercanidipine in paclitaxel-induced neuropathy model in rat. Materials and Methods. A total of 30 rats were divided into five groups of six rats in each group as follows: Gr I: 0.9% NaCl, Gr II: paclitaxel + 0.9% NaCl, Gr III: paclitaxel + lercanidipine 0.5 μg/kg, Gr IV: paclitaxel + lercanidipine 1 μg/kg, and Gr V: paclitaxel + lercanidipine 2.5 μg/kg. Paclitaxel-induced neuropathic pain in rat was produced by single intraperitoneal (i....

  3. Interleukin-17A Acts to Maintain Neuropathic Pain Through Activation of CaMKII/CREB Signaling in Spinal Neurons.

    Science.gov (United States)

    Yao, Cheng-Ye; Weng, Ze-Lin; Zhang, Jian-Cheng; Feng, Tao; Lin, Yun; Yao, Shanglong

    2016-08-01

    Immunity and neuroinflammation play major roles in neuropathic pain. Spinal interleukin (IL)-17A, as a mediator connecting innate and adaptive immunity, has been shown to be an important cytokine in neuroinflammation and acute neuropathic pain. However, the effects and underlying mechanisms of spinal IL-17A in the maintenance of neuropathic pain remain unknown. This study was designed to investigate whether spinal IL-17A acted to maintain neuropathic pain and to elucidate the underlying mechanisms in IL-17A knockout or wild-type (WT) mice following L4 spinal nerve ligation (L4 SNL). WT mice were treated with anti-IL-17A neutralized monoclonal antibody (mAb) or recombinant IL-17A (rIL-17A). We showed that IL-17A levels were significantly increased 1, 3, 7, and 14 days after SNL in spinal cord. Double immunofluorescence staining showed that astrocytes were the major cellular source of spinal IL-17A. IL-17A knockout or anti-IL-17A mAb treatment significantly ameliorated hyperalgesia 7 days after SNL, which was associated with a significant reduction of p-CaMKII and p-CREB levels in spinal cord, whereas rIL-17A treatment conferred the opposite effects. Furthermore, we showed that blocking CaMKII with KN93 significantly reduced SNL- or rIL-17A-induced hyperalgesia and p-CREB expression. Our in vitro data showed that KN93 also significantly inhibited rIL-17A-induced CREB activation in primary cultured spinal neurons. Taken together, our study indicates that astrocytic IL-17A plays important roles in the maintenance of neuropathic pain through CaMKII/CREB signaling pathway in spinal cord, and thus targeting IL-17A may offer an attractive strategy for the treatment of chronic persistent neuropathic pain. PMID:26166359

  4. 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. PMID:23219393

  5. 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

  6. Gene transfer of GLT-1, a glial glutamate transporter, into the spinal cord by recombinant adenovirus attenuates inflammatory and neuropathic pain in rats

    Directory of Open Access Journals (Sweden)

    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.

  7. A comparative study of efficacy of gabapentin in inflammation induced neuropathic animal pain models with conventional analgesic diclofenac

    OpenAIRE

    Arunim Swarup; Ruchika Agarwal; Sunil Malhotra; Abhay Shankar Dube

    2016-01-01

    Background: Some antiepileptic drugs have been shown to be clinically efficacious in treatment of neuropathic pain and are being used by clinicians. This study is proposed to evaluate the efficacy of these drugs as compared to conventional analgesics. Methods: Formalin test has been used as the model of acute and chronic inflammatory pain. Formalin has been characterized by the occurrence of two characteristic phases of increased pain sensitivity in rats. The ...

  8. Respective pharmacological features of neuropathic-like pain evoked by intrathecal BDNF versus sciatic nerve ligation in rats

    OpenAIRE

    M’Dahoma, Saïd; Barthélemy, Sandrine; Tromilin, Claire; Jeanson, Tiffany; Viguier, Florent; Michot, Benoit; Pezet, Sophie; Hamon, Michel; Bourgoin, Sylvie

    2015-01-01

    International audience Numerous reported data support the idea that Brain Derived Neurotrophic Factor (BDNF) is critically involved in both depression and comorbid pain. The possible direct effect of BDNF on pain mechanisms was assessed here and compared with behavioral/neurobiological features of neuropathic pain caused by chronic constriction injury to the sciatic nerve (CCI-SN). Sprague–Dawley male rats were either injected intrathecally with BDNF (3.0 ng i.t.) or subjected to unilatera...

  9. Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain

    OpenAIRE

    Ragavendran, J. Vaigunda; Laferrière, André; Xiao, Wen Hua; Bennett, Gary J.; Padi, Satyanarayana S.V.; Zhang, Ji; Coderre, Terence J.

    2013-01-01

    Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors combi...

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

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    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

  11. Incidence of neuropathic pain after radiofrequency denervation of the third occipital nerve

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    Gazelka HM

    2014-04-01

    Full Text Available Halena M Gazelka, Sarah Knievel, William D Mauck, Susan M Moeschler, Matthew J Pingree, Richard H Rho, Tim J Lamer Division of Pain Medicine, Mayo Clinic, Rochester, MN, USA Abstract: The purpose of this study was to identify the incidence of neuropathic pain occurring after radiofrequency neurotomy of the third occipital nerve (TON. This study was conducted at a teaching hospital from January 1, 2008, to March 31, 2010. With institutional review board approval, Current Procedural Terminology codes were used to identify patients who received radiofrequency ablation (RFA of the nerves supplying the C2-3 facet joint and the TON. The C3 dorsal ramus provides innervation to the C2-3 facet joint and the suboccipital cutaneous region, and procedures that included ablation to this region were reviewed for complications. Postprocedural data were collected by reviewing follow-up appointment notes and telephone calls. Included were patients who had new neuropathic pain in the distribution of the TON after RFA. They described what they were feeling as burning, tingling, or numbness. All patients who presented with complaints had normal neurologic findings and no secondary cause for their symptoms. The included patient medical records were then reviewed for severity and duration of symptoms and the need for treatment with pain medication. Sixty-four patients underwent C2-3 RFA or TON RFA, and 12 patients were identified as experiencing ablation-induced third occipital neuralgia, an incidence rate of 19%. This finding suggests that patients undergoing RFA of the nerves supplying the C2-3 joint or TON are at risk for postprocedural third occipital neuralgia. This possibility may affect providing informed consent as well as anticipating and managing postprocedural pain. Keywords: cervical spine, neuralgia, neurotomy, ablation

  12. Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition.

    Science.gov (United States)

    Kahle, Kristopher T; Schmouth, Jean-François; Lavastre, Valérie; Latremoliere, Alban; Zhang, Jinwei; Andrews, Nick; Omura, Takao; Laganière, Janet; Rochefort, Daniel; Hince, Pascale; Castonguay, Geneviève; Gaudet, Rébecca; Mapplebeck, Josiane C S; Sotocinal, Susana G; Duan, JingJing; Ward, Catherine; Khanna, Arjun R; Mogil, Jeffrey S; Dion, Patrick A; Woolf, Clifford J; Inquimbert, Perrine; Rouleau, Guy A

    2016-01-01

    HSN2is a nervous system predominant exon of the gene encoding the kinase WNK1 and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. The HSN2-containing splice variant is referred to as WNK1/HSN2. We created a knockout mouse specifically lacking theHsn2exon ofWnk1 Although these mice had normal spinal neuron and peripheral sensory neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K(+)-Cl(-)cotransporter KCC2 by increasing its inhibitory phosphorylation at Thr(906)and Thr(1007), resulting in an associated loss of GABA (γ-aminobutyric acid)-mediated inhibition of spinal pain-transmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Cl(-)such that GABA signaling resulted in a less hyperpolarized state (increased neuronal activity) rather than a more hyperpolarized state (decreased neuronal activity) in mouse spinal nerves. Pharmacologically antagonizing WNK activity reduced cold allodynia and mechanical hyperalgesia, decreased KCC2 Thr(906)and Thr(1007)phosphorylation, and restored GABA-mediated inhibition (hyperpolarization) of injured spinal cord lamina II neurons. These data provide mechanistic insight into, and a compelling therapeutic target for treating, neuropathic pain after nerve injury. PMID:27025876

  13. Ulinastatin attenuates neuropathic pain induced by L5-VRT via the calcineurin/IL-10 pathway.

    Science.gov (United States)

    Ouyang, Handong; Nie, Bilin; Wang, Peizong; Li, Qiang; Huang, Wan; Xin, Wenjun; Zeng, Weian; Liu, Xianguo

    2016-01-01

    Previous studies have shown that ulinastatin, an effective inhibitor of the inflammatory response in clinical applications, can attenuate hyperalgesia in rodents. However, the underlying mechanism remains unclear. In the present study, we first examined the change in the calcineurin level, which plays an important role in regulating cytokine release in the nervous system, following lumbar 5 ventral root transection in the rat. Furthermore, we determined whether intraperitoneal (i.p.) injection of ulinastatin attenuated pain behavior via inhibition of the calcineurin-mediated inflammatory response induced by lumbar 5 ventral root transection. The results showed that the paw withdrawal threshold and paw withdrawal latency were significantly decreased following lumbar 5 ventral root transection compared to the sham group. Neuropathic pain induced by lumbar 5 ventral root transection significantly decreased the expression of calcineurin in the DRG, and calcineurin was mostly located with NF-200-positive cells, IB4-positive cells, and CGRP-positive cells and less with GFAP-positive satellite cells. Furthermore, intrathecal (i.t.) injection of exogenous calcineurin attenuated the pain behavior induced by lumbar 5 ventral root transection. Importantly, intraperitoneal injection of ulinastatin alleviated the pain behavior and calcineurin downregulation induced by lumbar 5 ventral root transection. Lastly, the cytokine IL-10 was significantly decreased following lumbar 5 ventral root transection, and application of calcineurin (intrathecal) or ulinastatin (intraperitoneal) inhibited the IL-10 downregulation induced by lumbar 5 ventral root transection. These results suggested that ulinastatin, by acting on the CN/IL-10 pathway, might be a novel and effective drug for the treatment of neuropathic pain. PMID:27175013

  14. Molecular mechanisms underlying the enhanced analgesic effect of oxycodone compared to morphine in chemotherapy-induced neuropathic pain.

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    Karine Thibault

    Full Text Available Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone.

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

    Science.gov (United States)

    Jones, Erick; Romero-Ortega, Mario

    2016-01-01

    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. PMID:26760033

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain.

    Science.gov (United States)

    Masuda, Takahiro; Ozono, Yui; Mikuriya, Satsuki; Kohro, Yuta; Tozaki-Saitoh, Hidetoshi; Iwatsuki, Ken; Uneyama, Hisayuki; Ichikawa, Reiko; Salter, Michael W; Tsuda, Makoto; Inoue, Kazuhide

    2016-01-01

    Activation of purinergic receptors in the spinal cord by extracellular ATP is essential for neuropathic hypersensitivity after peripheral nerve injury (PNI). However, the cell type responsible for releasing ATP within the spinal cord after PNI is unknown. Here we show that PNI increases expression of vesicular nucleotide transporter (VNUT) in the spinal cord. Extracellular ATP content ([ATP]e) within the spinal cord was increased after PNI, and this increase was suppressed by exocytotic inhibitors. Mice lacking VNUT did not show PNI-induced increase in [ATP]e and had attenuated hypersensitivity. These phenotypes were recapitulated in mice with specific deletion of VNUT in spinal dorsal horn (SDH) neurons, but not in mice lacking VNUT in primary sensory neurons, microglia or astrocytes. Conversely, ectopic VNUT expression in SDH neurons of VNUT-deficient mice restored PNI-induced increase in [ATP]e and pain. Thus, VNUT is necessary for exocytotic ATP release from SDH neurons which contributes to neuropathic pain. PMID:27515581

  18. Preventive Effects of Bee Venom Derived Phospholipase A₂ on Oxaliplatin-Induced Neuropathic Pain in Mice.

    Science.gov (United States)

    Li, Dongxing; Kim, Woojin; Shin, Dasom; Jung, Yongjae; Bae, Hyunsu; Kim, Sun Kwang

    2016-01-01

    Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A₂ (bvPLA₂) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were observed at three days after an injection of oxaliplatin (6 mg/kg, i.p.) and then decreased gradually to a normal level on days 7-9. The oxaliplatin injection also induced infiltration of macrophages and upregulated levels of the pro-inflammatory cytokine interleukin (IL)-1β in the lumbar dorsal root ganglia (DRG). Daily treatment with bvPLA₂ (0.2 mg/kg, i.p.) for five consecutive days prior to the oxaliplatin injection markedly inhibited the development of cold and mechanical allodynia, and suppressed infiltration of macrophages and the increase of IL-1β level in the DRG. Such preventive effects of bvPLA₂ were completely blocked by depleting regulatory T cells (Tregs) with CD25 antibody pre-treatments. These results suggest that bvPLA₂ may prevent oxaliplatin-induced neuropathic pain by suppressing immune responses in the DRG by Tregs. PMID:26797636

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

    Directory of Open Access Journals (Sweden)

    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.

  20. In vivo and in vitro protective effects of omeprazole against neuropathic pain.

    Science.gov (United States)

    Chanchal, Sanjay K; Mahajan, Umesh B; Siddharth, Sumit; Reddy, Navyya; Goyal, Sameer N; Patil, Prakash H; Bommanahalli, Basavaraj P; Kundu, Chanakya N; Patil, Chandragouda R; Ojha, Shreesh

    2016-01-01

    Apart from reducing the acid secretion, omeprazole inhibits activation of the nuclear factor-κB, release of inflammatory cytokines, and chemotaxis of neutrophils. These mechanisms prompted us to evaluate antineuropathic effect of omeprazole in the chronic constriction injury (CCI)-induced rat model of neuropathic pain and LPS mediated ROS-induced U-87 cells. Omeprazole at 50 mg/kg/day/oral for 14 days significantly reduced the intensity of neuropathic pain estimated as paw withdrawal latency, withdrawal pressure threshold and restored the motor nerve conduction velocity in the constricted nerve, when compared with respective groups. The histological findings revealed the protective effect of omeprazole against the CCI-induced damage. Omeprazole significantly decreased the levels of tumor necrosis factor (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) as compared to their respective control groups. It also reduced the oxidative stress by up regulating the SOD, catalase activity and decreasing MDA content. Similarly, in-vitro study, LPS mediated ROS-induced U-87 cells, omeprazole reduced the oxidative stress as well as the release of TNF-α, IL-1β and IL-6. Altogether, these results suggest that, neuroprotective effect of omeprazole is mediated through preventing release of proinflammatory cytokines, augmenting endogenous anti-oxidant defense system, and maintain the structural integrity of sciatic nerve from the CCI-induced structural damage and inflammatory changes. PMID:27435304

  1. Glial TNFα in the spinal cord regulates neuropathic pain induced by HIV gp120 application in rats

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    Ouyang Handong

    2011-05-01

    Full Text Available Abstract Background HIV-associated sensory neuropathy (HIV-SN is one of the most common forms of peripheral neuropathy, affecting about 30% of people with acquired immune deficiency syndrome (AIDS. The symptoms of HIV-SN are dominated by neuropathic pain. Glia activation in the spinal cord has become an attractive target for attenuating chronic pain. This study will investigate the role of spinal TNFα released from glia in HIV-related neuropathic pain. Results Peripheral gp120 application into the rat sciatic nerve induced mechanical allodynia for more than 7 weeks, and upregulated the expression of spinal TNFα in the mRNA and the protein levels at 2 weeks after gp120 application. Spinal TNFα was colocalized with GFAP (a marker of astrocytes and Iba1 (a marker of microglia in immunostaining, suggesting that glia produce TNFα in the spinal cord in this model. Peripheral gp120 application also increased TNFα in the L4/5 DRG. Furthermore, intrathecal administration of TNFα siRNA or soluble TNF receptor reduced gp120 application-induced mechanical allodynia. Conclusions Our results indicate that TNFα in the spinal cord and the DRG are involved in neuropathic pain, following the peripheral HIV gp120 application, and that blockade of the glial product TNFα reverses neuropathic pain induced by HIV gp120 application.

  2. Antinociceptive Effects of Botulinum Toxin Type A on Trigeminal Neuropathic Pain.

    Science.gov (United States)

    Yang, K Y; Kim, M J; Ju, J S; Park, S K; Lee, C G; Kim, S T; Bae, Y C; Ahn, D K

    2016-09-01

    Previous studies have demonstrated that botulinum toxin type A (BoNT-A) attenuates orofacial nociception. However, there has been no evidence of the participation of the voltage-gated sodium channels (Navs) in the antinociceptive mechanisms of BoNT-A. This study investigated the cellular mechanisms underlying the antinociceptive effects of BoNT-A in a male Sprague-Dawley rat model of trigeminal neuropathic pain produced by malpositioned dental implants. The left mandibular second molar was extracted under anesthesia, followed by a miniature dental implant placement to induce injury to the inferior alveolar nerve. Mechanical allodynia was monitored after subcutaneous injection of BoNT-A at 3, 7, or 12 d after malpositioned dental implant surgery. Subcutaneous injections of 1 or 3 U/kg of BoNT-A on postoperative day 3 significantly attenuated mechanical allodynia, although 0.3 U/kg of BoNT-A did not affect the air-puff threshold. A single injection of 3 U/kg of BoNT-A produced prolonged antiallodynic effects over the entire experimental period. Treatment with BoNT-A on postoperative days 7 and 12, when pain had already been established, also produced prolonged antiallodynic effects. Double treatments with 1 U/kg of BoNT-A produced prolonged, more antiallodynic effects as compared with single treatments. Subcutaneous administration of 3 U/kg of BoNT-A significantly inhibited the upregulation of Nav isoform 1.7 (Nav1.7) expression in the trigeminal ganglion in the nerve-injured animals. These results suggest that antinociceptive effects of BoNT-A are mediated by an inhibition of upregulated Nav1.7 expression in the trigeminal ganglion. BoNT-A is therefore a potential new therapeutic agent for chronic pain control, including neuropathic pain. PMID:27418174

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

    DEFF Research Database (Denmark)

    Vollert, Jan; Kramer, M; Barroso, A; Freynhagen, R; Haanpää, M; Hansson, P; Jensen, T S; Kuehler, B M; Maier, C; Mainka, T; Reimer, M; Segerdahl, M; Serra, J; Solà, R; Tölle, T R; Treede, R D; Baron, R

    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 into...

  4. 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.

  5. 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.

  6. 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

  7. Enhanced Expression of TREK-1 Is Related with Chronic Constriction Injury of Neuropathic Pain Mouse Model in Dorsal Root Ganglion.

    Science.gov (United States)

    Han, Hyo Jo; Lee, Seung Wook; Kim, Gyu-Tae; Kim, Eun-Jin; Kwon, Byeonghun; Kang, Dawon; Kim, Hyun Jeong; Seo, Kwang-Suk

    2016-05-01

    Neuropathic pain is a complex state showing increased pain response with dysfunctional inhibitory neurotransmission. The TREK family, one of the two pore domain K⁺ (K2P) channel subgroups were focused among various mechanisms of neuropathic pain. These channels influence neuronal excitability and are thought to be related in mechano/thermosensation. However, only a little is known about the expression and role of TREK-1 and TREK-2, in neuropathic pain. It is performed to know whether TREK-1 and/ or 2 are positively related in dorsal root ganglion (DRG) of a mouse neuropathic pain model, the chronic constriction injury (CCI) model. Following this purpose, Reverse Transcription Polymerase Chain Reaction (RT-PCR) and western blot analyses were performed using mouse DRG of CCI model and compared to the sham surgery group. Immunofluorescence staining of isolectin- B4 (IB4) and TREK were performed. Electrophysiological recordings of single channel currents were analyzed to obtain the information about the channel. Interactions with known TREK activators were tested to confirm the expression. While both TREK-1 and TREK-2 mRNA were significantly overexpressed in DRG of CCI mice, only TREK-1 showed significant increase (~9 fold) in western blot analysis. The TREK-1-like channel recorded in DRG neurons of the CCI mouse showed similar current-voltage relationship and conductance to TREK-1. It was easily activated by low pH solution (pH 6.3), negative pressure, and riluzole. Immunofluorescence images showed the expression of TREK-1 was stronger compared to TREK-2 on IB4 positive neurons. These results suggest that modulation of the TREK-1 channel may have beneficial analgesic effects in neuropathic pain patients. PMID:27133259

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Science.gov (United States)

    Andresen, Sven R; Bing, Jette; Hansen, Rikke M; Biering-Sørensen, Fin; Johannesen, Inger L; Hagen, Ellen Merete; Rice, Andrew S C; Nielsen, Jørgen F; Bach, Flemming W; Finnerup, Nanna B

    2016-09-01

    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, double-blind, placebo-controlled, parallel multicenter study was performed to investigate the effect of ultramicronized PEA (PEA-um) as add-on therapy on neuropathic pain in individuals with SCI. A pain diary was completed and questionnaires were completed before and after the 12-week treatment with either placebo or PEA-um. The primary outcome measure was the change in mean neuropathic pain intensity from the 1-week baseline period to the last week of treatment measured on a numeric rating scale ranging from 0 to 10. The primary efficacy analysis was the intention to treat (baseline observation carried forward). Secondary outcomes included a per protocol analysis and effects on spasticity, evoked pain, sleep problems, anxiety, depression, and global impression of change. We randomized 73 individuals with neuropathic pain due to SCI, of which 5 had a major protocol violation, and thus 68 were included in the primary analysis. There was no difference in mean pain intensity between PEA-um and placebo treatment (P = 0.46, mean reductions in pain scores 0.4 (-0.1 to 0.9) vs 0.7 (0.2-1.2); difference of means 0.3 (-0.4 to 0.9)). There was also no effect of PEA-um as add-on therapy on spasticity, insomnia, or psychological functioning. PEA was not associated with more adverse effects than placebo. PMID:27227691

  11. 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.

  12. 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.

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

    OpenAIRE

    Wilkes D; Li G; Angeles CF; Patterson JT; Huang LY

    2012-01-01

    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 ...

  14. Protective Effect of Ethanol Extracts of Hericium erinaceus on Alloxan-Induced Diabetic Neuropathic Pain in Rats

    OpenAIRE

    Yi, Zhang; Shao-long, Yang; Ai-hong, Wang; Zhi-chun, Sun; Ya-fen, Zhuo; Ye-ting, Xu; Yu-ling, He

    2015-01-01

    We investigated the effects of Hericium erinaceus (HEE) on alloxan induced diabetic neuropathic pain in laboratory rats. Alloxan induced diabetic rats were administered orally HEE. After 6 weeks of treatments, treatment with HEE 40 mg/kg in diabetic animals showed significant increase in pain threshold and paw withdrawal threshold and significant decrease in serum glucose and urine glucose. We also observed a significant increase in lactate dehydrogenase (LDH), Lipid peroxidation (LPO), gluta...

  15. Concurrent Activation of the Somatosensory Forebrain and Deactivation of Periaqueductal Grey Associated With Diabetes-Induced Neuropathic Pain

    OpenAIRE

    Paulson, Pamela E.; Wiley, John W.; Morrow, Thomas J.

    2007-01-01

    We combined behavioral testing with brain imaging using 99mTc-HMPAO (Amersham Health), to identify CNS structures reflecting alterations in pain perception in the streptozotocin (STZ) model of Type 1 diabetes. We induced diabetic hyperglycemia (blood glucose >300 mg/dl) by injecting male Sprague-Dawley rats with STZ (45 mg/kg i.p.). Four weeks after STZ, diabetic rats exhibited behaviors indicative of neuropathic pain (hypersensitivity thermal stimuli) and this hypersensitivity persisted for ...

  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. 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.

  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

    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......-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. Population analyses of efficacy and safety of ABT-594 in subjects with diabetic peripheral neuropathic pain.

    Science.gov (United States)

    Dutta, Sandeep; Hosmane, Balakrishna S; Awni, Walid M

    2012-06-01

    ABT-594, a neuronal nicotinic acetylcholine receptor ligand, is 30- to 100-fold more potent than morphine in animal models of nociceptive and neuropathic pain. Efficacy and safety of ABT-594 in subjects with painful diabetic polyneuropathy was evaluated in a phase 2 study. The objective of this work was to use a nonlinear mixed effects model-based approach for characterizing the relationship between dose and response (efficacy and safety) of ABT-594. Subjects (N = 266) were randomized into four groups in a double-blind, placebo-controlled, 7-week study to receive twice daily regimens of placebo or 150, 225, and 300 μg of ABT-594. The primary efficacy variable, pain score (11-point Likert scale), was assessed on five occasions. The probability of change from baseline pain score of ≥1, ≥2, and ≥3 was modeled using cumulative logistic regression with dose and days of treatment as explanatory variables. The incidence of five most frequently occurring adverse events (AEs) was modeled using linear logistic regression. ABT-594 ED(50) values (improvement in 50% of subjects) for improvement in pain scores of ≥1, ≥2, and ≥3 were 50, 215, and 340 μg, respectively, for the average number of days (33) on treatment. The rank order of ED(50) values for AEs was nausea, vomiting, dizziness, headache, and abnormal dreams; nicotine users were less sensitive to AEs. Population pharmacodynamic models developed to characterize the improvement in pain score and incidence of adverse events indicate an approximately twofold separation between the ED(50) values for efficacy and AEs. PMID:22328206

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

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    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.

  1. 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. PMID:26713106

  2. Afferent hyperexcitability in neuropathic pain and the inconvenient truth about its degeneracy.

    Science.gov (United States)

    Ratté, Stéphanie; Prescott, Steven A

    2016-02-01

    Neuropathic pain, which arises from damage to the nervous system, is a major unmet clinical challenge. Reversing the neuronal hyperexcitability induced by nerve damage is a logical treatment strategy but has proven frustratingly difficult. Here, we propose a novel explanation for that difficulty. Changes in several different ion channels are individually sufficient to cause hyperexcitability in primary somatosensory neurons. Despite offering multiple drug targets, this scenario is problematic: if multiple sufficient changes are triggered by nerve injury, then no single change is necessary for hyperexcitability. This so-called degeneracy compromises therapeutic interventions because drug effects on any one ion channel can be circumvented by changes occurring in other ion channels. Overcoming degeneracy demands a more integrative approach to drug discovery. PMID:26363576

  3. BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals.

    Science.gov (United States)

    Chen, Wenling; Walwyn, Wendy; Ennes, Helena S; Kim, Hyeyoung; McRoberts, James A; Marvizón, Juan Carlos G

    2014-05-01

    NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75(NTR) ), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75(NTR) inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr(1472) phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and a Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain. PMID:24611998

  4. 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

    2016-01-01

    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. PMID:26190414

  5. Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations

    Science.gov (United States)

    van Hecke, Oliver; Kamerman, Peter R.; Attal, Nadine; Baron, Ralf; Bjornsdottir, Gyda; Bennett, David L.H.; Bennett, Michael I.; Bouhassira, Didier; Diatchenko, Luda; Freeman, Roy; Freynhagen, Rainer; Haanpää, Maija; Jensen, Troels S.; Raja, Srinivasa N.; Rice, Andrew S.C.; Seltzer, Ze'ev; Thorgeirsson, Thorgeir E.; Yarnitsky, David; Smith, Blair H.

    2015-01-01

    Abstract For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic “entry level” set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of “possible” neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC “entry level” set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability. PMID:26469320

  6. Brain-Derived Neurotrophic Factor from Microglia: A Molecular Substrate for Neuropathic Pain

    OpenAIRE

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

    2011-01-01

    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 dir...

  7. 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

    2016-10-01

    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. PMID:27181607

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    Chun Jerold

    2008-02-01

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

  10. Mice undergoing neuropathic pain induce anxiogenic-like effects and hypernociception in cagemates.

    Science.gov (United States)

    Baptista-de-Souza, Daniela; Nunciato, Ana C; Pereira, Barbara C; Fachinni, Gabriel; Zaniboni, Caroline R; Canto-de-Souza, Azair

    2015-10-01

    Rodents can recognize pain-related responses in conspecifics. Therefore, cohabitation with a conspecific animal with chronic pain can potentially promote a stressful situation, which can trigger behavioral changes such as anxiety and depression and alter nociceptive responses. In this study we investigated the effect of cohabitation with a mouse undergoing sciatic nerve constriction (neuropathic pain model). The cagemates were evaluated for nociception (writhing test), anxiety (elevated plus-maze and open field tests), depression (forced swim, tail suspension, and sucrose preference tests), and corticosterone levels. Male Swiss mice were housed in pairs for 14 days, and then divided into three groups: cagemate nerve constriction, in which one animal of each pair was subjected to constriction of the sciatic nerve; cagemate sham, in which one animal from each pair was subjected to the same surgery but without constriction; and control, in which animals were not subjected to any surgical procedure. After 14 days, the cagemates were evaluated using behavioral tests. Social interaction with a conspecific undergoing constriction of the sciatic nerve induced hypernociception and increased anxiety-related responses, whereas in depression tests inconclusive responses and no changes in corticosterone levels were found. In conclusion, cohabitation with suffering conspecifics induces changes in nociceptive responses, as well as in affective responses including anxiety. PMID:26258589

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Differential expression of ATP-gated P2X receptors in DRG between chronic neuropathic pain and visceralgia rat models.

    Science.gov (United States)

    Chen, Lin; Liu, Yu-Wei; Yue, Kai; Ru, Qin; Xiong, Qi; Ma, Bao-Miao; Tian, Xiang; Li, Chao-Ying

    2016-03-01

    There are divergences between neuropathic pain and visceralgia in terms of the duration, location, and character of hyperalgesia. It is generally recognized that nociceptive receptors, including P2X receptors, may play different roles in nociceptive mechanisms. The different roles of P2X1-7 receptors have not been fully understood both in neuropathic pain and visceral hyperalgesia. In order to explore the different expressions of P2X1-7 receptors in these two hyperalgesia models, the lumbosacral dorsal root ganglion (DRG) neurons from rat sciatic nerve chronic constriction injury (CCI) model and neonatal colorectal distention (NCRD) model were studied (both the primary nociceptive neuron afferents of those two models projected to the same segment of spinal cord). Both immunohistochemistry (IHC) technique and real-time fluorescence quantitative polymerase chain reaction (RT-PCR) technology were applied to analyze the protein expression levels and nucleic acid of P2X1-7 receptors. We found that except P2X2 and P2X3, the expression levels of P2X1 and P2X5 receptors increased in neuropathic pain while those expression levels of P2X4, P2X6, and P2X7 receptors increased in visceral pain. Our results also suggested that in addition to P2X2/3 heteromeric, other P2X subunits may also involved in generation heteromeric such as P2X1/5 and/or P2X2/5 in neuropathic pain and P2X4/6 and/or P2X4/7 in visceral pain. PMID:26531254

  13. Treatment of localized neuropathic pain of different etiologies with the 5% lidocaine medicated plaster – a case series

    Directory of Open Access Journals (Sweden)

    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

  14. Chronic Pain: Where the Body Meets the Brain

    OpenAIRE

    Crofford, Leslie J

    2015-01-01

    Chronic musculoskeletal pain is one of the most intractable clinical problems faced by clinicians and can be devastating for patients. Central pain amplification is perceived pain that cannot be fully explained on the basis of somatic or neuropathic processes and is due to physiologic alterations in pain transmission or descending pain modulatory pathways. In any individual, central pain amplification may complicate nociceptive or neuropathic pain. Furthermore, patients with somatic symptom d...

  15. 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

    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...

  16. Effect of electroacupuncture at distal–proximal acupoint combinations on spinal interleukin-1 beta in a rat model of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Huili Jiang

    2015-01-01

    Conclusion: EA at distal + proximal acupoints, distal points, as well as proximal points attenuated upregulation of spinal IL-1β, alleviated the extent of neuropathic pain hypersensitivity, and promoted mechanical withdrawal threshold, resulting in EA analgesia.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. A comparative study of efficacy and safety of gabapentin versus amitriptyline as coanalgesics in patients receiving opioid analgesics for neuropathic pain in malignancy

    OpenAIRE

    Manasi Banerjee; Santanu Pal; Biswamit Bhattacharya; Balaram Ghosh; Shirsendu Mondal; Joydeep Basu

    2013-01-01

    Objective: To assess the efficacy and safety of gabapentin and amitriptyline along with opioids in patients suffering from neuropathic pain in malignancy. Materials and Methods: Eighty-eight adult patients between 18 and 70 years of age with neuropathic pain in stage III malignant disease, matched for baseline charactistics, were randomly assigned to two groups. Group A received oral tramadol and gabapentin and group B received oral tramadol and amitriptyline. The treatment duration of e...

  19. A comparative study of efficacy and safety of gabapentin versus amitriptyline as coanalgesics in patients receiving opioid analgesics for neuropathic pain in malignancy

    OpenAIRE

    Banerjee, Manasi; Pal, Santanu; Bhattacharya, Biswamit; Ghosh, Balaram; Mondal, Shirsendu; Basu, Joydeep

    2013-01-01

    Objective: To assess the efficacy and safety of gabapentin and amitriptyline along with opioids in patients suffering from neuropathic pain in malignancy. Materials and Methods: Eighty-eight adult patients between 18 and 70 years of age with neuropathic pain in stage III malignant disease, matched for baseline charactistics, were randomly assigned to two groups. Group A received oral tramadol and gabapentin and group B received oral tramadol and amitriptyline. The treatment duration of each p...

  20. Overexpression of GRK6 attenuates neuropathic pain via suppression of CXCR2 in rat dorsal root ganglion.

    Science.gov (United States)

    Zhou, Yuan; Li, Rong-Ji; Li, Meng; Liu, Xuelian; Zhu, Hong-Yan; Ju, Zhong; Miao, Xiuhua; Xu, Guang-Yin

    2016-01-01

    G protein-coupled kinase (GRK) 6 is a member of the GRK family that mediates agonist-induced desensitization and signaling of G protein-coupled receptors (GPCRs), thus involving in a wide variety of processes including inflammation and nociception. Recent studies have indicated that chemokines play an important role in chronic pain via increased expression of respective GPCRs. This study was designed to investigate the role of GRK6 and its interaction with substrate chemokine receptors in dorsal root ganglion (DRG) in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Following induction of CCI, GRK6 expression was significantly downregulated in rat DRGs at L4-L6 segments. Overexpression of GRK6 using lentiviral-mediated production strategy via sciatic nerve injection markedly attenuated mechanical allodynia and thermal hyperalgesia in CCI rats. Overexpression of GRK6 also drastically reversed the hyperexcitability of DRG neurons innervating the hind paw and suppressed the enhanced expression of CXCR2 in DRGs of CCI rats. In addition, co-immunoprecipitation, immunofluorescence, and correlation analysis supported the interaction between GRK6 and CXCR2. These results suggest that GRK6 might be a key molecular involved in peripheral mechanism of neuropathic pain and that overexpression of GRK6 might be a potential strategy for treatment for neuropathic pain through inhibition of CXCR2 signal pathway. PMID:27145805

  1. Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain.

    Science.gov (United States)

    Berrocoso, Esther; Mico, Juan-Antonio; Vitton, Olivier; Ladure, Philippe; Newman-Tancredi, Adrian; Depoortère, Ronan; Bardin, Laurent

    2011-03-25

    Milnacipran, a serotonin/norepinephrine reuptake inhibitor (SNRI), has shown efficacy against several chronic pain conditions, including fibromyalgia. Here, we evaluated, in rats, its anti-allodynic effects following acute or sub-chronic treatment in a model of neuropathic pain (chronic constriction injury, CCI, of the sciatic nerve). Amitriptyline, a tricyclic antidepressant active pre-clinically and clinically against neuropathic pains, was added as a comparison compound. Upon acute i.p. administration, milnacipran was potently efficacious in the CCI model. It significantly reduced thermal allodynia in the cold (4°C) plate test (MED=2.5mg/kg), and attenuated mechanical allodynia in the von Frey filaments test (MED=10mg/kg). Given sub-chronically (7day, b.i.d.), milnacipran was effective at 10mg/kgi.p. in both tests. Acute amitriptyline (10mg/kgi.p.) was efficacious against mechanical, but less so against cold allodynia; under sub-chronic conditions, it was only active against mechanical allodynia. These data show that milnacipran is as efficacious as the reference compound amitriptyline in a pre-clinical model of injury-induced neuropathy, and demonstrate for the first time that it is active acutely and sub-chronically against cold allodynia. They also suggest that milnacipran has the potential to alleviate allodynia associated with nerve compression-induced neuropathic pain in the clinic (for example following discal hernia, avulsion or cancer-induced tissue damage). PMID:21277295

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

    Science.gov (United States)

    Leppert, Wojciech; Kowalski, Grzegorz

    2015-01-01

    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. PMID:26675083

  3. Pain Mechanisms and Centralized Pain in Temporomandibular Disorders.

    Science.gov (United States)

    Harper, D E; Schrepf, A; Clauw, D J

    2016-09-01

    Until recently, most clinicians and scientists believed that the experience of pain is perceptually proportional to the amount of incoming peripheral nociceptive drive due to injury or inflammation in the area perceived to be painful. However, many cases of chronic pain have defied this logic, leaving clinicians perplexed as to how patients are experiencing pain with no obvious signs of injury in the periphery. Conversely, there are patients who have a peripheral injury and/or inflammation but little or no pain. What makes some individuals experience intense pain with minimal peripheral nociceptive stimulation and others experience minimal pain with serious injury? It is increasingly well accepted in the scientific community that pain can be generated and maintained or, through other mechanisms, suppressed by changes in the central nervous system, creating a complete mismatch between peripheral nociceptive drive and perceived pain. In fact, there is no known chronic pain condition where the observed extent of peripheral damage reproducibly engenders the same level of pain across individuals. Temporomandibular disorders (TMDs) are no exception. This review focuses on the idea that TMD patients range on a continuum-from those whose pain is generated peripherally to those whose pain is centralized (i.e., generated, exacerbated, and/or maintained by central nervous system mechanisms). This article uses other centralized chronic pain conditions as a guide, and it suggests that the mechanistic variability in TMD pain etiology has prevented us from adequately treating many individuals who are diagnosed with the condition. As the field moves forward, it will be imperative to understand each person's pain from its own mechanistic standpoint, which will enable clinicians to deliver personalized medicine to TMD patients and eventually provide relief in even the most recalcitrant cases. PMID:27422858

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    Wenbin Wan

    2016-01-01

    Full Text Available 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 emerging evidence reveals that HMGB1 plays an essential role in neuroinflammation through receptors such as Toll-like receptors (TLR, receptor for advanced glycation end products (RAGE, C-X-X motif chemokines receptor 4 (CXCR4, and N-methyl-D-aspartate (NMDA receptor. In this review, we present evidence from studies that address the role of HMGB1 in NPP. First, we review studies aimed at determining the role of HMGB1 in NPP and discuss the possible mechanisms underlying HMGB1-mediated NPP progression where receptors for HMGB1 are involved. Then we review studies that address HMGB1 as a potential therapeutic target for NPP.

  6. Irrational drug use in neuropathic pain treatment: a two-year data analysis

    Directory of Open Access Journals (Sweden)

    Tan E

    2013-01-01

    Full Text Available Background: Neuropathic pain (NeP manifests as chronic pain and causes significant medical and economic burden for both the individual and the society. Treatment of NeP is often symptomatic and includes single or combination drug therapy. Many drugs that are not recommended in the guidelines are also widely used. Aim: The present study was aimed at determining the annual cost of NeP treatment in Turkey and to assess the amount of resource loss due to irrational drug use and its associated complications. Methods: Each item in NeP prescriptions and their relevant costs between July 2007 and June 2009 was retrospectively analyzed. Results: The number of prescriptions for NeP was 8646358 and 9650641 for the first and second years, respectively. The irrational items were 7513299 in the first year and 8360754 in the second year. The proportion of irrational treatment cost was 48.5% for the first year and 48.6% for the second year. Total cost of these prescriptions was estimated to be 47924534 Turkish Liras and 60715905 Turkish Liras for the first and second years, respectively. The estimated irrational treatment cost of NeP together with the additional burden exceeded half of the total cost. Conclusions: Further studies on health economics perspective are needed to confirm these results. Better education of healthcare professionals and better regulations in reimbursement will help to improve this problem.

  7. 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....

  8. 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

  9. Synthesis and Evaluation of Novel α-Aminoamides Containing an Indole Moiety for the Treatment of Neuropathic Pain

    OpenAIRE

    Haotian Li; Shiyong Fan; Jingchao Cheng; Ping Zhang; Bohua Zhong; Weiguo Shi

    2016-01-01

    The α-aminoamide family of sodium ion channel blockers have exhibited analgesic effects on neuropathic pain. Here, a series of novel α-aminoamides containing an indole ring were designed and synthesized. These compounds were evaluated in mice using a formalin test and they exhibited significant anti-allodynia activities. However, the analgesic mechanism of these compounds remains unclear; a subset of the synthesized compounds can only moderately inhibit the sodium ion channel, Nav1.7, in a wh...

  10. Role of SIP30 in the development and maintenance of peripheral nerve injury-induced neuropathic pain

    OpenAIRE

    Zhang, Yu-Qiu; Guo, Ning; Peng, Guangdun; Han, Mei; Raincrow, Jeremy; Chiu, Chi-hua; Coolen, Lique M.; Wenthold, Robert J.; Zhao, Zhi-Qi; Jing, Naihe; Yu, Lei

    2009-01-01

    Using the chronic constriction injury (CCI) model of neuropathic pain, we profiled gene expression in the rat spinal cord, and identified SIP30 as a gene whose expression was elevated after CCI. SIP30 was previously shown to interact with SNAP25, but whose function was otherwise unknown. We now show that in the spinal cord, SIP30 was present in dorsal horn laminae where peripheral nociceptive inputs first synapse, colocalizing with nociception-related neuropeptides CGRP and substance P. With ...

  11. 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.

  12. Preventive Effects of Bee Venom Derived Phospholipase A2 on Oxaliplatin-Induced Neuropathic Pain in Mice

    OpenAIRE

    Dongxing Li; Woojin Kim; Dasom Shin; Yongjae Jung; Hyunsu Bae; Sun Kwang Kim

    2016-01-01

    Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A2 (bvPLA2) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were...

  13. Ameliorative potential of Butea monosperma on chronic constriction injury of sciatic nerve induced neuropathic pain in rats

    OpenAIRE

    Venkata R.K. Thiagarajan; Palanichamy Shanmugam; Uma M. Krishnan; Arunachalam Muthuraman; Nirmal Singh

    2012-01-01

    The present study was designed to investigate the ameliorative role of ethanolic extract from leaves of Butea monosperma in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal hyperalgesia, cold chemical allodynia, mechanical hyperalgesia & allodynia in the left hind paw and tail thermal hyperalgesia. Further on, thiobarbituric acid reac...

  14. Spinal cord T-cell infiltration in the spared nerve injury model of neuropathic pain: a time course study

    OpenAIRE

    Clarke C.

    2012-01-01

    Background : Numerous studies have shown that immune cells infiltrate the spinal cord after peripheral nerve injury and that they play a major contribution to sensory hypersensitivity in rodents. In particular, the role of monocyte-derived cells and T lymphocytes seems to be prominent in this process. This exciting new perspective in research on neuropathic pain opens many different areas of work, including the understanding of the function of these cells and how they impact on neural functio...

  15. Loss of Ca(2+)-permeable AMPA receptors in synapses of tonic firing substantia gelatinosa neurons in the chronic constriction injury model of neuropathic pain.

    Science.gov (United States)

    Chen, Yishen; Derkach, Victor A; Smith, Peter A

    2016-05-01

    Synapses transmitting nociceptive information in the spinal dorsal horn undergo enduring changes following peripheral nerve injury. Indeed, such injury alters the expression of the GluA2 subunit of glutamatergic AMPA receptors (AMPARs) in the substantia gelatinosa and this predicts altered channel conductance and calcium permeability, leading to an altered function of excitatory synapses. We therefore investigated the functional properties of synaptic AMPA receptors in rat substantia gelatinosa neurons following 10-20d chronic constriction injury (CCI) of the sciatic nerve; a model of neuropathic pain. We measured their single-channel conductance and sensitivity to a blocker of calcium permeable AMPA receptors (CP-AMPARs), IEM1460 (50μM). In putative inhibitory, tonic firing neurons, CCI reduced the average single-channel conductance of synaptic AMPAR from 14.4±3.5pS (n=12) to 9.2±1.0pS (n=10, pnerve injury acting at synapses of inhibitory neurons to reduce their drive and therefore inhibitory tone in the spinal cord, therefore contributing to the central sensitization associated with neuropathic pain. PMID:26948545

  16. Macrophage-Colony Stimulating Factor Derived from Injured Primary Afferent Induces Proliferation of Spinal Microglia and Neuropathic Pain in Rats

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    Okubo, Masamichi; Yamanaka, Hiroki; Kobayashi, Kimiko; Dai, Yi; Kanda, Hirosato; Yagi, Hideshi; Noguchi, Koichi

    2016-01-01

    Peripheral nerve injury induces proliferation of microglia in the spinal cord, which can contribute to neuropathic pain conditions. However, candidate molecules for proliferation of spinal microglia after injury in rats remain unclear. We focused on the colony-stimulating factors (CSFs) and interleukin-34 (IL-34) that are involved in the proliferation of the mononuclear phagocyte lineage. We examined the expression of mRNAs for macrophage-CSF (M-CSF), granulocyte macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF) and IL-34 in the dorsal root ganglion (DRG) and spinal cord after spared nerve injury (SNI) in rats. RT-PCR and in situ hybridization revealed that M-CSF and IL-34, but not GM- or G-CSF, mRNAs were constitutively expressed in the DRG, and M-CSF robustly increased in injured-DRG neurons. M-CSF receptor mRNA was expressed in naive rats and increased in spinal microglia following SNI. Intrathecal injection of M-CSF receptor inhibitor partially but significantly reversed the proliferation of spinal microglia and in early phase of neuropathic pain induced by SNI. Furthermore, intrathecal injection of recombinant M-CSF induced microglial proliferation and mechanical allodynia. Here, we demonstrate that M-CSF is a candidate molecule derived from primary afferents that induces proliferation of microglia in the spinal cord and leads to induction of neuropathic pain after peripheral nerve injury in rats. PMID:27071004

  17. 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.

  18. Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection.

    Science.gov (United States)

    Okada-Ogawa, Akiko; Nakaya, Yuka; Imamura, Yoshiki; Kobayashi, Masayuki; Shinoda, Masamichi; Kita, Kozue; Sessle, Barry J; Iwata, Koichi

    2015-05-01

    In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT)-VenusA rats expressing fluorescent protein and the VGAT in Vc neurons. The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. The background activity and mechanical-evoked responses of Vc nociceptive neurons were significantly depressed after intrathecal application of the GABA receptor agonist muscimol in sham rats but not in IANX rats. Furthermore, the expression of potassium-chloride co-transporter 2 (KCC2) in the Vc was significantly reduced in IANX rats compared with sham rats. The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment. These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at

  19. 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

  20. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.

    Science.gov (United States)

    Nurmikko, Turo J; Serpell, Mick G; Hoggart, Barbara; Toomey, Peter J; Morlion, Bart J; Haines, Derek

    2007-12-15

    Cannabinoids are known to have analgesic properties. We evaluated the effect of oro-mucosal sativex, (THC: CBD), an endocannabinoid system modulator, on pain and allodynia, in 125 patients with neuropathic pain of peripheral origin in a five-week, randomised, double-blind, placebo-controlled, parallel design trial. Patients remained on their existing stable analgesia. A self-titrating regimen was used to optimise drug administration. Sixty-three patients were randomised to receive sativex and 62 placebo. The mean reduction in pain intensity scores (primary outcome measure) was greater in patients receiving sativex than placebo (mean adjusted scores -1.48 points vs. -0.52 points on a 0-10 Numerical Rating Scale (p=0.004; 95% CI: -1.59, -0.32). Improvements in Neuropathic Pain Scale composite score (p=0.007), sleep NRS (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patient's Global Impression of Change (psativex vs. placebo. Sedative and gastrointestinal side effects were reported more commonly by patients on active medication. Of all participants, 18% on sativex and 3% on placebo withdrew during the study. An open-label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks. PMID:17997224

  1. [Progress in study on endocannabinoids and cannabinoid receptors in the treatment for neuropathic pain].

    Science.gov (United States)

    Liu, Peng; Zhang, Wei; Zhang, Shaobo; Zhang, Yibao; Wang, Jing

    2016-08-01

    Endocannabinoids and cannabinoid receptors are expressed in various central pain modulation regions. They maintain in dynamic changes in the expression level and distribution under different pathological and physiological conditions. These changes possess advantage as well as disadvantage. Exogenous administration of endocannabinoids exerts analgesic effect in different pain models, which is mainly mediated by the cannabinoid CB1 and CB2 receptors. Inhibition of enzymes for degrading endocannabinoids in different pain models also shows analgesic effect due to the increased local levels of endocannabinoids. PMID:27600019

  2. 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

  3. 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

  4. 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. PMID:26143011

  5. Therapeutic potential of RQ-00311651, a novel T-type Ca2+ channel blocker, in distinct rodent models for neuropathic and visceral pain.

    Science.gov (United States)

    Sekiguchi, Fumiko; Kawara, Yuma; Tsubota, Maho; Kawakami, Eri; Ozaki, Tomoka; Kawaishi, Yudai; Tomita, Shiori; Kanaoka, Daiki; Yoshida, Shigeru; Ohkubo, Tsuyako; Kawabata, Atsufumi

    2016-08-01

    T-type Ca channels (T channels), particularly Cav3.2 among the 3 isoforms, play a role in neuropathic and visceral pain. We thus characterized the effects of RQ-00311651 (RQ), a novel T-channel blocker, in HEK293 cells transfected with human Cav3.1 or Cav3.2 by electrophysiological and fluorescent Ca signaling assays, and also evaluated the antiallodynic/antihyperalgesic activity of RQ in somatic, visceral, and neuropathic pain models in rodents. RQ-00311651 strongly suppressed T currents when tested at holding potentials of -65 ∼ -60 mV, but not -80 mV, in the Cav3.1- or Cav3.2-expressing cells. RQ-00311651 also inhibited high K-induced Ca signaling in those cells. In mice, RQ, administered intraperitoneally (i.p.) at 5 to 20 mg/kg or orally at 20 to 40 mg/kg, significantly suppressed the somatic hyperalgesia and visceral pain-like nociceptive behavior/referred hyperalgesia caused by intraplantar and intracolonic administration of NaHS or Na2S, H2S donors, respectively, which involve the enhanced activity of Cav3.2 channels. RQ-00311651, given i.p. at 5 to 20 mg/kg, exhibited antiallodynic or antihyperalgesic activity in rats with spinal nerve injury-induced neuropathy or in rats and mice with paclitaxel-induced neuropathy. Oral and i.p. RQ at 10 to 20 mg/kg also suppressed the visceral nociceptive behavior and/or referred hyperalgesia accompanying cerulein-induced acute pancreatitis and cyclophosphamide-induced cystitis in mice. The analgesic and antihyperalgesic/antiallodynic doses of oral and i.p. RQ did not significantly affect the locomotor activity and motor coordination. Together, RQ is considered a state-dependent blocker of Cav3.1/Cav3.2 T channels and may serve as an orally available analgesic for treatment of neuropathic and inflammatory pain including distinct visceral pain with minimum central side effects. PMID:27023424

  6. Treadmill measures of ambulation rates in ovine models of spinal cord injury and neuropathic pain.

    Science.gov (United States)

    Safayi, S; Miller, J W; Wilson, S; Shivapour, S K; Oelfke, T F; Ford, A L; Klarmann Staudt, A; Abode-Iyamah, K; Reddy, C G; Jeffery, N D; Fredericks, D C; Gillies, G T; Howard, M A

    2016-01-01

    Our laboratories are developing treadmill-based gait analysis employing sheep to investigate potential efficacy of intra-dural spinal cord stimulation in the treatment of spinal cord injury and neuropathic pain. As part of efforts to establish the performance characteristics of the experimental arrangement, this study measured the treadmill speed via a tachometer, video belt-marker timing and ambulation-rate observations of the sheep. The data reveal a 0.1-0.3% residual drift in the baseline (unloaded) treadmill speed which increases with loading, but all three approaches agree on final speed to within 1.7%, at belt speeds of ≈ 4 km/h. Using the tachometer as the standard, the estimated upper limit on uncertainty in the video belt-marker approach is ± 0.18 km h(-1) and the measured uncertainty is ± 0.15 km h(-1). Employment of the latter method in determining timing differences between contralateral hoof strikes by the sheep suggests its utility in assessing severity of SCI and responses to therapeutic interventions. PMID:26785329

  7. Heme oxygenase-1 inhibits neuropathic pain in rats with diabetic mellitus

    Institute of Scientific and Technical Information of China (English)

    Qian Kong; Kang Liu; Lingxi Wu; Long Wang

    2012-01-01

    A diabetes mellitus model was established through single intraperitoneal injection of streptozotocin into rats.Seven days later,model rats were intraperitoneally administered zinc protoporphyrin,a heme oxygenase-1 inducer,and cobalt protoporphyrin,a heme oxygenase-1 inhibitor,once every two days,for 5 successive weeks.After administration,the paw withdrawal mechanical threshold of diabetic mellitus rats significantly decreased,the myelin sheath of the sciatic nerve thickened or showed vacuole defects,the number of spinal dorsal horn neurons reduced,some neurons degenerated and were necrotic,and heme oxygenase-1 was visible in the cytoplasm of spinal dorsal horn neurons.Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling demonstrated that the number of apoptotic neurons increased,which could be inhibited by cobalt protoporphyrin,however,zinc protoporphyrin led to an opposite effect.Our experimental findings indicate that heme oxygenase-1 attenuates neuropathic pain in diabetic mellitus rats through amelioration of peripheral neuropathy and inhibition of spinal dorsal horn neuron apoptosis.

  8. Differential expression of Cathepsin S and X in the spinal cord of a rat neuropathic pain model

    Directory of Open Access Journals (Sweden)

    Schmitz Beate

    2008-08-01

    Full Text Available Abstract Background Ample evidence suggests a substantial contribution of cellular and molecular changes in the spinal cord to the induction and persistence of chronic neuropathic pain conditions. While for a long time, proteases were mainly considered as protein degrading enzymes, they are now receiving growing interest as signalling molecules in the pain pathology. In the present study we focused on two cathepsins, CATS and CATX, and studied their spatiotemporal expression and activity during the development and progression of neuropathic pain in the CNS of the rat 5th lumbar spinal nerve transection model (L5T. Results Immediately after the lesion, both cathepsins, CATS and CATX, were upregulated in the spinal cord. Moreover, we succeeded in measuring the activity of CATX, which was substantially increased after L5T. The differential expression of these proteins exhibited the same spatial distribution and temporal progression in the spinal cord, progressing up to the medulla oblongata in the late phase of chronic pain. The cellular distribution of CATS and CATX was, however, considerably different. Conclusion The cellular distribution and the spatio-temporal development of the altered expression of CATS and CATX suggest that these proteins are important players in the spinal mechanisms involved in chronic pain induction and maintenance.

  9. Effect of Repeated Electroacupuncture Intervention on Hippocampal ERK and p38MAPK Signaling in Neuropathic Pain Rats

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    Jun-ying Wang

    2015-01-01

    Full Text Available Results of our past studies showed that hippocampal muscarinic acetylcholine receptor (mAChR-1 mRNA and differentially expressed proteins participating in MAPK signaling were involved in electroacupuncture (EA induced cumulative analgesia in neuropathic pain rats, but the underlying intracellular mechanism remains unknown. The present study was designed to observe the effect of EA stimulation (EAS on hippocampal extracellular signal-regulated kinases (ERK and p38 MAPK signaling in rats with chronic constrictive injury (CCI of the sciatic nerve, so as to reveal its related intracellular targets in pain relief. After CCI, the thermal pain thresholds of the affected hind were significantly decreased compared with the control group (P<0.05. Following one and two weeks’ EAS of ST 36-GB34, the pain thresholds were significantly upregulated (P<0.05, and the effect of EA2W was remarkably superior to that of EA2D and EA1W (P<0.05. Correspondingly, CCI-induced decreased expression levels of Ras, c-Raf, ERK1 and p-ERK1/2 proteins, and p38 MAPK mRNA and p-p38MAPK protein in the hippocampus tissues were reversed by EA2W (P<0.05. The above mentioned results indicated that EA2W induced cumulative analgesic effect may be closely associated with its function in removing neuropathic pain induced suppression of intracellular ERK and p38MAPK signaling in the hippocampus.

  10. Respective pharmacological features of neuropathic-like pain evoked by intrathecal BDNF versus sciatic nerve ligation in rats.

    Science.gov (United States)

    M'Dahoma, Saïd; Barthélemy, Sandrine; Tromilin, Claire; Jeanson, Tiffany; Viguier, Florent; Michot, Benoit; Pezet, Sophie; Hamon, Michel; Bourgoin, Sylvie

    2015-11-01

    Numerous reported data support the idea that Brain Derived Neurotrophic Factor (BDNF) is critically involved in both depression and comorbid pain. The possible direct effect of BDNF on pain mechanisms was assessed here and compared with behavioral/neurobiological features of neuropathic pain caused by chronic constriction injury to the sciatic nerve (CCI-SN). Sprague-Dawley male rats were either injected intrathecally with BDNF (3.0 ng i.t.) or subjected to unilateral CCI-SN. Their respective responses to anti-hyperalgesic drugs were assessed using the Randall-Selitto test and both immunohistochemical and RT-qPCR approaches were used to investigate molecular/cellular mechanisms underlying hyperalgesia in both models. Long lasting hyperalgesia and allodynia were induced by i.t. BDNF in intact healthy rats like those found after CCI-SN. Acute treatment with the BDNF-TrkB receptor antagonist cyclotraxin B completely prevented i.t. BDNF-induced hyperalgesia and partially reversed this symptom in both BDNF-pretreated and CCI-SN lesioned rats. Acute administration of the anticonvulsant pregabalin, the NMDA receptor antagonist ketamine, the opioid analgesics morphine and tapentadol or the antidepressant agomelatine also transiently reversed hyperalgesia in both i.t. BDNF injected- and CCI-SN lesioned-rats. Marked induction of microglia activation markers (OX42, Iba1, P-p38), proinflammatory cytokine IL-6, NMDA receptor subunit NR2B and BDNF was found in spinal cord and/or dorsal root ganglia of CCI-SN rats. A long lasting spinal BDNF overexpression was also observed in BDNF i.t. rats, indicating an autocrine self-induction, with downstream long lasting TrkB-mediated neuropathic-like pain. Accordingly, TrkB blockade appeared as a relevant approach to alleviate not only i.t. BDNF- but also nerve lesion-evoked neuropathic pain. PMID:26343858

  11. Characterization of a neuropathic pain model: sciatic cryoneurolysis in the rat.

    Science.gov (United States)

    DeLeo, J A; Coombs, D W; Willenbring, S; Colburn, R W; Fromm, C; Wagner, R; Twitchell, B B

    1994-01-01

    Cryoanalgesia, the technique of freezing peripheral nerves, is used clinically for the treatment of postoperative and chronic pain. Paradoxically, this same technique produces characteristics in a rat model suggestive of neuropathic pain. We have developed a peripheral neuropathy model by freezing the proximal sciatic nerve (sciatic cryoneurolysis, SCN) using a cryoprobe cooled to -60 degrees C in a 30/5/30 sec freeze-thaw-freeze sequence. Each freeze cycle produced a transient ice ball on the surface of the nerve. These studies provide behavioral evidence that SCN is a valid mononeuropathy animal model. All animals demonstrate some degree of autotomy following SCN. The average onset of autotomy occurs 4 days postoperatively and peaks in severity and incidence at 14 days. By examining the latency of responses to a noxious heat stimulus, we have shown there is no direct relationship between an hypoesthetic paw and autotomy, i.e., autotomy did not occur immediately after the freeze lesion when the limb was dysfunctional. Rather, autotomy peaked when sensation was returning to the affected limb. The transient time course of certain behaviors including hypoesthesia and possible return of limb sensation, autotomy, touch-evoked allodynia, foot edema and the presence of spontaneous nociceptive behaviors demonstrate a multiple phase nociceptive process. The temporary nature of these nociceptive behaviors is in sharp contrast to the prolonged bilateral mechanical allodynia evident when these behaviors subside. The surgical anesthetics used during the SCN procedure are shown to variably alter or suppress autotomy following SCN.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8159445

  12. Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain

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    Zhang Zhi-Jun

    2012-07-01

    Full Text Available Abstract Background Neuropathic pain in the trigeminal system is frequently observed in clinic, but the mechanisms involved are largely unknown. In addition, the function of immune cells and related chemicals in the mechanism of pain has been recognized, whereas few studies have addressed the potential role of chemokines in the trigeminal system in chronic pain. The present study was undertaken to test the hypothesis that chemokine C-C motif ligand 2 (CCL2-chemokine C-C motif receptor 2 (CCR2 signaling in the trigeminal nucleus is involved in the maintenance of trigeminal neuropathic pain. Methods The inferior alveolar nerve and mental nerve transection (IAMNT was used to induce trigeminal neuropathic pain. The expression of ATF3, CCL2, glial fibrillary acidic protein (GFAP, and CCR2 were detected by immunofluorescence histochemical staining and western blot. The cellular localization of CCL2 and CCR2 were examined by immunofluorescence double staining. The effect of a selective CCR2 antagonist, RS504393 on pain hypersensitivity was checked by behavioral testing. Results IAMNT induced persistent (>21 days heat hyperalgesia of the orofacial region and ATF3 expression in the mandibular division of the trigeminal ganglion. Meanwhile, CCL2 expression was increased in the medullary dorsal horn (MDH from 3 days to 21 days after IAMNT. The induced CCL2 was colocalized with astroglial marker GFAP, but not with neuronal marker NeuN or microglial marker OX-42. Astrocytes activation was also found in the MDH and it started at 3 days, peaked at 10 days and maintained at 21 days after IAMNT. In addition, CCR2 was upregulated by IAMNT in the ipsilateral medulla and lasted for more than 21 days. CCR2 was mainly colocalized with NeuN and few cells were colocalized with GFAP. Finally, intracisternal injection of CCR2 antagonist, RS504393 (1, 10 μg significantly attenuated IAMNT-induced heat hyperalgesia. Conclusion The data suggest that CCL2-CCR

  13. The CONECSI trial: results of a randomized controlled trial of a multidisciplinary cognitive behavioral program for coping with chronic neuropathic pain after spinal cord injury.

    Science.gov (United States)

    Heutink, Matagne; Post, Marcel W M; Bongers-Janssen, Helma M H; Dijkstra, Catja A; Snoek, Govert J; Spijkerman, Dorien C M; Lindeman, Eline

    2012-01-01

    Many people with spinal cord injury (SCI) rate chronic neuropathic pain as one of the most difficult problems to manage. The aim of the CONECSI (COping with NEuropathiC Spinal cord Injury pain) trial was to evaluate a multidisciplinary cognitive behavioral treatment program for persons with chronic neuropathic pain after SCI. The intervention consisted of educational, cognitive, and behavioral elements. A total of 61 people were randomized to either the intervention group or the waiting list control group in 4 Dutch rehabilitation centers. Primary outcomes were pain intensity and pain-related disability (Chronic Pain Grade questionnaire), and secondary outcomes were mood (Hospital Anxiety and Depression Scale), participation in activities (Utrecht Activities List), and life satisfaction (Life Satisfaction Questionnaire). Measurements were performed at baseline, and at 3, and 6 months follow-up. The primary statistical technique was random coefficient analysis. The analyses showed significant changes over time on both primary (t1-t2), and 2 out of 4 secondary outcomes (both t1-t2 and t1-t3). Significant intervention effects (Time*Group interactions) were found for anxiety and participation in activities, but not for the primary outcomes. Subsequent paired t tests showed significant changes in the intervention group that were not seen in the control group: decrease of pain intensity, pain-related disability, anxiety, and increase of participation in activities. This study implies that a multidisciplinary cognitive behavioral program might have beneficial effects on people with chronic neuropathic SCI pain. PMID:22100355

  14. Caloric Vestibular Stimulation Reduces Pain and Somatoparaphrenia in a Severe Chronic Central Post-Stroke Pain Patient: A Case Study

    Science.gov (United States)

    2016-01-01

    Central post-stroke pain is a neuropathic syndrome characterized by intolerable contralesional pain and, in rare cases, somatic delusions. To date, there is limited evidence for the effective treatments of this disease. Here we used caloric vestibular stimulation to reduce pain and somatoparaphrenia in a 57-year-old woman suffering from central post-stroke pain. Resting-state functional magnetic resonance imaging was used to assess the neurological effects of this treatment. Following vestibular stimulation we observed impressive improvements in motor skills, pain, and somatic delusions. In the functional connectivity study before the vestibular stimulation, we observed differences in the patient’s left thalamus functional connectivity, with respect to the thalamus connectivity of a control group (N = 20), in the bilateral cingulate cortex and left insula. After the caloric stimulation, the left thalamus functional connectivity with these regions, which are known to be involved in the cortical response to pain, disappeared as in the control group. The beneficial use of vestibular stimulation in the reduction of pain and somatic delusion in a CPSP patient is now documented by behavioral and imaging data. This evidence can be applied to theoretical models of pain and body delusions. PMID:27028404

  15. Caloric Vestibular Stimulation Reduces Pain and Somatoparaphrenia in a Severe Chronic Central Post-Stroke Pain Patient: A Case Study.

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    Grazia Fernanda Spitoni

    Full Text Available Central post-stroke pain is a neuropathic syndrome characterized by intolerable contralesional pain and, in rare cases, somatic delusions. To date, there is limited evidence for the effective treatments of this disease. Here we used caloric vestibular stimulation to reduce pain and somatoparaphrenia in a 57-year-old woman suffering from central post-stroke pain. Resting-state functional magnetic resonance imaging was used to assess the neurological effects of this treatment. Following vestibular stimulation we observed impressive improvements in motor skills, pain, and somatic delusions. In the functional connectivity study before the vestibular stimulation, we observed differences in the patient's left thalamus functional connectivity, with respect to the thalamus connectivity of a control group (N = 20, in the bilateral cingulate cortex and left insula. After the caloric stimulation, the left thalamus functional connectivity with these regions, which are known to be involved in the cortical response to pain, disappeared as in the control group. The beneficial use of vestibular stimulation in the reduction of pain and somatic delusion in a CPSP patient is now documented by behavioral and imaging data. This evidence can be applied to theoretical models of pain and body delusions.

  16. Dynamic long-term microstructural and ultrastructural alterations in sensory nerves of rats of paclitaxel-induced neuropathic pain

    Institute of Scientific and Technical Information of China (English)

    Wu Yuan; Li Jun; Zhou Junfei; Feng Yi

    2014-01-01

    Background Paclitaxel,as a first line anti-neoplastic compound,frequently produces long-term pain after tumors have been treated.Clinical manifestations are varied and non-specific.Pathology of the nervous system during the development of the neuropathic pain is unclear.Thus,eady diagnosis and treatment is often unsatisfying for patients.This study aimed to promote considerate understanding of the structural alteration of sensory nerves.Methods All rats were simply randomized into 3 groups:paclitaxel group,vehicle group and saline group.An established rat model of paclitaxel-induced peripheral neuropathy (2 mg/kg) was chosen for our research,behavior tests were operated during the procedure of 56 days.All rats were sampled on days 0,3,7,28 and 56.The hind paw plantar skin,sciatic nerves,dorsal root ganglion and attached fibers,and lumbar spinal cord were processed for light and electron microscopy.The differences among 3 groups were analyzed with one-way analysis of vadance (ANOVA).Results We affirmed that paclitaxel-induced mechano-aliodynia and mechano-hyperalgesia occured after a 3-7-day delay,and this pain peaked at day 28 and persisted to day 56.Paclitaxel and vehicle treatment both evoked thermalhyperalgesia.Paclitaxel-induced axonal and myelin sheath degeneration was evident.At days 3 and 7,significant increases in atypical mitochondria in both myelinated axons and C-fibers of paclitaxel-treated nerves indicated that injured mitochondria correlated to specific paclitaxel-induced neuropathic pain,and the abnormity sustained till day 56.Microtubule was unaffected in myelinated axons or C-fibers in paclitaxel-or vehicle-treated rats.Significant increase of G ratio was evident with paclitaxel injection at days 7 and 28.Conclusion Our research suggests a causal role for axonal degeneration,abnormalities in axonal mitochondria,and structural modification of axonal microtubules in paclitaxel-induced neuropathic pain,and the abnormal mitochondria could be connected

  17. Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations

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    Finnerup, Nanna B; Attal, Nadine; Haroutounian, Simon; McNicol, Ewan; Baron, Ralf; Dworkin, Robert H; Gilron, Ian; Haanpaa, Maija; Hansson, Per; Jensen, Troels S; Kamerman, Peter R; Lund, Karen; Moore, Andrew; Raja, Srinivasa N; Rice, Andrew SC; Rowbotham, Michael; Sena, Emily; Siddall, Philip; Smith, Blair H; Wallace, Mark

    2015-01-01

    Summary Background Neuropathic pain is difficult to treat. New treatments, clinical trials and standards of quality for assessing evidence justify an update of evidence-based recommendations for its pharmacological treatment. Methods The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain conducted a systematic review of randomised double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including unpublished trials (retrieved from clinicaltrials.gov and pharmaceutical websites). Meta-analysis used Numbers Needed to Treat (NNT) for 50 % pain relief as primary measure and assessed publication bias. Recommendations used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Findings In total 229 studies were included. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-review journals reported greater effects than online studies (R2=9·3%, p<0·01). Trial outcomes were generally modest even for effective drugs : in particular NNTs were 3·6 (95 % CI 3·0–4·4) for tricyclic antidepressants (TCAs), 6·4 (95 % CI 5·2–8·4) for serotonin- noradrenaline reuptake inbibitor (SNRI) antidepressants duloxetine and venlafaxine, 7·7 (95 % CI 6·5–9·4) for pregabalin and 6·3 (95 % CI 5·0–8·3) for gabapentin. NNTs were higher for gabapentin ER/enacarbil and capsaicin high concentration patches, lower for opioids and botulinum toxin A (BTX-A) and undetermined for lidocaine patches. Final quality of evidence was lower for lidocaine patches and BTX-A. Tolerability/safety and values/preferences were high for lidocaine patches and lower for opioids and TCAs. This permitted a strong GRADE recommendation for use and proposal as first line for TCAs, SNRIs, pregabalin, gabapentin and gabapentin ER/enacarbil in neuropathic pain, a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin

  18. 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. PMID:25113605

  19. Protective Effect of Ethanol Extracts of Hericium erinaceus on Alloxan-Induced Diabetic Neuropathic Pain in Rats.

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    Yi, Zhang; Shao-Long, Yang; Ai-Hong, Wang; Zhi-Chun, Sun; Ya-Fen, Zhuo; Ye-Ting, Xu; Yu-Ling, He

    2015-01-01

    We investigated the effects of Hericium erinaceus (HEE) on alloxan induced diabetic neuropathic pain in laboratory rats. Alloxan induced diabetic rats were administered orally HEE. After 6 weeks of treatments, treatment with HEE 40 mg/kg in diabetic animals showed significant increase in pain threshold and paw withdrawal threshold and significant decrease in serum glucose and urine glucose. We also observed a significant increase in lactate dehydrogenase (LDH), Lipid peroxidation (LPO), glutathione peroxidase (GPx) activity, glutathione reductase (GR) activity, catalase (CAT) activity, Na(+)K(+)ATPase activity, and glutathione S transferase (GST) activity along with significant decreased levels of glutathione (GSH) content in diabetic rats. The total antioxidant status (TAOS) in the HEE-treated groups was significantly lower than that in the alloxan-treated group. HEE can offer pain relief in diabetic neuropathic pain. The improvement in diabetic state after HEE treatment along with the antioxidant activity could be the probable way by which it had alleviated diabetic neuropathy. PMID:25960754

  20. Protective Effect of Ethanol Extracts of Hericium erinaceus on Alloxan-Induced Diabetic Neuropathic Pain in Rats

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    Zhang Yi

    2015-01-01

    Full Text Available We investigated the effects of Hericium erinaceus (HEE on alloxan induced diabetic neuropathic pain in laboratory rats. Alloxan induced diabetic rats were administered orally HEE. After 6 weeks of treatments, treatment with HEE 40 mg/kg in diabetic animals showed significant increase in pain threshold and paw withdrawal threshold and significant decrease in serum glucose and urine glucose. We also observed a significant increase in lactate dehydrogenase (LDH, Lipid peroxidation (LPO, glutathione peroxidase (GPx activity, glutathione reductase (GR activity, catalase (CAT activity, Na+K+ATPase activity, and glutathione S transferase (GST activity along with significant decreased levels of glutathione (GSH content in diabetic rats. The total antioxidant status (TAOS in the HEE-treated groups was significantly lower than that in the alloxan-treated group. HEE can offer pain relief in diabetic neuropathic pain. The improvement in diabetic state after HEE treatment along with the antioxidant activity could be the probable way by which it had alleviated diabetic neuropathy.

  1. Increasing bioavailability of (R)-alpha-lipoic acid to boost antioxidant activity in the treatment of neuropathic pain.

    Science.gov (United States)

    Maglione, Emilia; Marrese, Cinzia; Migliaro, Elisa; Marcuccio, Fortuna; Panico, Claudia; Salvati, Carmine; Citro, Giuseppe; Quercio, Marco; Roncagliolo, Federico; Torello, Carlo; Brufani, Mario

    2015-01-01

    a-lipoic acid (a-LA) is a potent natural antioxidant because it has a broad spectrum of action towards a great many free radical species and boosts the endogenous antioxidant systems.Although it is a multi-functional molecule, its pharmacokinetic characteristics pose restrictions to its use in the treatment of oxidative stress-dependent illnesses. Formulations that increase the bioavailability of a-LA have a better potential efficacy as adjuvants for the treatment of these conditions.This objective was achieved with a liquid formulation for oral use containing only R-aLA, the natural enantiomeric and most active form of a-lipoic acid.For the first time, the effects of this formulation were evaluated on neuropathic pain, a symptom caused by an increase in oxidative stress, regardless of the underlying cause. Neuropathic patients who have used this dietary supplement noticed an improvement in their quality of life and a significant reduction was observed in a number of certain descriptive pain parameters (intensity, burning, unpleasantness, superficial pain).Undoubtedly further, more in-depth, studies need to be conducted; however, this first investigation confirms the role of R-aLA as an anti-oxidant for the aetiological treatment of peripheral neuropathy. Increasing its plasma bioavailability even after a non-invasive administration through the oral route is a good starting point for proposing a valid adjuvant for the treatment of pain symptoms. PMID:26694149

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-09-05

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

  4. Histamine H4 receptor activation alleviates neuropathic pain through differential regulation of ERK, JNK, and P38 MAPK phosphorylation.

    Science.gov (United States)

    Sanna, Maria D; Stark, Holger; Lucarini, Laura; Ghelardini, Carla; Masini, Emanuela; Galeotti, Nicoletta

    2015-12-01

    Histamine plays a complex role in pain modulation with opposite roles in nociception for histamine receptor subtypes 1, 2, and 3. The histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses with a proinflammatory activity, but little is known about the role in nociception of neuronal H4R. To investigate the effects of neuronal H4R in pain transmission, the effects produced by the H4R agonist ST-1006 were detected in the spared nerve injury model of neuropathic pain. ST-1006 counteracted mechanical allodynia in neuropathic mice, an effect prevented by the H4R antagonist JNJ 10191584. In spared nerve injury mice, an early over-phosphorylation of ERK1 and ERK2 was observed in the dorsal root ganglia (DRG), spinal cord, and sciatic nerve. A progressive and long-lasting activation of JNK1 was observed in the sciatic nerve and, to a lesser extent, in the spinal cord and DRG. An increased p-P38 content was detected in the spinal cord and DRG, with no modification in the sciatic nerve. Administration of ST-1006 prevented phosphorylation of all 3 MAPK within DRG, and phosphorylation of ERK1, ERK2, and pJNK1 in the sciatic nerve. In the spinal cord, the H4R agonist prevented selectively the pERK2 increase with no effect on pJNK1 and p-P38 levels. Double immunofluorescence experiments showed a neuronal localization and site of action for H4R. These findings suggest a prevalent modulation of ERK activity after H4R stimulation and indicate the DRG as prominent site of action for H4R-mediated antineuropathic activity. Targeting neuronal H4R with selective agonists could have therapeutic potential for neuropathic pain treatment. PMID:26270581

  5. Injury-specific promoters enhance herpes simplex virus mediated gene therapy for treating neuropathic pain in rodents

    Science.gov (United States)

    Smith, Sherika N.; Paige, Candler; Velazquez, Kandy T.; Smith, Terika P.; Raja, Srinivasa N.; Wilson, Steven P.; Sweitzer, Sarah M.

    2015-01-01

    Chronic neuropathic pain is often difficult to treat with current pain medications. Gene therapy is currently being explored as a therapeutic approach for the treatment of neuropathic and cancer pain. In this study we sought to use an injury-specific promoter to deliver the mu opioid receptor (MOR) transgene such that expression would only occur during the injured state in response to release of injury-specific galanin. To determine whether an injury specific promoter can produce neuron-specific MOR expression and enhanced antinociception we compared animals infected with a galanin promoter virus (galMOR) or a human cytomegalovirus (CMV) promoter virus. (cmvMOR). In behavioral assays, we found an earlier onset and a larger magnitude of antinociception in animals infected with galMOR compared to cmvMOR. Immunohistochemistry of dorsal root ganglion (DRG) neurons revealed a significant increase in MOR positive staining in cmvMOR and galMOR treated mice. Spinal cord sections from galMOR treated mice showed a greater increase in density but not area of MOR positive staining. These results suggest that using injury-specific promoters to drive gene expression in primary afferent neurons can influence the onset and magnitude of antinociception in a rodent model of neuropathic pain and can be used to upregulate MOR expression in populations of neurons that are potentially injury specific. Perspective An injury specific promoter (galMOR) was used to drive MOR expression in a population- and injury- specific manner. GalMOR increased antinociception and density of MOR staining in spinal cord. This article presents evidence that promoter selection is an important component in successful gene expression in an injury- and population-specific manner. PMID:25576797

  6. Validity and reliability of the Spanish version of the DN4 (Douleur Neuropathique 4 questions questionnaire for differential diagnosis of pain syndromes associated to a neuropathic or somatic component

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    Bouhassira Didier

    2007-12-01

    Full Text Available Abstract Background This study assesses the validity and reliability of the Spanish version of DN4 questionnaire as a tool for differential diagnosis of pain syndromes associated to a neuropathic (NP or somatic component (non-neuropathic pain, NNP. Methods A study was conducted consisting of two phases: cultural adaptation into the Spanish language by means of conceptual equivalence, including forward and backward translations in duplicate and cognitive debriefing, and testing of psychometric properties in patients with NP (peripheral, central and mixed and NNP. The analysis of psychometric properties included reliability (internal consistency, inter-rater agreement and test-retest reliability and validity (ROC curve analysis, agreement with the reference diagnosis and determination of sensitivity, specificity, and positive and negative predictive values in different subsamples according to type of NP. Results A sample of 164 subjects (99 women, 60.4%; age: 60.4 ± 16.0 years, 94 (57.3% with NP (36 with peripheral, 32 with central, and 26 with mixed pain and 70 with NNP was enrolled. The questionnaire was reliable [Cronbach's alpha coefficient: 0.71, inter-rater agreement coefficient: 0.80 (0.71–0.89, and test-retest intra-class correlation coefficient: 0.95 (0.92–0.97] and valid for a cut-off value ≥ 4 points, which was the best value to discriminate between NP and NNP subjects. Discussion This study, representing the first validation of the DN4 questionnaire into another language different than the original, not only supported its high discriminatory value for identification of neuropathic pain, but also provided supplemental psychometric validation (i.e. test-retest reliability, influence of educational level and pain intensity and showed its validity in mixed pain syndromes.

  7. Nerve injury evoked loss of latexin expression in spinal cord neurons contributes to the development of neuropathic pain.

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    Hilmar Nils Kühlein

    Full Text Available Nerve injury leads to sensitization mechanisms in the peripheral and central nervous system which involve transcriptional and post-transcriptional modifications in sensory nerves. To assess protein regulations in the spinal cord after injury of the sciatic nerve in the Spared Nerve Injury model (SNI we performed a proteomic analysis using 2D-difference gel electrophoresis (DIGE technology. Among approximately 2300 protein spots separated on each gel we detected 55 significantly regulated proteins after SNI whereof 41 were successfully identified by MALDI-TOF MS. Out of the proteins which were regulated in the DIGE analyses after SNI we focused on the carboxypeptidase A inhibitor latexin because protease dysfunctions contribute to the development of neuropathic pain. Latexin protein expression was reduced after SNI which could be confirmed by Western Blot analysis, quantitative RT-PCR and in-situ hybridisation. The decrease of latexin was associated with an increase of the activity of carboxypeptidase A indicating that the balance between latexin and carboxypeptidase A was impaired in the spinal cord after peripheral nerve injury due to a loss of latexin expression in spinal cord neurons. This may contribute to the development of cold allodynia because normalization of neuronal latexin expression in the spinal cord by AAV-mediated latexin transduction or administration of a small molecule carboxypeptidase A inhibitor significantly reduced acetone-evoked nociceptive behavior after SNI. Our results show the usefulness of proteomics as a screening tool to identify novel mechanisms of nerve injury evoked hypernociception and suggest that carboxypeptidase A inhibition might be useful to reduce cold allodynia.

  8. Short-Term Efficacy of Ultramicronized Palmitoylethanolamide in Peripheral Neuropathic Pain

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    Dario Cocito

    2014-01-01

    Full Text Available Introduction. This study evaluates the efficacy of palmitoylethanolamide ultramicronized (PEA-um as an add-on treatment in patients with diabetic or traumatic neuropathic pain (NP. Methods. 30 patients with chronic NP were assessed with Visual Analogue Scale (VAS, NP Symptom Inventory (NPSI, and Health Questionnaire Five Dimensions (EQ-5D, both at baseline and after 10 and 40 days of treatment with 1200 mg/die of PEA-um. All other therapies were maintained stable during the follow-up period. Results. VAS mean score significantly improved within the first 10 days, ranging from 8.20 ± 1.53 to 6.40 ± 1.83 (P<0.002, with a further decrease to 5.80 ± 2.04 (P<0.001 after 40 days of PEA-um administration. Moreover, NPSI total score improved from 5.2 ± 1.5 to 3.8 ± 2.1 (P: 0.025 and EQ-5D ranged from −0.30 ± 0.65 to 0.5 ± 0.34 (P<0.001 between T0 and T2. Conclusions. This study reports the prospective short-term efficacy data of oral PEA-um in patients with diabetic or traumatic NP. A significant improvement was observed both in VAS and NPSI scores and in quality of life scales after 40 days of treatment, although some limitations should be considered, including the short followup and the open-label study design.

  9. Short-term efficacy of ultramicronized palmitoylethanolamide in peripheral neuropathic pain.

    Science.gov (United States)

    Cocito, Dario; Peci, Erdita; Ciaramitaro, Palma; Merola, Aristide; Lopiano, Leonardo

    2014-01-01

    Introduction. This study evaluates the efficacy of palmitoylethanolamide ultramicronized (PEA-um) as an add-on treatment in patients with diabetic or traumatic neuropathic pain (NP). Methods. 30 patients with chronic NP were assessed with Visual Analogue Scale (VAS), NP Symptom Inventory (NPSI), and Health Questionnaire Five Dimensions (EQ-5D), both at baseline and after 10 and 40 days of treatment with 1200 mg/die of PEA-um. All other therapies were maintained stable during the follow-up period. Results. VAS mean score significantly improved within the first 10 days, ranging from 8.20 ± 1.53 to 6.40 ± 1.83 (P < 0.002), with a further decrease to 5.80 ± 2.04 (P < 0.001) after 40 days of PEA-um administration. Moreover, NPSI total score improved from 5.2 ± 1.5 to 3.8 ± 2.1 (P: 0.025) and EQ-5D ranged from -0.30 ± 0.65 to 0.5 ± 0.34 (P < 0.001) between T0 and T2. Conclusions. This study reports the prospective short-term efficacy data of oral PEA-um in patients with diabetic or traumatic NP. A significant improvement was observed both in VAS and NPSI scores and in quality of life scales after 40 days of treatment, although some limitations should be considered, including the short followup and the open-label study design. PMID:24967102

  10. Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation

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    Wang Hung-Chen

    2011-06-01

    Full Text Available Abstract Background Intrathecal lidocaine reverses tactile allodynia after nerve injury, but whether neuropathic pain is attenuated by intrathecal lidocaine pretreatment is uncertain. Methods Sixty six adult male Sprague-Dawley rats were divided into three treatment groups: (1 sham (Group S, which underwent removal of the L6 transverse process; (2 ligated (Group L, which underwent left L5 spinal nerve ligation (SNL; and (3 pretreated (Group P, which underwent L5 SNL and was pretreated with intrathecal 2% lidocaine (50 μl. Neuropathic pain was assessed based on behavioral responses to thermal and mechanical stimuli. Expression of sodium channels (Nav1.3 and Nav1.8 in injured dorsal root ganglia and microglial proliferation/activation in the spinal cord were measured on post-operative days 3 (POD3 and 7 (POD7. Results Group L presented abnormal behavioral responses indicative of mechanical allodynia and thermal hyperalgesia, exhibited up-regulation of Nav1.3 and down-regulation of Nav1.8, and showed increased microglial activation. Compared with ligation only, pretreatment with intrathecal lidocaine before nerve injury (Group P, as measured on POD3, palliated both mechanical allodynia (p p 1.3 up-regulation (p = 0.003, and mitigated spinal microglial activation (p = 0.026 by inhibiting phosphorylation (activation of p38 MAP kinase (p = 0.034. p38 activation was also suppressed on POD7 (p = 0.002. Conclusions Intrathecal lidocaine prior to SNL blunts the response to noxious stimuli by attenuating Nav1.3 up-regulation and suppressing activation of spinal microglia. Although its effects are limited to 3 days, intrathecal lidocaine pretreatment can alleviate acute SNL-induced neuropathic pain.

  11. Unusual responses to electrocutaneous stimulation in refractory cervicobrachial pain: clues to a neuropathic pathogenesis.

    Science.gov (United States)

    Arroyo, J F; Cohen, M L

    1992-01-01

    Refractory cervicobrachial pain (RCBP) is a common syndrome of uncertain pathogenesis, frequently seen in an occupational context. It is characterised by widespread neck, shoulder girdle and arm pain, often of dysaesthetic quality including burning, associated with paraesthesiae, impaired perception of touch, allodynia, hyperalgesia and hyperpathia. Despite these clinical features, the syndrome has not attracted investigation with other than standard neurophysiological tests. Electrocutaneous electrical stimulation (ECS), following a well-described and validated method, was chosen as a tool to investigate the nociceptive status in RCBP. A commercially available calibrate transcutaneous electrical nerve stimulation (TENS) machine was used to determine perception threshold and pain tolerance with respect to the amplitude of current and duration of pulse. Fifteen patients with typical RCBP and ten normal volunteers were studied. The response profiles obtained were reproducible over time in both patients and controls and were able clearly to distinguish between affected and non-affected limbs. The perception threshold and pain tolerance in the unaffected limbs of patients did not differ from those in normal subjects. In the affected limbs there was reduction in pain tolerance, invariably accompanied by spread of sensation and persistence of dysaesthesiae, both induced by ECS. These results define the limbs affected by RCBP as regions of secondary hyperalgesia at the clinical level. It is suggested that neural dysfunction may be involved in the pathogenesis of RCBP, although a confident distinction between peripheral and central processes cannot be made on the basis of these findings, which call for further investigation. PMID:1458699

  12. Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models

    OpenAIRE

    Jayamanne, Angelo; Greenwood, Ruth; Mitchell, Vanessa A; Aslan, Sevda; Piomelli, Daniele; Vaughan, Christopher W

    2005-01-01

    While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB1 receptor-mediated motor and psychotropic side effects. The actions of endocannabinoids, such as anandamide are terminated by removal from the extracellular space, then subsequent enzymatic degradation by fatty-acid amide hydrolase (FAAH). In the present study, we compared the effect of a selective FAAH inhibitor, URB597, to that of a pan-cannabinoid receptor agonist HU210...

  13. Synthesis and Evaluation of Novel α-Aminoamides Containing an Indole Moiety for the Treatment of Neuropathic Pain.

    Science.gov (United States)

    Li, Haotian; Fan, Shiyong; Cheng, Jingchao; Zhang, Ping; Zhong, Bohua; Shi, Weiguo

    2016-01-01

    The α-aminoamide family of sodium ion channel blockers have exhibited analgesic effects on neuropathic pain. Here, a series of novel α-aminoamides containing an indole ring were designed and synthesized. These compounds were evaluated in mice using a formalin test and they exhibited significant anti-allodynia activities. However, the analgesic mechanism of these compounds remains unclear; a subset of the synthesized compounds can only moderately inhibit the sodium ion channel, Nav1.7, in a whole-cell patch clamp assay. Overall, these results suggest that introduction of an indole moiety to α-aminoamide derivatives can significantly improve their bioactivity and further study is warranted. PMID:27347907

  14. Relationships between changes in pain severity and other patient-reported outcomes: an analysis in patients with posttraumatic peripheral neuropathic pain

    Directory of Open Access Journals (Sweden)

    Zlateva Gergana

    2011-03-01

    Full Text Available Abstract Background The objective of this study is to use the pain numeric rating scale (NRS to evaluate associations between change in pain severity and changes in sleep, function, and mood assessed via patient-reported outcomes (PROs in patients with posttraumatic pain. Methods This is a secondary analysis of a clinical trial evaluating pregabalin in patients with posttraumatic peripheral neuropathic pain (N = 254. Regression models were used to determine associations between changes in pain (0-10 NRS as the predictor and scores on the following PRO measures as the outcome: Pain Interference Index; Hospital Anxiety and Depression Scale anxiety and depression subscales; Medical Outcomes Study-Sleep Scale 9-item Sleep Problems Index and Sleep Disturbance subscale; and Daily Sleep Interference Scale (0-10 NRS. Results Change in pain severity showed clear, direct relationships with changes in function, anxiety, depression, and sleep PROs, all of which were statistically significant (P 51 years tended to be consistent with results from the overall sample. Conclusions Overall, a direct relationship exists between pain and various aspects of patient's well-being and functioning, which can provide a quantitative assessment of how improvements in pain may be expected to relate to other patient outcomes. (http://ClinicalTrials.gov Identifier number NCT00292188; EudraCT #2005-003048-78.

  15. Neuropathic Itch

    OpenAIRE

    Oaklander, Anne Louise

    2011-01-01

    Chronic itch can be caused by dysfunctions of itch-sensing neurons that produce sensory hallucinations of pruritogenic stimuli. The cellular and molecular mechanisms are still unknown. All neurological disease categories have been implicated and neurological causes should be considered for patients with otherwise-unexplained itch. The same neurological illnesses that cause neuropathic pain can also or instead cause itch. These include shingles (particularly of the head or neck), small-fiber p...

  16. La evaluación del dolor experimental en el laboratorio: los modelos de dolor neuropático en animales Evaluation of experimental pain in the laboratory: models of neuropathic pain in animal's

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    J. E. Baños

    2006-11-01

    Full Text Available Pese a los avances realizados en los últimos años, el dolor neuropático constituye aún un serio problema asistencial. Los tratamientos disponibles sólo permiten aliviar adecuadamente un tercio de los pacientes. Los modelos experimentales pueden contribuir a conocer la fisiopatología de este cuadro clínico, así como a probar nuevos fármacos. Existen básicamente dos tipos de modelos, aquellos que realizan una lesión en el nervio periférico y los que causan alteraciones en el sistema nervioso central. A pesar de sus limitaciones, los modelos animales pueden contribuir a avanzar en el conocimiento de este síndrome y algunos de ellos pueden ayudar a predecir la utilidad terapéutica de nuevos medicamentos. Obviamente, sólo los ensayos clínicos bien diseñados permitirán conocer su eficacia real en el ámbito clínico.In spite of the advancement of pain research in the last decade, the therapy of neuropathic pain is still an unresolved issue. Available treatments only adequately improve only a third of patients. Experimental models may contribute to the knowledge of its pathophysiology, as well as to the development of new drugs. Basically, two types of animal models are available: those that cause a lesion in the peripheral nerves and those that injury the central nervous system. Beyond these limitations, animal models may help to improve the knowledge of neuropathic pain and some of them have predictive value on the usefulness of analgesic efficacy of new drugs. Obviously, only well-designed, controlled clinical trials will permit to establish their actual efficacy in the clinical setting.

  17. Correlation between pain response and improvements in patient-reported outcomes and health-related quality of life in duloxetine-treated patients with diabetic peripheral neuropathic pain

    Directory of Open Access Journals (Sweden)

    Ogawa K

    2015-08-01

    Full Text Available Kei Ogawa,1 Shinji Fujikoshi,2 William Montgomery,3 Levent Alev1 1Medical Science, 2Statistical Science, Eli Lilly Japan K.K., Kobe, Japan; 3Global Patient Outcomes and Real World Evidence, Eli Lilly Australia Pty Ltd, West Ryde, NSW, Australia Objective: We assessed whether quality of life (QoL improvement in duloxetine-treated patients with diabetic peripheral neuropathic pain (DPNP correlates with the extent of pain relief.Methods: Pooled data from three multicountry, double-blind, 12-week, placebo-controlled trials of duloxetine-treated (duloxetine 60 mg once daily; total number =335 patients with DPNP were analyzed. Based on improvement in 24-hour average pain scores, patients were stratified into four groups. Improvement in QoL, which was measured as the change from baseline in two patient-reported health outcome measures (Short Form [SF]-36 and five-dimension version of the EuroQol Questionnaire [EQ-5D], was evaluated and compared among the four groups. Pearson’s correlation coefficient was calculated to assess the correlation between improvement in pain scores and improvement in QoL.Results: The group with more pain improvement generally showed greater mean change from baseline in all of the SF-36 scale scores and on the EQ-5D index. Pearson’s correlation coefficients ranged from 0.114 to 0.401 for the SF-36 scale scores (P<0.05, and it was 0.271 for the EQ-5D (P<0.001.Conclusion: Improvement in pain scores was positively correlated with improvement in QoL and patient-reported outcomes in duloxetine-treated patients. Keywords: diabetic peripheral neuropathic pain, duloxetine, efficacy, function, quality of life

  18. Delayed Exercise Is Ineffective at Reversing Aberrant Nociceptive Afferent Plasticity or Neuropathic Pain After Spinal Cord Injury in Rats.

    Science.gov (United States)

    Detloff, Megan Ryan; Quiros-Molina, Daniel; Javia, Amy S; Daggubati, Lekhaj; Nehlsen, Anthony D; Naqvi, Ali; Ninan, Vinu; Vannix, Kirsten N; McMullen, Mary-Katharine; Amin, Sheena; Ganzer, Patrick D; Houlé, John D

    2016-08-01

    Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that correlates with sensory fiber sprouting. Recent data indicate that exercise initiated early after SCI prevents the development of allodynia and modulated nociceptive afferent plasticity. This study determined if delaying exercise intervention until pain is detected would similarly ameliorate established SCI-induced pain. Adult, female Sprague-Dawley rats with a C5 unilateral contusion were separated into SCI allodynic and SCI non-allodynic cohorts at 14 or 28 days postinjury when half of each group began exercising on automated running wheels. Allodynia, assessed by von Frey testing, was not ameliorated by exercise. Furthermore, rats that began exercise with no allodynia developed paw hypersensitivity within 2 weeks. At the initiation of exercise, the SCI Allodynia group displayed marked overlap of peptidergic and non-peptidergic nociceptive afferents in the C7 and L5 dorsal horn, while the SCI No Allodynia group had scant overlap. At the end of 5 weeks of exercise both the SCI Allodynia and SCI No Allodynia groups had extensive overlap of the 2 c-fiber types. Our findings show that exercise therapy initiated at early stages of allodynia is ineffective at attenuating neuropathic pain, but rather that it induces allodynia-aberrant afferent plasticity in previously pain-free rats. These data, combined with our previous results, suggest that there is a critical therapeutic window when exercise therapy may be effective at treating SCI-induced allodynia and that there are postinjury periods when exercise can be deleterious. PMID:26671215

  19. The lesion of dorsolateral funiculus changes the antiallodynic effect of the intrathecal muscimol and baclofen in distinct phases of neuropathic pain induced by spinal nerve ligation in rats.

    Science.gov (United States)

    Dias, Quintino Moura; Prado, Wiliam A

    2016-06-01

    The abnormal firing of damaged primary afferents and the changes in the central nervous system (CNS) play important role in the initiation and maintenance phases of neuropathic pain. These phases of neuropathic pain involve changes in the GABAergic control of descending pathways that travel through the dorsolateral funiculus (DLF). The present study shows that unilateral DLF lesion increased the antiallodynic effect of muscimol (0.2μg/5μL) (a GABAA receptor agonist) in the initiation, but not maintenance phase of the mechanical allodynia induced by a spinal nerve ligation (SNL) of the ipsilateral hindpaw of rats. The unilateral DLF lesion increased the antiallodynic effect of baclofen (0.8μg/5μL) (a GABAB receptor agonist) in the initiation phase and reduced your effect in the maintenance phase of the mechanical allodynia induced by a spinal nerve ligation (SNL) of the ipsilateral paw of rats. The unilateral DLF lesion significantly reduced the proallodynic effect of an intrathecal injection of phaclofen (30μg/5μL) (a GABAB receptor antagonist), but not bicuculline (0.3μg/5μL) (a GABAA receptor antagonist). The effect of DLF lesion on the proallodynic effect of phaclofen was observed in the maintenance, but not in the initiation phase of the mechanical allodynia induced by SNL. We than conclude that the spinal GABAergic neurotransmission is negatively modulated by DLF using GABAA and GABAB receptors, in the initiation phase of mechanical allodynia induced by SNL. In addition, the integrity of DLF is necessary for the effectiveness of GABAergic transmission that occurs via spinal GABAB, but not GABAA receptors, in the maintenance phase of mechanical allodynia induced by SNL. PMID:27063286

  20. Clinical analysis and treatment of central pain due to headinjury

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    @@Central pain is induced by the involvement of the abnormal pain pathway due to diseases of the central nervous system. Central pain after brain trauma is common clinically, but it is often misdiagnosed and neglected because of lack of objective disturbances. We treated 20 cases of central pain after head injury by invigorating blood circulation and satisfactory result was obtained.

  1. Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain.

    Science.gov (United States)

    Guillemyn, Karel; Starnowska, Joanna; Lagard, Camille; Dyniewicz, Jolanta; Rojewska, Ewelina; Mika, Joanna; Chung, Nga N; Utard, Valérie; Kosson, Piotr; Lipkowski, Andrzej W; Chevillard, Lucie; Arranz-Gibert, Pol; Teixidó, Meritxell; Megarbane, Bruno; Tourwé, Dirk; Simonin, Frédéric; Przewlocka, Barbara; Schiller, Peter W; Ballet, Steven

    2016-04-28

    Herein, the opioid pharmacophore H-Dmt-d-Arg-Aba-β-Ala-NH2 (7) was linked to peptide ligands for the nociceptin receptor. Combination of 7 and NOP ligands (e.g., H-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) led to binding affinities in the low nanomolar domain. In vitro, the hybrids behaved as agonists at the opioid receptors and antagonists at the nociceptin receptor. Intravenous administration of hybrid 13a (H-Dmt-d-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) to mice resulted in potent and long lasting antinociception in the tail-flick test, indicating that 13a was able to permeate the BBB. This was further supported by a cell-based BBB model. All hybrids alleviated allodynia and hyperalgesia in neuropathic pain models. Especially with respect to hyperalgesia, they showed to be more effective than the parent compounds. Hybrid 13a did not result in significant respiratory depression, in contrast to an equipotent analgesic dose of morphine. These hybrids hence represent a promising avenue toward analgesics for the dual treatment of acute and neuropathic pain. PMID:27035422

  2. Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord.

    Science.gov (United States)

    Taves, Sarah; Berta, Temugin; Liu, Da-Lu; Gan, Sophie; Chen, Gang; Kim, Yong Ho; Van de Ven, Thomas; Laufer, Stefan; Ji, Ru-Rong

    2016-07-01

    Previous studies have shown that activation of p38 mitogen-activating kinase (MAPK) in spinal microglia participates in the generation of inflammatory and neuropathic pain in various rodent models. However, these studies focused on male mice to avoid confounding effects of the estrous cycle of females. Recent studies have shown that some spinal pro-inflammatory signaling such as Toll-like receptor 4-mediated signaling contributes to pain hypersensitivity only in male mice. In this study we investigated the distinct role of spinal p38 in inflammatory and neuropathic pain using a highly selective p38 inhibitor skepinone. Intrathecal injection of skepinone prevented formalin induced inflammatory pain in male but not female mice. Furthermore, intrathecal skepinone reduced chronic constriction injury (CCI) induced neuropathic pain (mechanical allodynia) in male mice on CCI-day 7 but not CCI-day 21. This male-dependent inhibition of neuropathic pain also occurred in rats following intrathecal skepinone. Nerve injury induced spinal p38 activation (phosphorylation) in CX3CR1-GFP(+) microglia on CCI-day 7, and this activation was more prominent in male mice. In contrast, CCI induced comparable microgliosis and expression of the microglial markers CX3CR1 and IBA-1 in both sexes. Notably, intraperitoneal or local perineural administration of skepinone inhibited CCI-induced mechanical allodynia in both sexes of mice. Finally, skepinone only reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina IIo neurons of spinal cord slices of males 7days post CCI. Therefore, the sex-specific p38 activation and signaling is confined to the spinal cord in inflammatory and neuropathic pain conditions. PMID:26472019

  3. Antiallodynic effects of alpha lipoic acid in an optimized RR-EAE mouse model of MS-neuropathic pain are accompanied by attenuation of upregulated BDNF-TrkB-ERK signaling in the dorsal horn of the spinal cord

    OpenAIRE

    Khan, Nemat; Gordon, Richard; Woodruff, Trent M.; Smith, Maree T.

    2015-01-01

    Neuropathic pain may affect patients with multiple sclerosis (MS) even in early disease. In an experimental autoimmune encephalomyelitis (EAE)-mouse model of MS, chronic alpha lipoic acid (ALA) treatment reduced clinical disease severity, but MS-neuropathic pain was not assessed. Hence, we investigated the pain-relieving efficacy and mode of action of ALA using our optimized relapsing-remitting (RR)-EAE mouse model of MS-associated neuropathic pain. C57BL/6 mice were immunized with MOG35-55 a...

  4. Spinal CPEB-mtROS-CBP signaling pathway contributes to perineural HIV gp120 with ddC-related neuropathic pain in rats.

    Science.gov (United States)

    Iida, Takafumi; Yi, Hyun; Liu, Shue; Huang, Wan; Kanda, Hirotsugu; Lubarsky, David A; Hao, Shuanglin

    2016-07-01

    Human immunodeficiency virus (HIV) patients treated with nucleoside reverse transcriptase inhibitors (NRTIs), have been known to develop neuropathic pain. While there has been a major shift away from some neurotoxic NRTIs in current antiretroviral therapy, a large number of HIV patients alive today have previously received them, and many have developed painful peripheral neuropathy. The exact mechanisms by which HIV with NRTIs contribute to the development of neuropathic pain are not known. Previous studies suggest that cytoplasmic polyadenylation element-binding protein (CPEB), reactive oxygen species (ROS), and cAMP-response element-binding protein (CREB)-binding protein (CBP), are involved in the neuroimmunological diseases including inflammatory/neuropathic pain. In this study, we investigated the role of CPEB, mitochondrial ROS (mtROS), or CBP in neuropathic pain induced by HIV envelope protein gp120 combined with antiretroviral drug. The application of recombinant gp120 into the sciatic nerve plus systemic ddC (one of NRTIs) induced mechanical allodynia. Knockdown of CPEB or CBP using intrathecal antisense oligodeoxynucleotide (AS-ODN) reduced mechanical allodynia. Intrathecal mitochondrial superoxide scavenger mito-tempol (Mito-T) increased mechanical withdrawal threshold. Knockdown of CPEB using intrathecal AS-ODN, reduced the up-regulated mitochondrial superoxide in the spinal dorsal horn in rats with gp120 combined with ddC. Intrathecal Mito-T lowered the increased expression of CBP in the spinal dorsal horn. Immunostaining studies showed that neuronal CPEB positive cells were co-localized with MitoSox positive profiles, and that MitoSox positive profiles were co-localized with neuronal CBP. Our studies suggest that neuronal CPEB-mtROS-CBP pathway in the spinal dorsal horn, plays an important role in the gp120/ddC-induced neuropathic pain in rats. PMID:27090160

  5. Analgesic effectiveness and tolerability of oral oxycodone/naloxone and pregabalin in patients with lung cancer and neuropathic pain: an observational analysis

    Science.gov (United States)

    De Santis, Stefano; Borghesi, Cristina; Ricciardi, Serena; Giovannoni, Daniele; Fulvi, Alberto; Migliorino, Maria Rita; Marcassa, Claudio

    2016-01-01

    Introduction Cancer-related pain has a severe negative impact on quality of life. Combination analgesic therapy with oxycodone and pregabalin is effective for treating neuropathic cancer pain. We investigated the efficacy and tolerability of a dose-escalation combination therapy with prolonged-release oxycodone/naloxone (OXN-PR) and pregabalin in patients with non-small-cell lung cancer and severe neuropathic pain. Methods This was a 4-week, open-label, observational study. Patients were treated with OXN-PR and pregabalin. Average pain intensity ([API] measured on a 0–10 numerical rating scale) and neuropathic pain (Douleur Neuropathique 4) were assessed at study entry and at follow-up visits. The primary endpoint was response to treatment, defined as a reduction of API at T28 ≥30% from baseline. Secondary endpoints included other efficacy measures, as well as patient satisfaction and quality of life (Brief Pain Inventory Short Form), Hospital Anxiety and Depression Scale, and Symptom Distress Scale; bowel function was also assessed. Results A total of 56 patients were enrolled. API at baseline was 8.0±0.9, and decreased after 4 weeks by 48% (4.2±1.9; Ppatients responded to treatment. Significant improvements were also reported in number/severity of breakthrough cancer pain episodes (P=0.001), Brief Pain Inventory Short Form (P=0.0002), Symptom Distress Scale (Ppatients were satisfied/very satisfied with the new analgesic treatment. Combination therapy had a good safety profile. Conclusion OXN-PR and pregabalin were safe and highly effective in a real-world setting of severe neuropathic cancer pain, with a high rate of satisfaction, without interference on bowel function. PMID:27445495

  6. Antinociceptive Effects of the Serotonin and Noradrenaline Reuptake Inhibitors Milnacipran and Duloxetine on Vincristine-Induced Neuropathic Pain Model in Mice

    OpenAIRE

    Katsuyama, Soh; Aso, Hiromu; Otowa, Akira; Yagi, Tomomi; Kishikawa, Yukinaga; Komatsu, Takaaki; Sakurada, Tsukasa; NAKAMURA, Hitoshi

    2014-01-01

    Vincristine is an anticancer drug used to treat a variety of cancer types, but it frequently causes peripheral neuropathy. Neuropathic pain is often associated with the appearance of abnormal sensory signs, such as allodynia. Milnacipran and duloxetine, serotonin/noradrenaline reuptake inhibitors, have shown efficacy against several chronic pain syndromes. In this study, we investigated the attenuation of vincristine-induced mechanical allodynia in mice by milnacipran and duloxetine. To induc...

  7. Randomised phase II trial (NCT00637975 evaluating activity and toxicity of two different escalating strategies for pregabalin and oxycodone combination therapy for neuropathic pain in cancer patients.

    Directory of Open Access Journals (Sweden)

    Marina Chiara Garassino

    Full Text Available PURPOSE: Neuropathic pain is commonly associated with cancer. Current treatments include combination opioid and adjuvant therapies, but no guidelines are available for dose escalation strategies. This phase II study compared the efficacy and tolerability of two dose escalation strategies for oxycodone and pregabalin combination therapy. METHODS: Patients (N = 75 with oncological neuropathic pain, previously untreated with pregabalin, were recruited in 5 Italian institutions between 2007 and 2010. Patients were randomised to two different dose escalation strategies (arm A; N = 38 oxycodone at a fixed dose with increasing pregabalin doses; (arm B; N = 37 pregabalin at a fixed dose with increasing oxycodone doses. Patients were evaluated from daily diaries and follow-ups at 3, 7, 10, and 14 days after beginning treatment with a numerical rating scale (NRS, neuropathic pain scale (SDN, and well-being scale (ESAS. The primary endpoint was a ≥1/3 reduction in pain (NRS; secondary endpoints included the time to analgesia and adverse effects. The study had a 90% probability of detecting the best strategy for a true difference of at least 15%. RESULTS: More patients in arm A (76% than arm B (64% achieved ≥1/3 overall pain reduction even after controlling for baseline factors (gender, baseline pain. Group A reported fewer side effects than group B; constipation 52.8% vs. 66.7%; nausea: 27.8% vs. 44.4%; drowsiness: 44.4% vs. 55.6%; confusion: 16.7% vs. 27.8%; itching: 8.3% vs. 19.4%. CONCLUSIONS: Both strategies effectively controlled neuropathic pain, but according to the adopted selection design arm A is preferable to arm B for pain control. TRIAL REGISTRATION: ClinicalTrials.gov NCT00637975.

  8. Economic and humanistic burden of post-trauma and post-surgical neuropathic pain among adults in the United States

    Directory of Open Access Journals (Sweden)

    Parsons B

    2013-06-01

    Full Text Available Bruce Parsons,1 Caroline Schaefer,2 Rachael Mann,3 Alesia Sadosky,1 Shoshana Daniel,4 Srinivas Nalamachu,5 Brett R Stacey,6 Edward C Nieshoff,7 Michael Tuchman,8 Alan Anschel91Pfizer, Inc, New York, NY, USA; 2Covance Market Access Services, Inc, Gaithersburg, MD, USA; 3Covance Market Access Services, Inc, San Diego, CA, USA; 4Covance Market Access Services, Inc, Conshohocken, PA, USA; 5International Clinical Research Institute, Overland Park, KS, USA; 6Oregon Health and Science University, Portland, OR, USA; 7Rehabilitation Institute of Michigan/Wayne State University, Detroit, MI, USA; 8Palm Beach Neurological Center, Palm Beach Gardens, FL, USA; 9Rehabilitation Institute of Chicago, Chicago, IL, USABackground: Neuropathic pain (NeP can be chronic, debilitating, and can interfere with sleep, functioning, and emotional well being. While there are multiple causes of NeP, few studies have examined the disease burden and treatment patterns associated with post-traumatic/post-surgical (PTPS NeP.Objective: To characterize pain, health status, function, health care resource utilization, lost productivity, and costs among subjects with PTPS NeP in the United States.Methods: This observational study enrolled 100 PTPS NeP subjects recruited during routine visits from general practitioner and specialist sites. Subjects completed a one-time questionnaire with validated measures of pain severity and pain interference, health status, sleep, anxiety and depression, productivity, and study-specific items on demographics, employment status, and out-of-pocket expenses. Investigators completed a case report form based on a 6-month retrospective chart review, recording subjects' clinical characteristics as well as current and previous medications/treatments for NeP. Subjects were stratified into mild, moderate, and severe pain groups.Results: Subjects' demographic characteristics were: mean age of 54.9 years, 53% female, and 22% employed for pay. Mean pain

  9. Evaluation of the safety and efficacy of pregabalin in older patients with neuropathic pain: results from a pooled analysis of 11 clinical studies

    Directory of Open Access Journals (Sweden)

    Zlateva Gergana

    2010-11-01

    Full Text Available Abstract Background Older patients are typically underrepresented in clinical trials of medications for chronic pain. A post hoc analysis of multiple clinical studies of pregabalin in patients with painful diabetic peripheral neuropathy (DPN or postherpetic neuralgia (PHN was conducted to evaluate the efficacy and safety of pregabalin in older patients. Methods Data from 11 double-blind, randomized, placebo-controlled clinical studies of pregabalin in patients with DPN or PHN were pooled. Efficacy outcomes included change in Daily Pain Rating Scale score, ≥30% and ≥50% responders, and endpoint pain score ≤3. Safety was based on adverse events (AEs. Primary efficacy was analyzed by analysis of covariance with terms for treatment, age category, protocol, baseline pain, and treatment-by-age category interaction. Results 2516 patients (white, n = 2344 [93.2%]; men, n = 1347 [53.5%]; PHN, n = 1003 [39.9%]; pregabalin, n = 1595 were included in the analysis. Patients were grouped by age: 18 to 64 years (n = 1236, 65 to 74 years (n = 766, and ≥75 years (n = 514. Baseline mean pain and sleep interference scores were comparable across treatment and age groups. Significant improvements in endpoint mean pain were observed for all pregabalin dosages versus placebo in all age groups (p ≤ 0.0009, except for the lowest dosage (150 mg/day in the youngest age group. Clinically meaningful pain relief, defined as ≥30% and ≥50% pain response, was observed in all age groups. The most common AEs were dizziness, somnolence, peripheral edema, asthenia, dry mouth, weight gain, and infections. The relative risks for these AEs increased with pregabalin dose, but did not appear related to older age or type of neuropathic pain. Conclusions Pregabalin (150-600 mg/day significantly reduced pain in older patients (age ≥65 years with neuropathic pain and improvements in pain were comparable to those observed in younger patients. Titration of pregabalin to the

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

    OpenAIRE

    Sagen J; Castellanos DA; Hama AT

    2016-01-01

    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 p...

  11. The influence of μ-opioid and noradrenaline reuptake inhibition in the modulation of pain responsive neurones in the central amygdala by tapentadol in rats with neuropathy

    OpenAIRE

    L. Gonçalves; Friend, L. V.; Dickenson, A. H.

    2015-01-01

    Treatments for neuropathic pain are either not fully effective or have problematic side effects. Combinations of drugs are often used. Tapentadol is a newer molecule that produces analgesia in various pain models through two inhibitory mechanisms, namely central μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition. These two components interact synergistically, resulting in levels of analgesia similar to opioid analgesics such as oxycodone and morphine, but with more tolerabl...

  12. Peripheral Neuropathic Facial/Trigeminal Pain and RANTES/CCL5 in Jawbone Cavitation

    Directory of Open Access Journals (Sweden)

    Johann Lechner

    2015-01-01

    Full Text Available Introduction. In this study, we elucidate the possible causative role of chronic subclinical inflammation in jawbone of patients with atypical facial pain (AFP and trigeminal neuralgia (TRN in the local overexpression of the chemokine regulated on activation and normal T-cell expressed and secreted (RANTES/C-C motif ligand 5 CCL5. Neurons contain opioid receptors that transmit antipain reactions in the peripheral and central nervous system. Proinflammatory chemokines like RANTES/CCL5 desensitize μ-opioid receptors in the periphery sensory neurons and it has been suggested that RANTES modifies the nociceptive reaction. Materials and Methods. In 15 patients with AFP/TRN, we examined fatty degenerated jawbone (FDOJ samples for the expression of seven cytokines by multiplex analysis and compared these results with healthy jawbones. Results. Each of these medullary jawbone samples exhibited RANTES as the only highly overexpressed cytokine. The FDOJ cohort with AFP/TRN showed a mean 30-fold overexpression of RANTES compared to healthy jawbones. Conclusions. To the best of our knowledge, no other research has identified RANTES overexpression in silent inflamed jawbones as a possible cause for AFP/TRN. Thus, we hypothesize that the surgical clearing of FDOJ might diminish RANTES signaling pathways in neurons and contribute to resolving chronic neurological pain in AFP/TRN patients.

  13. Tumor necrosis factor-α and neuropathic pain%肿瘤坏死因子-α和神经病理性疼痛

    Institute of Scientific and Technical Information of China (English)

    郑亚国; 马正良

    2011-01-01

    Background Neuropathic pain is a chronic pain state which is usually produced by injured nervous system.Because of its complex mechanisms,there still has been in lack of efficacious drugs to manage.Objective TNF-α is an important pro-inflammatory cytokine which is released early during nerve injury and neuroinflammation. Recently,many studies show that TNF-α which is expressed by activated immune cells in both peripheral nerve and spinal cord plays a critical role in the development of neuropathic pain.Content This article makes a brief review of the role of TNF-α on neuropathic pain,providing a theory basis for anti- TNF-α therapy in alleviating neuropathic pain.Trend As the pathophysiological mechanisms of neuropathic pain are much better understood,TNF-α may be a new target for neuropathic pain therapeutics.%背景 神经病理性疼痛(Neuropatlic pain,NP)是神经系统损伤引起的一种慢性疼痛,其发病机制复杂,至今尚缺乏有效的治疗药物.目的 肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)是神经损伤和神经炎症过程早期释放的重要致炎细胞因子.近年来,许多研究显示外周及脊髓免疫细胞激活后表达的TNF-α在NP形成过程中具有重要的作用.内容 现就TNF-α在NP中的作用作一综述,为临床抗TNF-α治疗NP提供理论依据.趋向 随着对TNF-α在神经病理性疼痛中机制的深入理解,TNF-α可能成为临床上治疗NP的新靶点.

  14. A comparative study of efficacy and safety of gabapentin versus amitriptyline as coanalgesics in patients receiving opioid analgesics for neuropathic pain in malignancy

    Directory of Open Access Journals (Sweden)

    Manasi Banerjee

    2013-01-01

    Full Text Available Objective: To assess the efficacy and safety of gabapentin and amitriptyline along with opioids in patients suffering from neuropathic pain in malignancy. Materials and Methods: Eighty-eight adult patients between 18 and 70 years of age with neuropathic pain in stage III malignant disease, matched for baseline charactistics, were randomly assigned to two groups. Group A received oral tramadol and gabapentin and group B received oral tramadol and amitriptyline. The treatment duration of each patient was 6 months. Visual analog scale (VAS was the primary efficacy parameter. Verbal rating scale (VRS score, percentage of pain relief (PPR, and global pain score (GPS were the secondary efficacy parameters. Oral morphine tablets or fentanyl transdermal patch were used as rescue medication. Data analysis was carried out in Graph Pad instat. Results: There was decline in VAS pain score from baseline in both the groups in the early phase of the study though there was no statistically detectable difference between them at any study point. Similar changes were seen in the secondary efficacy parameters too. Thus both the drugs were effective in providing relief to cancer patients with neuropathic pain though there was no statistically detectable difference in efficacy between them. Six patients in group A and eight patients in group B required rescue medication. A total of 12 subjects in the gabapentin group and 15 subjects in the amitriptyline group experienced adverse events which were of mild to moderate grades. Conclusions: Amitriptyline may be a suitable alternative for management of neuropathic pain in cancer patients although gabapentin is widely used for this purpose. The lower cost of amitriptyline may favor patient compliance with lesser number of drop-outs.

  15. Synthesis and Evaluation of Novel α-Aminoamides Containing an Indole Moiety for the Treatment of Neuropathic Pain

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    Haotian Li

    2016-06-01

    Full Text Available The α-aminoamide family of sodium ion channel blockers have exhibited analgesic effects on neuropathic pain. Here, a series of novel α-aminoamides containing an indole ring were designed and synthesized. These compounds were evaluated in mice using a formalin test and they exhibited significant anti-allodynia activities. However, the analgesic mechanism of these compounds remains unclear; a subset of the synthesized compounds can only moderately inhibit the sodium ion channel, Nav1.7, in a whole-cell patch clamp assay. Overall, these results suggest that introduction of an indole moiety to α-aminoamide derivatives can significantly improve their bioactivity and further study is warranted.

  16. Gamma knife irradiation of injured sciatic nerve induces histological and behavioral improvement in the rat neuropathic pain model

    OpenAIRE

    木内(矢ヶ崎), 有希

    2013-01-01

    博士(医学) 乙第2786号, 著者名:Yuki Yagasaki・Motohiro Hayashi・Noriko Tamura・Yoriko Kawakami,タイトル:Gamma knife irradiation of injured sciatic nerve induces histological and behavioral improvement in the rat neuropathic pain model, 掲載誌:PLoS One(1932-6203), 巻・頁・年:8巻4号 p.e61010 (2013),著作権関連情報:© 2013 Yagasaki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the o...

  17. Quality assurance experience with the randomized neuropathic bone pain trial (Trans-Tasman Radiation Oncology Group, 96.05)

    International Nuclear Information System (INIS)

    Background and purpose: Trans-Tasman Radiation Oncology Group 96.05 is a prospective randomized controlled trial comparing a single 8 Gy with 20 Gy in five fractions of radiotherapy (RT) for neuropathic pain due to bone metastases. This paper summarizes the quality assurance (QA) activities for the first 234 patients (accrual target 270). Materials and methods: Independent audits to assess compliance with eligibility/exclusion criteria and appropriateness of treatment of the index site were conducted after each cohort of approximately 45 consecutive patients. Reported serious adverse events (SAEs) in the form of cord/cauda equina compression or pathological fracture developing at the index site were investigated and presented in batches to the Independent Data Monitoring Committee. Finally, source data verification of the RT prescription page and treatment records was undertaken for each of the first 234 patients to assess compliance with the protocol. Results: Only one patient was found conclusively not to have genuine neuropathic pain, and there were no detected 'geographical misses' with RT fields. The overall rate of detected infringements for other eligibility criteria over five audits (225 patients) was 8% with a dramatic improvement after the first audit. There has at no stage been a statistically significant difference in SAEs by randomization arm. There was a 22% rate of RT protocol variations involving ten of the 14 contributing centres, although the rate of major dose violations (more than ±10% from protocol dose) was only 6% with no statistically significant difference by randomization arm (P=0.44). Conclusions: QA auditing is an essential but time-consuming component of RT trials, including those assessing palliative endpoints. Our experience confirms that all aspects should commence soon after study activation

  18. Antiallodynic effects of alpha lipoic acid in an optimized RR-EAE mouse model of MS-neuropathic pain are accompanied by attenuation of upregulated BDNF-TrkB-ERK signaling in the dorsal horn of the spinal cord.

    Science.gov (United States)

    Khan, Nemat; Gordon, Richard; Woodruff, Trent M; Smith, Maree T

    2015-06-01

    Neuropathic pain may affect patients with multiple sclerosis (MS) even in early disease. In an experimental autoimmune encephalomyelitis (EAE)-mouse model of MS, chronic alpha lipoic acid (ALA) treatment reduced clinical disease severity, but MS-neuropathic pain was not assessed. Hence, we investigated the pain-relieving efficacy and mode of action of ALA using our optimized relapsing-remitting (RR)-EAE mouse model of MS-associated neuropathic pain. C57BL/6 mice were immunized with MOG35-55 and adjuvants (Quil A and pertussis toxin) to induce RR-EAE; sham-mice received adjuvants only. RR-EAE mice received subcutaneous ALA (3 or 10 mg kg(-1) day(-1)) or vehicle for 21 days (15-35 d.p.i.; [days postimmunization]); sham-mice received vehicle. Hindpaw hypersensitivity was assessed blinded using von Frey filaments. Following euthanasia (day 35 d.p.i.), lumbar spinal cords were removed for immunohistochemical and molecular biological assessments. Fully developed mechanical allodynia in the bilateral hindpaws of vehicle-treated RR-EAE mice was accompanied by marked CD3(+) T-cell infiltration, microglia activation, and increased brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling in the dorsal horn of the lumbar spinal cord. Consequently, phospho-ERK, a marker of central sensitization in neuropathic pain, was upregulated in the spinal dorsal horn. Importantly, hindpaw hypersensitivity was completely attenuated in RR-EAE mice administered ALA at 10 mg kg(-1) day(-1) but not 3 mg kg(-1) day(-1). The antiallodynic effect of ALA (10 mg kg(-1) day(-1)) was associated with a marked reduction in the aforementioned spinal dorsal horn markers to match their respective levels in the vehicle-treated sham-mice. Our findings suggest that ALA at 10 mg kg(-1) day(-1) produced its antiallodynic effects in RR-EAE mice by reducing augmented CD3(+) T-cell infiltration and BDNF-TrkB-ERK signaling in the spinal dorsal horn. PMID:26171221

  19. Spinal cord injury pain: mechanisms and management.

    Science.gov (United States)

    Finnerup, Nanna Brix; Baastrup, Cathrine

    2012-06-01

    Patients with spinal cord injury (SCI) may experience several types of chronic pain, including peripheral and central neuropathic pain, pain secondary to overuse, painful muscle spasms, and visceral pain. An accurate classification of the patient's pain is important for choosing the optimal treatment strategy. In particular, neuropathic pain appears to be persistent despite various treatment attempts. In recent years, we have gained increasing knowledge of SCI pain mechanisms from experimental models and clinical studies. Nevertheless, treatment remains difficult and inadequate. In line with the recommendations for peripheral neuropathic pain, evidence from randomized controlled treatment trials suggests that tricyclic antidepressants and pregabalin are first-line treatments. This review highlights the diagnosis and classification of SCI pain and recent improvements in the understanding of underlying mechanisms, and provides an update on treatment of SCI pain. PMID:22392531

  20. Gabapentin reverses central pain sensitization following a collagenase-induced intrathalamic hemorrhage in rats

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    Castel A

    2013-12-01

    Full Text Available Aude Castel, Pascal VachonFaculty of Veterinary Medicine, Department of Veterinary Biomedicine, University of Montreal, Saint-Hyacinthe, QC, CanadaPurpose: The treatment of central neuropathic pain remains amongst the biggest challenges for pain specialists. The main objective of this study was to assess gabapentin (GBP, amitriptyline (AMI, and carbamazepine (CARBA for the treatment of a rodent central neuropathic pain model.Methods: Male Sprague Dawley rats were trained on the rotarod, Hargreaves, Von Frey and acetone behavioral tests, and baseline values were obtained prior to surgery. A stereotaxic injection of either a collagenase solution or saline was made in the right ventral posterolateral thalamic nucleus. The rats were tested on days 2, 4, 8, and 11 postsurgery. They were retested at regular intervals from day 15 to day 25 postsurgery, after oral administration of either the vehicle (n=7 and n=8 rats with intracerebral injections of collagenase and saline, respectively or the different drugs (GBP [60 mg/kg], AMI [10 mg/kg], CARBA [100 mg/kg]; n=8 rats/drug.Results: A significant decrease in the mechanical thresholds and no change in heat threshold were observed in both hind limbs in the collagenase group, as we had previously shown elsewhere. Reversal of the mechanical hypersensitivity was achieved only with GBP (P<0.05. AMI and CARBA, at the dosages used, failed to show any effect on mechanical thresholds. Transient cold allodynia was observed in some collagenase-injected rats but failed to be statistically significant.Conclusion: Intrathalamic hemorrhaging in the ventrolateral thalamic nucleus induced a bilateral mechanical allodynia, which was reversed by GBP but not AMI or CARBA.Keywords: central pain, thalamus, amitriptyline, carbamazepine

  1. Central adaptation of pain perception in response to rehabilitation of musculoskeletal pain

    DEFF Research Database (Denmark)

    Andersen, Lars L; Andersen, Christoffer H; Sundstrup, Emil;

    2012-01-01

    Understanding the mechanisms of long-standing musculoskeletal pain and adaptations in response to physical rehabilitation is important for developing optimal treatment strategies. The influence of central adaptations of pain perception in response to rehabilitation of musculoskeletal pain remains...

  2. Persistent facial pain conditions

    DEFF Research Database (Denmark)

    Forssell, Heli; Alstergren, Per; Bakke, Merete;

    2016-01-01

    Persistent facial pains, especially temporomandibular disorders (TMD), are common conditions. As dentists are responsible for the treatment of most of these disorders, up-to date knowledge on the latest advances in the field is essential for successful diagnosis and management. The review covers...... TMD, and different neuropathic or putative neuropathic facial pains such as persistent idiopathic facial pain and atypical odontalgia, trigeminal neuralgia and painful posttraumatic trigeminal neuropathy. The article presents an overview of TMD pain as a biopsychosocial condition, its prevalence......, clinical features, consequences, central and peripheral mechanisms, diagnostic criteria (DC/TMD), and principles of management. For each of the neuropathic facial pain entities, the definitions, prevalence, clinical features, and diagnostics are described. The current understanding of the pathophysiology...

  3. Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain

    DEFF Research Database (Denmark)

    Hald, Andreas; Nedergaard, S; Hansen, RR;

    2009-01-01

    of spinal cord glial activation in three different murine pain models to investigate if microglial activation is a general prerequisite for astrocyte activation in pain models. We found that two different types of cancer induced pain resulted in severe spinal astrogliosis without activation of microglia......Activation of spinal cord microglia and astrocytes is a common phenomenon in nerve injury pain models and is thought to exacerbate pain perception. Following a nerve injury, a transient increase in the presence of microglia takes place while the increased numbers of astrocytes stay elevated...

  4. Costing the components of pain management. Analysis of Trans-Tasman Radiation Oncology Group trial (TROG 96.05): One versus five fractions for neuropathic bone pain

    International Nuclear Information System (INIS)

    Background and purpose: Bone metastases causing neuropathic pain (NBP) have traditionally been treated with fractionated radiotherapy (RT). A recently reported randomised Trans-Tasman Radiation Oncology Group trial (TROG 96.05) supports this approach in many cases [Roos DE, Turner SL, O'Brien PC et al. Randomised trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol 2005;75:54-63]. This study sought to compare costs to the Australian health-care system for patients receiving 1 versus 5 fractions for NBP. Patients and methods: The RT and medication costs for 245 patients treated on TROG 96.05 were determined from trial data out to 3 months from RT. Admission costs and causes were derived from hospital records. Results: RT costs (including re-treatments) were calculated to be 222 and 724 Australian dollars (A$) per patient for the 8 Gy/1 and 20 Gy/5 arms, respectively. This difference increased when analgesics (A$192 versus A$229) and related hospital admissions (A$1411 versus A$1893) were considered. Sensitivity analysis demonstrated an incremental cost saving of between A$795 and A$1468 for single fraction RT. Admission rates had the strongest potential to distort cost differences. Conclusions: Clinical outcomes are paramount in choice of fractionation scheme but are optimally considered in the light of economic implications. Overall cost differences between fractionation schedules may vary greatly from those incurred by the RT treatment centre alone. Ideally, such economic evaluations should be planned at the outset of a trial

  5. Internal-specific morphological analysis of sciatic nerve fibers in a radiofrequency-induced animal neuropathic pain model.

    Directory of Open Access Journals (Sweden)

    Samjin Choi

    Full Text Available This study investigated the reversible effects of pulsed radiofrequency (PRF treatment at 42 °C on the ultrastructural and biological changes in nerve and collagen fibers in the progression of neuropathic pain after rat sciatic nerve injury. Assessments of morphological changes in the extracellular matrices by atomic force microscopy and hematoxylin-eosin, Masson's trichrome and picrosirius-red staining as well as the expressions of two fibril-forming collagens, types-I and -III, and two inflammatory cytokines, TNF-α and IL-6, were evaluated on day 30 after RF exposure. There were four groups for different RF thermal treatments: no treatment, no current, PRF, and continuous RF (CRF. An RF procedure similar to that used in human clinical trials was used in this study. The CRF treatment at 82 °C led to neural and collagen damage by the permanent blockage of sensory nociceptors. The PRF treatment led to excellent performance and high expandability compared to CRF, with effects including slight damage and swelling of myelinated axons, a slightly decreased amount of collagen fibers, swelling of collagen fibril diameters, decreased immunoreactivity of collagen types-I and -III, presence of newly synthesized collagen, and recovery of inflammatory protein immunoreactivity. These evidence-based findings suggest that PRF-based pain relief is responsible for the temporary blockage of nerve signals as well as the preferential destruction of pain-related principal sensory fibers like the Aδ and C fibers. This suggestion can be supported by the interaction between the PRF-induced electromagnetic field and cell membranes; therefore, PRF treatment provides pain relief while allowing retention of some tactile sensation.

  6. A Medication Combination for the Treatment of Central Poststroke Pain via the Adjuvant Use of Prednisone With Gabapentin: A Case Report.

    Science.gov (United States)

    Batlle, Luis; Mattie, Ryan; Irwin, Robert

    2016-03-01

    Central poststroke pain is a neuropathic pain syndrome that can occur from pathology of the brain. The case presented is of a woman with multiple comorbidities who was found to have an acute infarct in the left middle and anterior cerebral artery territories. She began to complain of worsening diffuse right upper and lower extremity pain, and central poststroke pain was diagnosed. First-line agents were contraindicated as the result of medical comorbidities, and chronic kidney disease only permitted the use of low-dose gabapentin. The patient's morbid obesity inspired the use of an adjunct medication protocol of a prednisone taper for proper treatment. After starting this treatment regimen, the patient experienced significant pain relief with eventual resolution. A steroid-based treatment protocol was used successfully in the early stages of central poststroke pain with proper side effect management and may have prevented difficult treatment management in the outpatient setting. PMID:26409194

  7. Neuropathic osteoarthropathy: iconographic essay

    International Nuclear Information System (INIS)

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

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

    Science.gov (United States)

    Vadivelu, Nalini; Kai, Alice; Maslin, Benjamin; Kodumudi, Gopal; Legler, Aron; Berger, Jack M

    2015-01-01

    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. PMID:25609974

  9. Direct and indirect pharmacological modulation of CCL2/CCR2 pathway results in attenuation of neuropathic pain - In vivo and in vitro evidence.

    Science.gov (United States)

    Piotrowska, Anna; Kwiatkowski, Klaudia; Rojewska, Ewelina; Slusarczyk, Joanna; Makuch, Wioletta; Basta-Kaim, Agnieszka; Przewlocka, Barbara; Mika, Joanna

    2016-08-15

    The repeated administration of microglial inhibitor (minocycline) and CCR2 antagonist (RS504393) attenuated the neuropathic pain symptoms in rats following chronic constriction injury of the sciatic nerve, which was associated with decreased spinal microglia activation and the protein level of CCL2 and CCR2. Furthermore, in microglia primary cell cultures minocycline downregulated both CCL2 and CCR2 protein levels after lipopolysaccharide-stimulation. Additionally, in astroglia primary cell cultures minocycline decreased the expression of CCL2, but not CCR2. Our results provide new evidence that modulation of CCL2/CCR2 pathway by microglial inhibitor as well as CCR2 antagonist is effective for neuropathic pain development in rats. PMID:27397071

  10. Hypolocomotion, asymmetrically directed behaviors (licking, lifting, flinching, and shaking and dynamic weight bearing (gait changes are not measures of neuropathic pain in mice

    Directory of Open Access Journals (Sweden)

    Schorscher-Petcu Ara

    2010-06-01

    Full Text Available Abstract Background Spontaneous (non-evoked pain is a major clinical symptom of neuropathic syndromes, one that is understudied in basic pain research for practical reasons and because of a lack of consensus over precisely which behaviors reflect spontaneous pain in laboratory animals. It is commonly asserted that rodents experiencing pain in a hind limb exhibit hypolocomotion and decreased rearing, engage in both reflexive and organized limb directed behaviors, and avoid supporting their body weight on the affected side. Furthermore, it is assumed that the extent of these positive or negative behaviors can be used as a dependent measure of spontaneous chronic pain severity in such animals. In the present study, we tested these assumptions via blinded, systematic observation of digital video of mice with nerve injuries (chronic constriction or spared nerve injury, and automated assessment of locomotor behavior using photocell detection and dynamic weight bearing (i.e., gait using the CatWalk® system. Results We found no deficits in locomotor activity or rearing associated with neuropathic injury. The frequency of asymmetric (ipsilaterally directed behaviors were too rare to be seriously considered as representing spontaneous pain, and in any case did not statistically exceed what was blindly observed on the contralateral hind paw and in control (sham operated and unoperated mice. Changes in dynamic weight bearing, on the other hand, were robust and ipsilateral after spared nerve injury (but not chronic constriction injury. However, we observed timing, pharmacological, and genetic dissociation of mechanical allodynia and gait alterations. Conclusions We conclude that spontaneous neuropathic pain in mice cannot be assessed using any of these measures, and thus caution is warranted in making such assertions.

  11. Molecular basis for the dosing time-dependency of anti-allodynic effects of gabapentin in a mouse model of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Tsuda Makoto

    2010-11-01

    Full Text Available Abstract Background Neuropathic pain is characterized by hypersensitivity to innocuous stimuli (tactile allodynia that is nearly always resistant to NSAIDs or even opioids. Gabapentin, a GABA analogue, was originally developed to treat epilepsy. Accumulating clinical evidence supports the effectiveness of this drug for diverse neuropathic pain. In this study, we showed that the anti-allodynic effect of gabapentin was changed by the circadian oscillation in the expression of its target molecule, the calcium channel α2δ-1 subunit. Results Mice were underwent partial sciatic nerve ligation (PSL to create a model of neuropathic pain. The paw withdrawal threshold (PWT in PSL mice significantly decreased and fluctuated with a period length about 24 h. The PWT in PSL mice was dose-dependently increased by intraperitoneal injection of gabapentin, but the anti-allodynic effects varied according to its dosing time. The protein levels of α2δ-1 subunit were up-regulated in the DRG of PSL mice, but the protein levels oscillated in a circadian time-dependent manner. The time-dependent oscillation of α2δ-1 subunit protein correlated with fluctuations in the maximal binding capacity of gabapentin. The anti-allodynic effect of gabapentin was attenuated at the times of the day when α2δ-1 subunit protein was abundant. Conclusions These findings suggest that the dosing time-dependent difference in the anti-allodynic effects of gabapentin is attributable to the circadian oscillation of α2δ-1 subunit expression in the DRG and indicate that the optimizing its dosing schedule helps to achieve rational pharmacotherapy for neuropathic pain.

  12. Protective immunity of rAd5/NR2B vaccine against concomitant aversiveness of spontaneous neuropathic pain following spinal nerve ligation injury

    OpenAIRE

    Wang, Gong-Ming; Wang, Xiao-Yan; Liu, Guang-Jie; Cheng, Kun; Wang, Hua; Guo, Shou-Gang

    2015-01-01

    Objective: Peripheral nerve injury elicits an aversive state of spontaneous neuropathic pain, and up to now, the modulation of this concomitant aversive state remains a major therapeutic challenge. NMDA receptor subunits NR2B in the rACC are critically involved in the processing of this aversive state and then a strategy targeted at the NR2B subunit might be promising for modulation of the aversive state. Thus, in the present study, using negative reinforcement animal model to reveal spontane...

  13. Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense.

    Science.gov (United States)

    Walters, Edgar T

    2014-08-01

    Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain-derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain. PMID:25017887

  14. Effects of continuous peripheral nerve block by tetrodotoxin on growth associated protein-43 expression during neuropathic pain development

    Institute of Scientific and Technical Information of China (English)

    Chen Wang; Xiaoyu Huang

    2007-01-01

    BACKGROUND: Peripheral nerve injury may lead to neuropathic pain and cause a markedly increase expression of growth associated protein-43 (GAP-43) in the spinal cord and dorsal root ganglion, local anesthetics blocking electrical impulse propagation of nerve fibers may also affect the expression of GAP-43 in the spinal cord and dorsal root ganglion.OBJECTIVE: To determine the effects of continuous peripheral nerve block by tetrodotoxin before and after nerve injury on GAP-43 expression in the dorsal root ganglion during the development of neuropathic pain.DESIGN: A randomized controlled animal experiment.SETTINGS: Department of Anesthesiology, the Second Hospital of Xiamen City; Department of Anesthesiology, the Second Affiliated Hospital of Shantou University Medical College. MATERIALS: Thirty-five Sprague Dawley (SD) rats, weighing 200 - 250 g, were randomly divided into four groups: control group (n =5), simple sciatic nerve transection group (n =10), peripheral nerve block before and after sciatic nerve transection groups (n =10). All the sciatic nerve transection groups were divided into two subgroups according to the different postoperative survival periods: 3 and 7 days (n =5) respectively. Mouse anti-GAP-43 monoclonal antibody (Sigma Co., Ltd.), supervision TM anti-mouse reagent (HRP, Changdao antibody diagnosis reagent Co., Ltd., Shanghai), and HMIAS-100 image analysis system (Qianping Image Engineering Company, Tongji Medical University) were employed in this study. METHODS: This experiment was carried out hi the Department of Surgery and Pathological Laboratory, the Second Affiliated Hospital of Shantou University Medical College from April 2005 to April 2006.①The animals were anesthetized and the right sciatic nerve was exposed and transected at 1 cm distal to sciatic notch.②Tetrodotoxin 10 μg/kg was injected percutaneously between the greater trochanter and the posterior superior iliac spine of right hind limb to block the sciatic nerve proximally

  15. Effect ofFerula sinkiangensis K.M. Shen on pain threshold and Fos protein expression and astrocyte activation in the spinal cord of neuropathic pain rats

    Institute of Scientific and Technical Information of China (English)

    Huang Yi-fei; Hu Wei; Li Lei; Liu Yan-lu

    2015-01-01

    BACKGROUND:Ferula sinkiangensis K.M. Shen is composed of volatile oil, resin and gum that have the anti-inflammatory, anti-alergic, antispasmodic and analgesic effects. But its analgesic mechanism is unclear. OBJECTIVE: To observe the effect ofFerula sinkiangensis K.M. Shen on heat pain, mechanical pain, Fos protein expression and astrocyte activation in spinal cord of rats with neuropathic pain. METHODS: Eighty adult Sprague-Dawley rat models of chronic sciatic nerve injury were randomly divided into five groups and then intragasticaly administeredFerula sinkiangensis K.M. Shen at low, moderate and high doses (0.075, 0.15, 0.30 g/kg), celecoxib or physiological saline. Heat pain and mechanical pain were measured at 1 day before operation and at 1, 2, 3, 5, 7, 14 days after operation. The spinal cord tissue at S4-5 segments was harvested and Fos protein expression and astrocyte activation in the spinal cord of rats were observed by immunohistochemical staining method. RESULTS AND CONCLUSION: After 1 and 5 days of medication, behavioral pain scores of rats in the low-, moderate-, and high-doseFerula sinkiangensis K.M. Shen groups were significantly higher than that in the physiological saline group (P < 0.01). The largest reduction in heat pain threshold was measured in the moderate-doseFerula sinkiangensis K.M. Shen group compared to the other groups (P < 0.01). The most significant reduction in rat mechanical pain threshold was measured in the high-doseFerula sinkiangensis K.M. Shen group than in the other groups (P < 0.01). At each time point post-operation, the number of Fos protein-positive cels in the low-, moderate- and high-doseFerula sinkiangensis K.M. Shen and celecoxib groups was significantly lower than that in the physiological saline group (P < 0.05); the number of Fos protein-positive cels in the moderate- and high-doseFerula sinkiangensis K.M Shen groups was significantly higher than that in the celecoxib group (P< 0.05). At each time point post

  16. An early granulocyte colony-stimulating factor treatment attenuates neuropathic pain through activation of mu opioid receptors on the injured nerve.

    Science.gov (United States)

    Liao, Ming-Feng; Yeh, Shin-Rung; Lo, Ai-Lun; Chao, Po-Kuan; Lee, Yun-Lin; Hung, Yu-Hui; Lu, Kwok-Tung; Ro, Long-Sun

    2016-01-01

    Several studies have shown that the mu opioid receptor (MOR) located in the peripheral nerves can be activated after nerve injury and that it attenuates peripheral nociceptive signals to the spinal dorsal horn. Various cytokines and phosphorylated-p38 (p-p38) activation in the dorsal horn also play an important role in neuropathic pain development. Granulocyte-colony stimulating factor (GCSF) is a growth factor that can stimulate granulocyte formation and has been shown to exert an analgesic effect on neuropathic pain through recruiting opioid-containing leukocytes to the injured nerve. However, the underlying mechanisms are not well understood. Herein, the results of behavior tests in addition to MOR levels in the injured sciatic nerve and the levels of p-p38 and various cytokines in the spinal dorsal horn were studied in vehicle-treated or GCSF-treated chronic constriction injured (CCI) rats at different time points (i.e., 1, 3, and 7 days, respectively) after nerve injury. The results showed that a single early systemic GCSF treatment after nerve injury can up-regulate MORs in the injured nerve, which can decrease peripheral nociceptive signals. Thereafter, those changes suppress the pro-inflammatory cytokine IL-6 but enhance the anti-inflammatory cytokine IL-4, followed by decreases in p-p38 in the dorsal horn, and thus further attenuate neuropathic pain. PMID:27180600

  17. A Comparison of Surgical Invasions for Spinal Nerve Ligation with or without Paraspinal Muscle Removal in a Rat Neuropathic Pain Model

    Science.gov (United States)

    Huang, Yi-Gang; Zhang, Qing; Wu, Hao

    2016-01-01

    L5 spinal nerve ligation (SNL) in rats is one of the most popular models for studying neuropathic pain because of its high reproducibility. During the surgery, a part of the L5 paraspinal muscle is usually removed, which produces extra trauma and may potentially affect the physiological processes involved in neuropathic pain. To reduce the surgical trauma, the paraspinal muscle retraction was developed for exposure of the spinal nerve. The current study was aimed at comparing the surgical invasions between the L5 SNL models with paraspinal muscle removal or retraction. The results showed that both methods induced similar neuropathic pain behavior. However, the paraspinal muscle retraction group exhibited an average of 2.7 mg less blood loss than the muscle removal group. This group also showed a significantly lower increase in serum myoglobin and creatine phosphokinase levels on postoperative days 1 and 2, as well as a lower increase in interleukin-1β and interleukin-6 levels on postoperative day 1. The paraspinal muscle maintained normal morphological features following paraspinal muscle retraction. Our results indicate that the SNL rat model with paraspinal muscle retraction is a reliable physiological model that is reproducible, readily available, and less invasive than the model with muscle removal. PMID:27597970

  18. A Comparison of Surgical Invasions for Spinal Nerve Ligation with or without Paraspinal Muscle Removal in a Rat Neuropathic Pain Model.

    Science.gov (United States)

    Huang, Yi-Gang; Zhang, Qing; Wu, Hao; Zhang, Chang-Qing

    2016-01-01

    L5 spinal nerve ligation (SNL) in rats is one of the most popular models for studying neuropathic pain because of its high reproducibility. During the surgery, a part of the L5 paraspinal muscle is usually removed, which produces extra trauma and may potentially affect the physiological processes involved in neuropathic pain. To reduce the surgical trauma, the paraspinal muscle retraction was developed for exposure of the spinal nerve. The current study was aimed at comparing the surgical invasions between the L5 SNL models with paraspinal muscle removal or retraction. The results showed that both methods induced similar neuropathic pain behavior. However, the paraspinal muscle retraction group exhibited an average of 2.7 mg less blood loss than the muscle removal group. This group also showed a significantly lower increase in serum myoglobin and creatine phosphokinase levels on postoperative days 1 and 2, as well as a lower increase in interleukin-1β and interleukin-6 levels on postoperative day 1. The paraspinal muscle maintained normal morphological features following paraspinal muscle retraction. Our results indicate that the SNL rat model with paraspinal muscle retraction is a reliable physiological model that is reproducible, readily available, and less invasive than the model with muscle removal. PMID:27597970

  19. Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus-evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain.

    Science.gov (United States)

    Kumar, Naresh; Cherkas, Pavel S; Varathan, Vidya; Miyamoto, Makiko; Chiang, Chen Yu; Dostrovsky, Jonathan O; Sessle, Barry J; Coderre, Terence J

    2013-05-01

    Pregabalin is effective in treating many neuropathic pain conditions. However, the mechanisms of its analgesic effects remain poorly understood. The aim of the present study was to determine whether pregabalin suppresses facial mechanical hypersensitivity and evoked glutamate release in the medullary dorsal horn (MDH) in a rodent model of trigeminal neuropathic pain. Nociceptive mechanical sensitivity was assessed pre-operatively, and then post-operatively 1h following pregabalin or vehicle (saline) treatment on post-operative days 2 and 5 following infraorbital nerve transection (IONX). In addition, an in vivo microdialysis probe was inserted into the exposed medulla post-operatively and dialysate samples were collected. Glutamate release was then evoked by mustard oil (MO) application to the tooth pulp, and the effects of pregabalin or vehicle were examined on the MDH glutamate release. Glutamate concentrations in the dialysated samples were determined by HPLC, and data analyzed by ANOVA. IONX animals (but not control animals) showed facial mechanical hypersensitivity for several days post-operatively. In addition, tooth pulp stimulation with MO evoked a transient release of glutamate in the MDH of IONX animals. Compared to vehicle, administration of pregabalin significantly attenuated the facial mechanical hypersensitivity as well as the MO-evoked glutamate release in MDH. This study provides evidence in support of recent findings pointing to the usefulness of pregabalin in the treatment of orofacial neuropathic pain. PMID:23454190

  20. Restless legs syndrome: a new entity of neuropathic pain? Treatment with prolonged release oxycodone/naloxone combination

    Directory of Open Access Journals (Sweden)

    Gemignani F

    2016-04-01

    Full Text Available Franco Gemignani,1 Andrea Melpignano,1,2 Giulia Milioli,1,2 Silvia Riccardi,1,2 Liborio Parrino1,2 1Neurology Unit, Department of Neurosciences, University of Parma, Parma, Italy; 2Sleep Disorders Center, Department of Neurosciences, University of Parma, Parma, Italy Abstract: Restless legs syndrome (RLS is a disorder of sensorimotor integration characterized by an urge to move the legs when at rest, especially at night or in the evening, which is relieved by movement. Sensory symptoms may be prominent, often exhibiting features consistent with neuropathic pain. Iron deficiency and genetic factors are implicated in RLS causation in most patients. The pathogenetic model of impaired circadian dopaminergic modulation of sensorimotor integration circuitry at the spinal level is fitting with the co-occurrence of movement disorders, sensory symptoms, and sleep disruption in RLS. Accordingly, levodopa and dopamine agonists are effective for RLS symptoms, which compensate for the impaired descending control by diencephalo-spinal dopa(minergic pathway. Dopamine agonists are usually indicated as the first-line therapy, but their use in long-term treatment is often complicated by augmentation and impulse control disorder, thus alpha-2-delta ligands also are now considered the first line of treatment. It has been recognized that endogenous opioid system is also involved in the mechanisms generating RLS, possibly through an impaired modulation of pain pathways. Opioids can be considered as an alternative therapy, particularly in patients with augmentation and/or refractory to other treatments. Recently introduced prolonged-release oxycodone–naloxone was efficacious for short-term treatment of patients with severe RLS inadequately controlled with previous treatment. It will be important to assess whether opioids, as well as other drugs, are especially effective in definite RLS subtypes such as the painful phenotype. Keywords: small fiber neuropathy

  1. Association of computerized texture features on MRI with early treatment response following laser ablation for neuropathic cancer pain: preliminary findings.

    Science.gov (United States)

    Tiwari, Pallavi; Danish, Shabbar F; Jiang, Benjamin; Madabhushi, Anant

    2015-10-01

    Laser interstitial thermal therapy (LITT) has recently emerged as a new treatment modality for cancer pain management that targets the cingulum (pain center in the brain) and has shown promise over radio frequency (RF)-based ablation, due to magnetic resonance image (MRI) guidance that allows for precise ablation. Since laser ablation for pain management is currently exploratory and is only performed at a few centers worldwide, its short- and long-term effects on the cingulum are currently unknown. Traditionally, treatment effects for neurological conditions are evaluated by monitoring changes in intensities and/or volume of the ablation zone on post-treatment Gadolinium-contrast T1-w (Gd-T1) MRI. However, LITT introduces subtle localized changes corresponding to tissues response to treatment, which may not be appreciable on visual inspection of volumetric or intensity changes. Additionally, different MRI protocols [Gd-T1, T2w, gradient echo sequence (GRE), fluid-attenuated inversion recovery (FLAIR)] are known to capture complementary diagnostic information regarding the patient's response to treatment; the utility of these MRI protocols has so far not been investigated to evaluate early and localized response to LITT treatment in the context of neuropathic cancer pain. In this work, we present the first attempt at (a) examining early treatment-related changes on a per-voxel basis via quantitative comparison of computer-extracted texture descriptors across pre- and post-LITT multiparametric (MP-MRI) (Gd-T1, T2w, GRE, FLAIR), subtle microarchitectural texture changes that may not be appreciable on original MR intensities or volumetric differences, and (b) investigating the efficacy of different MRI protocols in accurately capturing immediate post-treatment changes reflected (1) within and (2) outside the ablation zone. A retrospective cohort of four patient studies comprising pre- and immediate (24 h) post-LITT 3 Tesla Gd-T1, T2w, GRE, and FLAIR acquisitions

  2. Role of Prelimbic GABAergic Circuits in Sensory and Emotional Aspects of Neuropathic Pain

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    Zizhen Zhang

    2015-08-01

    Full Text Available Noxious stimuli are detected by peripheral nociceptors and then transmitted to higher CNS centers, where they are perceived as an unpleasant sensation. The mechanisms that govern the emotional component associated with pain are still incompletely understood. Here, we used optogenetic approaches both in vitro and in vivo to address this issue. We found that peripheral nerve injury inhibits pyramidal cell firing in the prelimbic area of the prefrontal cortex as a result of feed-forward inhibition mediated by parvalbumin-expressing GABAergic interneurons. In addition, activation of inhibitory archaerhodopsin or excitatory channelrhodopsin-2 in these neurons decreased and increased pain responses, respectively, in freely moving mice and accordingly modulated conditioned place preference scores and place escape/avoidance behavior. Our findings thus demonstrate an important role of the prelimbic area in sensory and emotional aspects of pain and identify GABAergic circuits in this region as a potential target for pain therapeutics.

  3. A candidate gene study of serotonergic pathway genes and pain relief during treatment with escitalopram in patients with neuropathic pain shows significant association to serotonin receptor2C (HTR2C)

    DEFF Research Database (Denmark)

    Brasch-Andersen, Charlotte; Møller, Malik U; Christiansen, Lene;

    2011-01-01

    the association between polymorphisms in genes involved in the serotonergic pathway and the effect of escitalopram on peripheral neuropathic pain. METHODS: We genotyped 34 participants from a placebo-controlled trial of escitalopram in peripheral neuropathic pain for polymorphisms in five genes: the.......047), with 75% carrying the C allele being responders. The same tendency was seen in women. Similarly, carriership of the C allele at rs6318 was associated with better pain relief during treatment with escitalopram [odds ratio (OR) 15.5, p = 0.014)] Furthermore, there was a tendency of better relief with...... increasing number of short alleles for the 5-HTTLPR polymorphism of the serotonin transporter (OR 5.7, p = 0.057). None of the other polymorphisms showed a significant association with treatment response to escitalopram. CONCLUSION: This study indicates that variation in the HTR2C gene is associated to the...

  4. Antinociceptive effects of hydroalcoholic extract from Euterpe oleracea Mart. (Açaí) in a rodent model of acute and neuropathic pain

    OpenAIRE

    Sudo, Roberto T; Neto, Miguel L.; Monteiro, Carlos E.S.; Amaral, Rachel V.; Resende, Ângela C.; Souza, Pergentino J. C.; Zapata-Sudo, Gisele; de Moura, Roberto S

    2015-01-01

    Background Plants rich in flavonoids, such as açaí (Euterpe oleraceae Mart.), can induce antinociception in experimental animals. Here, we tested an extract obtained from the stones of açaí fruits (açaí stone extract, ASE), a native plant from the Amazon region of Brazil, in models of acute/inflammatory and chronic pain. Methods Antinociceptive effects of ASE were evaluated in the hot plate, formalin, acetic acid writhing, carrageenan, and neuropathic pain models, as well as in thermal hypera...

  5. Expression of the dopaminergic D1 and D2 receptors in the anterior cingulate cortex in a model of neuropathic pain

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    Ortega-Legaspi J Manuel

    2011-12-01

    Full Text Available Abstract Background The anterior cingulate cortex (ACC has been related to the affective component of pain. Dopaminergic mesocortical circuits, including the ACC, are able to inhibit neuropathic nociception measured as autotomy behaviour. We determined the changes in dopamine D1 and D2 (D1R and D2R receptor expression in the ACC (cg1 and cg2 in an animal model of neuropathic pain. The neuropathic group had noxious heat applied in the right hind paw followed 30 min. later by right sciatic denervation. Autotomy score (AS was recorded for eight days and subsequently classified in low, medium and high AS groups. The control consisted of naïve animals. A semiquantitative RT-PCR procedure was done to determine mRNA levels for D1R and D2R in cg1 and cg2, and protein levels were measured by Western Blot. Results The results of D1R mRNA in cg1 showed a decrease in all groups. D2R mRNA levels in cg1 decreased in low AS and increased in medium and high AS. Regarding D1R in cg2, there was an increase in all groups. D2R expression levels in cg2 decreased in all groups. In cg1, the D2R mRNA correlated positively with autotomy behaviour. Protein levels of D2R in cg1 increased in all groups but to a higher degree in low AS. In cg2 D2R protein only decreased discretely. D1R protein was not found in either ACC region. Conclusions This is the first evidence of an increase of inhibitory dopaminergic receptor (D2R mRNA and protein in cg1 in correlation with nociceptive behaviour in a neuropathic model of pain in the rat.

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

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    Suk-Yun Kang

    2012-01-01

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

  7. Anti-allodynic and Anti-hyperalgesic effects of an ethanolic extract and xylopic acid from the fruits of Xylopia aethiopica in murine models of neuropathic pain

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    Elvis O Ameyaw

    2014-01-01

    Full Text Available Background: Fruit extracts of Xylopia aethiopica are used traditionally in the management of pain disorders including headache and neuralgia. An animal model of vincristine-induced sensory neuropathy was developed after repeated intraperitoneal injection in rats and used in the present work to study the effects of the ethanolic extract of X. aethiopica (XAE and its diterpene xylopic acid (XA in vincristine-induced neuropathic pain. Materials and Methods: Vincristine (0.1 mg kg -1 day -1 was administered during two cycles of five consecutive days to induce chemotherapy-induced neuropathic pain. Static tactile anti-allodynic, anti-hyperalgesic, and cold anti-allodynic effects of XAE (30-300 mg kg -1 and XA (10-100 mg kg -1 were assessed using Von Frey filaments of bending forces of 4, 8, and 15 g, the Randall-Selitto paw pressure test, and cold water (4.5°C, respectively. Results: Administration of vincristine caused the development of allodynia and hyperalgesia with no significant motor deficit, spontaneous pain, and foot deformity. XAE (30-300 mg kg -1 and XA (10-100 mg kg -1 exhibited anti-hyperalgesic, tactile, and cold anti-allodynic properties with XA exhibiting greater potency than XAE. Pregabalin (10-100 mg kg -1 used as control produced similar effect. Conclusion: These findings establish the anti-allodynic and anti-hyperalgesic effects of the ethanolic fruit XAE and its major diterpene XA in vincristine-induced neuropathtic pain.

  8. Tolerability of NGX-4010, a capsaicin 8% patch, in conjunction with three topical anesthetic formulations for the treatment of neuropathic pain

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    Webster LR

    2012-01-01

    Full Text Available Lynn R Webster1, John F Peppin2, Frederick T Murphy3,4, Jeffrey K Tobias5, Geertrui F Vanhove51Lifetree Clinical Research and Pain Clinic, Lifetree Medical Inc, Salt Lake City, UT, USA; 2Clinical Research Division, The Pain Treatment Center of the Bluegrass, Lexington, KY, USA; 3Altoona Center for Clinical Research, Duncansville, PA, USA; 4University of Pennsylvania, School of Medicine, Philadelphia, PA, USA; 5NeurogesX Inc, San Mateo, CA, USABackground: The objective of this study was to assess the safety, tolerability, and preliminary efficacy of NGX-4010, a capsaicin 8% patch, following pretreatment with three different topical anesthetics in patients with peripheral neuropathic pain.Methods: This open-label, multicenter study enrolled 117 patients with post-herpetic neuralgia, HIV-associated distal sensory polyneuropathy, or painful diabetic neuropathy. Patients received pretreatment with one of three lidocaine 4%-based topical anesthetics (L.M.X.4® [Ferndale Laboratories Inc, Ferndale, MI], Topicaine® Gel [Estela Basso, Jupiter, FL], or Betacaine Enhanced Gel 4 [Tiberius Inc, Tampa, FL] for 60 minutes followed by a single 60- or 90-minute NGX-4010 application, and were followed for 12 weeks. Tolerability and safety measures included “pain now” Numeric Pain Rating Scale (NPRS scores, dermal assessments, medication use for treatment-related pain, adverse events (AEs, clinical laboratory parameters, physical examinations, and vital signs. The primary efficacy variable was the percentage change in mean NPRS scores for “average pain for the past 24 hours” from baseline to weeks 2 through 12.Results: Treatment with NGX-4010 following pretreatment with any of the three topical anesthetics was generally safe and well tolerated. Nearly all patients completed ≥90% of the planned NGX-4010 application duration. The most common treatment-related AEs, application-site burning and application-site pain, were transient, mostly mild or moderate

  9. Lumbar neuropathic pain of lower limbs treated by spinal infusion of ziconotide a case – report

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    Luca Quadrino

    2008-09-01

    Full Text Available The Author reports the case of a patient with severe lumbar pain unresponsive to NSAIDs. Initial treatment with tramadol gave poor results and a new protocol with hydromorphone – pregabalin was started. The analgesic response was observed only following high hydromorphone doses, associated with unacceptable side effects. A spinal device for continuous intrathecal infusion was then implanted, in order to administer ziconotide, a new opioid drug. Associated therapy included hydromorphone – pregabalin. At the 4 mcg/die dose ziconotide resulted highly effective (with a VAS reduction pain 6-7 to 2-3 even at 1st day after implantation; in addition at day 10, opioid dose was strongly reduced and pregabalin withdrawn. The treatment was associated with a good tolerability. The encouraging results prompted the Author to test ziconotide in further cases of severe chronic pain.

  10. Role of PAF receptor in proinflammatory cytokine expression in the dorsal root ganglion and tactile allodynia in a rodent model of neuropathic pain.

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    Shigeo Hasegawa

    Full Text Available BACKGROUND: Neuropathic pain is a highly debilitating chronic pain following damage to peripheral sensory neurons and is often resistant to all treatments currently available, including opioids. We have previously shown that peripheral nerve injury induces activation of cytosolic phospholipase A(2 (cPLA(2 in injured dorsal root ganglion (DRG neurons that contribute to tactile allodynia, a hallmark of neuropathic pain. However, lipid mediators downstream of cPLA(2 activation to produce tactile allodynia remain to be determined. PRINCIPAL FINDINGS: Here we provide evidence that platelet-activating factor (PAF is a potential candidate. Pharmacological blockade of PAF receptors (PAFRs reduced the development and expression of tactile allodynia following nerve injury. The expression of PAFR mRNA was increased in the DRG ipsilateral to nerve injury, which was seen mainly in macrophages. Furthermore, mice lacking PAFRs showed a reduction of nerve injury-induced tactile allodynia and, interestingly, a marked suppression of upregulation of tumor necrosis factor alpha (TNFalpha and interleukin-1beta (IL-1beta expression in the injured DRG, crucial proinflammatory cytokines involved in pain hypersensitivity. Conversely, a single injection of PAF near the DRG of naïve rats caused a decrease in the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner and an increase in the expression of mRNAs for TNFalpha and IL-1beta, both of which were inhibited by pretreatment with a PAFR antagonist. CONCLUSIONS: Our results indicate that the PAF/PAFR system has an important role in production of TNFalpha and IL-1beta in the DRG and tactile allodynia following peripheral nerve injury and suggest that blocking PAFRs may be a viable therapeutic strategy for treating neuropathic pain.

  11. Reduced Glutamatergic Currents and Dendritic Branching of Layer 5 Pyramidal Cells Contribute to Medial Prefrontal Cortex Deactivation in a Rat Model of Neuropathic Pain

    Science.gov (United States)

    Kelly, Crystle J.; Huang, Mei; Meltzer, Herbert; Martina, Marco

    2016-01-01

    Multiple studies have demonstrated that neuropathic pain is associated with major reorganization in multiple brain areas. In line with the strong emotional salience of chronic pain, involvement of the limbic system appears particularly important. Within the past few years, it has become clear that the functional deactivation of the prefrontal cortex (PFC) is critical for both the cognitive/emotional and the sensory components of pain. However, at the cellular level, details of this deactivation remain in large part unclear. Here we show that 1 week after a peripheral neuropathic injury (Spared Nerve Injury model) pyramidal cells in layer 5 (L5) of the rat medial PFC show responses to excitatory glutamatergic inputs that are reduced by about 50%, as well as reduced frequency of spontaneous excitatory synaptic currents. Additionally, these cells have reduced membrane capacitance and increased input resistance. All these findings are consistent with decreased dendritic length, thus we performed a detailed morphological analysis on a subset of the recorded neurons. We found that the apical dendrites proximal to the soma (excluding the tuft) are shorter and less complex in SNI animals, in agreement with the reduced capacitance and glutamatergic input. Finally, we used in vivo microdialysis to compare the basal concentrations of glutamate and GABA in the PFC of sham and SNI rats and found that ambient glutamate is decreased in SNI rats. Taken together, these data show that impaired glutamatergic transmission contributes to the functional deactivation of the mPFC in neuropathic pain. Additionally, the reduced branching of apical dendrites of L5 pyramidal neurons may underlay the gray matter reduction in chronic pain.

  12. The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model.

    Science.gov (United States)

    Wilkerson, Jenny L; Niphakis, Micah J; Grim, Travis W; Mustafa, Mohammed A; Abdullah, Rehab A; Poklis, Justin L; Dewey, William L; Akbarali, Hamid; Banks, Matthew L; Wise, Laura E; Cravatt, Benjamin F; Lichtman, Aron H

    2016-04-01

    Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents. The combination of opiates with the primary active constituent of cannabis (Δ(9)-tetrahydrocannabinol) produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonoylglycerol through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid-sparing effects in the mouse chronic constriction injury (CCI) of the sciatic nerve model of neuropathic pain. The dose-response relationships of i.p. administration of morphine and the selective MAGL inhibitor 2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate (MJN110) were tested alone and in combination at equieffective doses for reversal of CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED50 doses (95% confidence interval) of morphine and MJN110 were 2.4 (1.9-3.0) mg/kg and 0.43 (0.23-0.79) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required μ-opioid, CB1, and CB2 receptors. This combination did not reduce gastric motility or produce subjective cannabimimetic effects in the drug discrimination assay. Importantly, combinations of MJN110 and morphine given repeatedly (i.e., twice a day for 6 days) continued to produce antiallodynic effects with no evidence of tolerance. Taken together, these findings suggest that MAGL inhibition produces opiate-sparing events with diminished tolerance, constipation, and cannabimimetic side effects. PMID:26791602

  13. Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls – a hypothesis-generating pilot study

    Directory of Open Access Journals (Sweden)

    Bäckryd E

    2015-07-01

    Full Text Available Emmanuel Bäckryd,1,2 Bijar Ghafouri,1,2 Anders K Carlsson,1,2 Patrik Olausson,1,2 Björn Gerdle1,2 1Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden; 2Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, SwedenAbstract: Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11, and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients, two isoforms of alpha-1-antitrypsin (downregulated in patients, three isoforms of haptoglobin (upregulated in patients, and one isoform of pigment epithelium-derived factor (downregulated in patients. It has recently been hypothesized that the renin–angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin–angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis

  14. Fibromyalgia and neuropathic pain - differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia

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    Tölle Thomas R

    2011-05-01

    Full Text Available Abstract Background Patients with diabetic neuropathy (DPN and fibromyalgia differ substantially in pathogenetic factors and the spatial distribution of the perceived pain. We questioned whether, despite these obvious differences, similar abnormal sensory complaints and pain qualities exist in both entities. We hypothesized that similar sensory symptoms might be associated with similar mechanisms of pain generation. The aims were (1 to compare epidemiological features and co-morbidities and (2 to identify similarities and differences of sensory symptoms in both entities. Methods The present multi-center study compares epidemiological data and sensory symptoms of a large cohort of 1434 fibromyalgia patients and 1623 patients with painful diabetic neuropathy. Data acquisition included standard demographic questions and self-report questionnaires (MOS sleep scale, PHQ-9, PainDETECT. To identify subgroups of patients with characteristic combinations of symptoms (sensory profiles a cluster analysis was performed using all patients in both cohorts. Results Significant differences in co-morbidities (depression, sleep disturbance were found between both disorders. Patients of both aetiologies chose very similar descriptors to characterize their sensory perceptions. Burning pain, prickling and touch-evoked allodynia were present in the same frequency. Five subgroups with distinct symptom profiles could be detected. Two of the subgroups were characteristic for fibromyalgia whereas one profile occurred predominantly in DPN patients. Two profiles were found frequently in patients of both entities (20-35%. Conclusions DPN and fibromyalgia patients experience very similar sensory phenomena. The combination of sensory symptoms - the sensory profile - is in most cases distinct and almost unique for each one of the two entities indicating aetiology-specific mechanisms of symptom generation. Beside the unique aetiology-specific sensory profiles an overlap of

  15. A tarantula spider toxin, GsMTx4, reduces mechanical and neuropathic pain.

    Science.gov (United States)

    Park, Seung Pyo; Kim, Byung Moon; Koo, Jae Yeon; Cho, Hawon; Lee, Chang Hoon; Kim, Misook; Na, Heung Sik; Oh, Uhtaek

    2008-07-01

    Mechanosensitive channels mediate various physiological functions including somatic sensation or pain. One of the peptide toxins isolated from the venom of the Chilean rose tarantula spider (Grammostola spatulata), mechanotoxin 4 (GsMTx4) is known to block stretch-activated cation channels. Since mechanosensitive channels in sensory neurons are thought to be molecular sensors for mechanotransduction, i.e., for touch, pressure, proprioception, and pain, we considered that the venom might block some types of mechanical pain. In order to prepare sufficiently large amounts of GsMTx4 for in vivo nociceptive behavioral tests, we constructed recombinant peptide of GsMTx4. Because the amino-acid sequence of the toxin, but not the nucleotide sequence, is known, we back-translated its amino-acid sequence to nucleotide sequence of yeast codons, constructed a template DNA, subcloned this into a Pichia pastoris expression vector, and purified the recombinant peptide. Intraperitoneal injection of the recombinant GsMTx4 to rats significantly increased the mechanical threshold for paw withdrawal in Randall Sellito test, eliciting significant analgesic responses to inflammation-induced mechanical hyperalgesia. GsMTx4 also reduced mechanical allodynia induced by inflammation and by sciatic nerve injury in Von Frey test. However, the venom was ineffective at changing withdrawal latency in hot plate and tail-flick tests. These results suggest that GsMTx4 selectively alleviates mechanical hyperalgesia, which it presumably achieves by blocking mechanosensitive channels. Because the peptide venom induces analgesia for some forms of mechanical pain, GsMTx4 appears to have potential clinical use as a pain treatment. PMID:18359568

  16. Voluntary and evoked behavioral correlates in neuropathic pain states under different social housing conditions

    Science.gov (United States)

    Pitzer, Claudia; Kuner, Rohini

    2016-01-01

    Background There is an urgent need to develop and incorporate novel behavioral tests in classically used preclinical pain models. Most rodent studies are based upon stimulus-evoked hindpaw measurements even though chronic pain is usually a day and night experience. Chronic pain is indeed a debilitating condition that influences the sociability and the ability for voluntary tasks, but the relevant behavioral readouts for these aspects are mostly under-represented in the literature. Moreover, we lack standardization in most behavioral paradigms to guarantee reproducibility and ensure adequate discussion between different studies. This concerns not only the combination, application, and duration of particular behavioral tasks but also the effects of different housing conditions implicating social isolation. Results Our aim was to thoroughly characterize the classically used spared nerve injury model for 12 weeks following surgery. We used a portfolio of classical stimulus-evoked response measurements, detailed gait analysis with two different measuring systems (Dynamic weight bearing (DWB) system and CatWalk), as well as observer-independent voluntary wheel running and home cage monitoring (Laboras system). Additionally, we analyzed the effects of social isolation in all behavioral tasks. We found that evoked hypersensitivity temporally matched changes in static gait parameters, whereas some dynamic gait parameters were changed in a time-dependent manner. Interestingly, voluntary wheel running behavior was not affected in spared nerve injury mice but by social isolation. Besides a reduced climbing activity, spared nerve injury mice did not showed tremendous alterations in the home cage activity. Conclusion This is the first longitudinal study providing detailed insights into various voluntary behavioral parameters related to pain and highlights the importance of social environment on spontaneous non-evoked behaviors in a mouse model of chronic neuropathy. Our results

  17. Evaluación del uso de metadona en el tratamiento del dolor neuropático Evaluation of methadone use in the treatment of neuropathic pain

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    E.Y. Cardona Aristizabal

    2009-07-01

    Full Text Available Introducción: El dolor neuropático resulta de una lesión o disfunción del sistema nervioso. Su tratamiento es básicamente farmacológico e incluye el uso de antidepresivos y anticonvulsivantes, entre otros. Existe controversia en relación con la utilidad de los opioides en el manejo del dolor neuropático. La metadona es un opioide agonista mu, que además actúa bloqueando la recaptación de norepinefrina y serotonina en el asta dorsal, y es un antagonista del receptor de N-metil-D-Aspartato (NMDA. Objetivo: Valorar la respuesta analgésica obtenida en pacientes con dolor neuropático no oncológico tratados con metadona. Material y métodos: Se realizó un estudio retrospectivo, transversal. Se revisaron expedientes clínicos y se realizó una entrevista directa a los pacientes con dolor neuropático en tratamiento con metadona, durante el período comprendido entre el 1 de enero y 31 de julio de 2006, para valorar mejoría en la intensidad del dolor, la dosis del fármaco y los efectos adversos. Resultados: Se incluyó a 31 pacientes con dolor neuropático en tratamiento con metadona. La dosis diaria varió entre 2,5 y 60 mg (moda 10 mg/día. La intensidad del dolor medida por escala analógica visual fue de 8,7 ± 1,2 y 4,3 ± 1,8, antes y después de tratamiento con metadona, respectivamente, con disminución promedio del 49%. El efecto adverso más común fue la constipación (65%. Conclusiones: La metadona puede ser de utilidad en el tratamiento del dolor neuropático cuando otros fármacos no lo controlan adecuadamente.Introduction: Neuropathic pain results from nervous system injury or dysfunction. Medical treatment is the first line therapy, including antidepressants, anticonvulsants and other drugs. The analgesic efficacy of opioids in the treatment of neuropathic pain is controversial. Methadone is a Ì-opioid receptor agonist, which also acts by blocking norepinephrine and serotonin reuptake into the dorsal horn, and is an N

  18. Gram Scale Syntheses of (-)-Incarvillateine and Its Analogs. Discovery of Potent Analgesics for Neuropathic Pain.

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    Huang, Bin; Zhang, Fengying; Yu, Gang; Song, Yan; Wang, Xintong; Wang, Meiliang; Gong, Zehui; Su, Ruibin; Jia, Yanxing

    2016-04-28

    (-)-Incarvillateine (INCA) is the major antinociceptive component of Incarvillea sinensis, which has been used to treat rheumatism and relieve pain in traditional Chinese medicine. We have developed a concise and general synthetic approach for INCA, which enabled gram-scale asymmetric syntheses of (-)-INCA, (-)-incarvilline, (-)-isoincarvilline, and six other INCA analogues. The synthesis of isoincarvilline was reported for the first time. Three structurally simplified analogues of INCA were also synthesized. In vivo screening found that INCA and two structurally optimized analogues were efficacious in preventing the acetic acid-induced writhing response. Moreover, their analgesic efficacy was demonstrated in formalin induced pain model. More importantly, administration of 20 or 40 mg/kg INCA and two structurally optimized analogues showed strong analgesic effects in spared nerve injury (SNI) model, and their effective doses were lower than the current gold standard, gabapentin (100 mg/kg in this model). PMID:27022999

  19. Lumbar neuropathic pain of lower limbs treated by spinal infusion of ziconotide a case – report

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    Luca Quadrino

    2008-01-01

    The Author reports the case of a patient with severe lumbar pain unresponsive to NSAIDs. Initial treatment with tramadol gave poor results and a new protocol with hydromorphone – pregabalin was started. The analgesic response was observed only following high hydromorphone doses, associated with unacceptable side effects. A spinal device for continuous intrathecal infusion was then implanted, in order to administer ziconotide, a new opioid drug. Associated therapy included hydromorphone – p...

  20. Motor Cortex Stimulation for the Treatment of Chronic Facial, Upper Extremity, and Throat Pain.

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    2016-02-22

    Trigeminal Neuralgia (Burchiel Type I); Trigeminal Neuralgia (Burchiel Type II); Trigeminal Neuropathic Pain; Trigeminal Deafferentation Pain; Complex Regional Pain Syndrome (Types I and II, Involving the Upper Extremity); Glossopharyngeal Neuralgia; Upper Extremity Pain Due to Deafferentation of the Cervical Spine; Central Pain Syndromes

  1. Novel Epigallocatechin-3-Gallate (EGCG) Derivative as a New Therapeutic Strategy for Reducing Neuropathic Pain after Chronic Constriction Nerve Injury in Mice

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    Xifró, Xavier; Vidal-Sancho, Laura; Boadas-Vaello, Pere; Turrado, Carlos; Alberch, Jordi; Puig, Teresa; Verdú, Enrique

    2015-01-01

    Neuropathic pain is common in peripheral nerve injury and often fails to respond to ordinary medication. Here, we investigated whether the two novel epigallocatechin-3-gallate (EGCG) polyphenolic derivatives, compound 23 and 30, reduce the neuropathic pain in mice chronic constriction nerve injury (CCI). First, we performed a dose-response study to evaluate nociceptive sensation after administration of EGCG and its derivatives 23 and 30, using the Hargreaves test at 7 and 21 days after injury (dpi). We daily administered EGCG, 23 and 30 (10 to 100 mg/Kg; i.p.) during the first week post-CCI. None of the doses of compound 23 caused significant pain diminution, whereas 50mg/kg was optimal for both EGCG and 30 to delay the latency of paw withdrawal. With 50 mg/Kg, we showed that EGCC prevented the thermal hyperalgesia from 7 to 21 dpi and compound 30 from 14 to 56 dpi. To evaluate the molecular mechanisms underpinning why EGCG and compound 30 differentially prevented the thermal hyperalgesia, we studied several biochemical parameters in the dorsal horn of the spinal cord at 14 and 56 dpi. We showed that the effect observed with EGCG and compound 30 was related to the inhibition of fatty acid synthase (FASN), a known target of these polyphenolic compounds. Additionally, we observed that EGCG and compound 30 reduced the expression of CCI-mediated inflammatory proteins and the nuclear localization of nuclear factor-kappa B at 14 dpi, but not at 56 dpi. We also strongly detected a decrease of synaptic plasma membrane levels of N-methyl-D-asparte receptor 2B in CCI-mice treated with compound 30 at 56 dpi. Altogether, compound 30 reduced the chronic thermal hyperalgesia induced by CCI better than the natural compound EGCG. Thus, our findings provide a rationale for the preclinical development of compound 30 as an agent to treat neuropathic pain. PMID:25855977

  2. A randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of ABT-594 in patients with diabetic peripheral neuropathic pain.

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    Rowbotham, Michael C; Duan, W Rachel; Thomas, James; Nothaft, Wolfram; Backonja, Misha-Miroslav

    2009-12-01

    ABT-594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double-blind, placebo-controlled study was to evaluate the safety and analgesic efficacy of ABT-594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT-594 150 microg BID, ABT-594 225 microg BID, or ABT-594 300 microg BID. Patients were titrated to a fixed-dose of ABT-594 over 7 days and remained at this dose for another 6 weeks. Compared to placebo, all three ABT-594 treatment groups showed significantly greater decreases on the average diary-based 0-10 Pain Rating Scale (PRS) score from baseline to final evaluation, the primary efficacy measure (placebo, -1.1; 150 microg BID, -1.9; 225 microg BID, -1.9; 300 microg BID, -2.0). The proportion of patients achieving at least a 50% improvement in the average diary-based PRS was greater in all three ABT-594 treatment groups. However, adverse event (AE) dropout rates were significantly higher in all three ABT-594 treatment groups (28% for 150 microg BID, 46% for 225 microg BID, and 66% for 300 microg BID) than for the placebo group (9%). Consistent with the expected side-effect profile of NNR agonists, the most frequently reported AEs were nausea, dizziness, vomiting, abnormal dreams, and asthenia. This study establishes proof of concept for NNR agonists as a new class of compounds for treating neuropathic pain. PMID:19632048

  3. Ketamine for chronic pain: risks and benefits

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    Niesters, Marieke; Martini, Christian; Dahan, Albert

    2014-01-01

    The anaesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N-methyl-D-aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti-inflammatory effects at central sites. Current data on short term infusions indicate that ketamine produces potent analgesia during ...

  4. Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases.

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    Shetty, Ashok K; Bates, Adrian

    2016-05-01

    Several neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gamma-amino butyric acid positive (GABA-ergic) inhibitory interneurons. Strategies that enhance inhibitory neurotransmission in the affected brain regions may therefore ease several or most deficits linked to these disorders. This perception has incited a huge interest in testing the efficacy of GABA-ergic interneuron cell grafting into regions of the brain or spinal cord exhibiting hyperexcitability, dearth of GABA-ergic interneurons or impaired inhibitory neurotransmission, using preclinical models of neurological and psychiatric disorders. Interneuron progenitors from the embryonic ventral telencephalon capable of differentiating into diverse subclasses of interneurons have particularly received much consideration because of their ability for dispersion, migration and integration with the host neural circuitry after grafting. The goal of this review is to discuss the premise, scope and advancement of GABA-ergic cell therapy for easing neurological deficits in preclinical models of schizophrenia, chronic neuropathic pain, Alzheimer׳s disease and Parkinson׳s disease. As grafting studies in these prototypes have so far utilized either primary cells from the embryonic medial and lateral ganglionic eminences or neural progenitor cells expanded from these eminences as donor material, the proficiency of these cell types is highlighted. Moreover, future studies that are essential prior to considering the possible clinical application of these cells for the above neurological conditions are proposed. Particularly, the need for grafting studies utilizing medial ganglionic eminence-like progenitors generated from human pluripotent stem cells via directed differentiation approaches or somatic cells through direct reprogramming methods are emphasized. This article is part of a Special Issue

  5. Pharmacodynamic analysis of the analgesic effect of capsaicin 8% patch (QutenzaTM in diabetic neuropathic pain patients: detection of distinct response groups

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    Martini C

    2012-03-01

    Full Text Available Christian Martini1,*, Ashraf Yassen2,*, Erik Olofsen1, Paul Passier2, Malcom Stoker3, Albert Dahan1 1Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands; 2Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Global Development Europe, Leiderdorp, The Netherlands; 3Global Medical Sciences, Astellas Pharma Global Development Europe, Leiderdorp, The Netherlands*These authors contributed equally to this workAbstract: Treatment of chronic pain is associated with high variability in the response to pharmacological interventions. A mathematical pharmacodynamic model was developed to quantify the magnitude and onset/offset times of effect of a single capsaicin 8% patch application in the treatment of painful diabetic peripheral neuropathy in 91 patients. In addition, a mixture model was applied to objectively match patterns in pain-associated behavior. The model identified four distinct subgroups that responded differently to treatment: 3.3% of patients (subgroup 1 showed worsening of pain; 31% (subgroup 2 showed no change; 32% (subgroup 3 showed a quick reduction in pain that reached a nadir in week 3, followed by a slow return towards baseline (16% ± 6% pain reduction in week 12; 34% (subgroup 4 showed a quick reduction in pain that persisted (70% ± 5% reduction in week 12. The estimate of the response-onset rate constant, obtained for subgroups 1, 3, and 4, was 0.76 ± 0.12 week-1 (median ± SE, indicating that every 0.91 weeks the pain score reduces or increases by 50% relative to the score of the previous week (= t½. The response-offset rate constant could be determined for subgroup 3 only and was 0.09 ± 0.04 week-1 (t½ 7.8 weeks. The analysis allowed separation of a heterogeneous neuropathic pain population into four homogenous subgroups with distinct behaviors in response to treatment with capsaicin. It is argued that this model-based approach may have added value in analyzing

  6. Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK activation correlates with the analgesic effects of ketamine in neuropathic pain

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    Wang Wen

    2011-01-01

    Full Text Available Abstract Background We have previously reported that inhibition of astrocytic activation contributes to the analgesic effects of intrathecal ketamine on spinal nerve ligation (SNL-induced neuropathic pain. However, the underlying mechanisms are still unclear. c-Jun N-terminal kinase (JNK, a member of mitogen-activated protein kinase (MAPK family, has been reported to be critical for spinal astrocytic activation and neuropathic pain development after SNL. Ketamine can decrease lipopolysaccharide (LPS-induced phosphorylated JNK (pJNK expression and could thus exert its anti-inflammatory effect. We hypothesized that inhibition of astrocytic JNK activation might be involved in the suppressive effect of ketamine on SNL-induced spinal astrocytic activation. Methods Immunofluorescence histochemical staining was used to detect SNL-induced spinal pJNK expression and localization. The effects of ketamine on SNL-induced mechanical allodynia were confirmed by behavioral testing. Immunofluorescence histochemistry and Western blot were used to quantify the SNL-induced spinal pJNK expression after ketamine administration. Results The present study showed that SNL induced ipsilateral pJNK up-regulation in astrocytes but not microglia or neurons within the spinal dorsal horn. Intrathecal ketamine relieved SNL-induced mechanical allodynia without interfering with motor performance. Additionally, intrathecal administration of ketamine attenuated SNL-induced spinal astrocytic JNK activation in a dose-dependent manner, but not JNK protein expression. Conclusions The present results suggest that inhibition of JNK activation may be involved in the suppressive effects of ketamine on SNL-induced spinal astrocyte activation. Therefore, inhibition of spinal JNK activation may be involved in the analgesic effects of ketamine on SNL-induced neuropathic pain.

  7. Behavioral evidence for the differential regulation of p-p38 MAPK and p-NF-κB in rats with trigeminal neuropathic pain

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    Lee Min K

    2011-08-01

    Full Text Available Abstract Background We investigated the differential regulation of p-p38 MAPK or p-NF-κB in male Sprague-Dawley rats with inferior alveolar nerve injury resulting from mal-positioned dental implants. For this purpose, we characterized the temporal expression of p-p38 MAPK or p-NF-κB in the medullary dorsal horn and examined changes in nociceptive behavior after a blockade of p-p38 MAPK or p-NF-κB pathways in rats with trigeminal neuropathic pain. Results Under anesthesia, the left lower second molar was extracted and replaced with a mini dental implant to intentionally injure the inferior alveolar nerve. Western and immunofluorescence analysis revealed that p-p38 MAPK is upregulated in microglia following nerve injury and that this expression peaked on postoperative day (POD 3 through 7. However, the activation of p-NF-κB in astrocyte peaked on POD 7 through 21. The intracisternal administration of SB203580 (1 or 10 μg, a p38 MAPK inhibitor, on POD 3 but not on POD 21 markedly inhibits mechanical allodynia and the p-p38 MAPK expression. However, the intracisternal administration of SN50 (0.2 or 2 ng, an NF-κB inhibitor, on POD 21 but not on POD 3 attenuates mechanical allodynia and p-NF-κB expression. Dexamethasone (25 mg/kg decreases not only the activation of p38 MAPK but also that of NF-κB on POD 7. Conclusions These results suggest that early expression of p-p38 MAPK in the microglia and late induction of p-NF-κB in astrocyte play an important role in trigeminal neuropathic pain and that a blockade of p-p38 MAPK at an early stage and p-NF-κB at a late stage might be a potential therapeutic strategy for treatment of trigeminal neuropathic pain.

  8. Curcumin ameliorates neuropathic pain by down-regulating spinal IL-1β via suppressing astroglial NALP1 inflammasome and JAK2-STAT3 signalling

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    Liu, Shenbin; Li, Qian; Zhang, Meng-Ting; Mao-Ying, Qi-Liang; Hu, Lang-Yue; Wu, Gen-Cheng; Mi, Wen-Li; Wang, Yan-Qing

    2016-01-01

    Curcumin has been shown to possess strong anti-inflammatory activity in many diseases. It has been demonstrated that the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) cascade and the NAcht leucine-rich-repeat protein 1 (NALP1) inflammasome are important for the synthesis of Pro-Interleukin (IL)-1β and the processing of the inactive protein to its mature form, which plays an active role in the pathogenesis of neuropathic pain. The present study showed that repeated intraperitoneal injection of curcumin ameliorated SNI-induced mechanical and cold allodynia in a dose-dependent manner and inhibited the elevation of spinal mature IL-1β protein levels. Additionally, repeated curcumin treatment significantly inhibited the aggregation of the NALP1 inflammasome and the activation of the JAK2-STAT3 cascade in spinal astrocytes. Furthermore, the genetic down-regulation of NALP1 inflammasome activation by NALP1 siRNA and the pharmacological inhibition of the JAK2-STAT3 cascade by AG490 markedly inhibited IL-1β maturation and Pro-IL-1β synthesis, respectively, and reduced SNI-induced pain hypersensitivity. Our results suggest that curcumin attenuated neuropathic pain and down-regulated the production of spinal mature IL-1β by inhibiting the aggregation of NALP1 inflammasome and the activation of the JAK2-STAT3 cascade in astrocytes. PMID:27381056

  9. Satellite glial cell P2Y12 receptor in the trigeminal ganglion is involved in lingual neuropathic pain mechanisms in rats

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    Katagiri Ayano

    2012-03-01

    Full Text Available Abstract Background It has been reported that the P2Y12 receptor (P2Y12R is involved in satellite glial cells (SGCs activation, indicating that P2Y12R expressed in SGCs may play functional roles in orofacial neuropathic pain mechanisms. However, the involvement of P2Y12R in orofacial neuropathic pain mechanisms is still unknown. We therefore studied the reflex to noxious mechanical or heat stimulation of the tongue, P2Y12R and glial fibrillary acidic protein (GFAP immunohistochemistries in the trigeminal ganglion (TG in a rat model of unilateral lingual nerve crush (LNC to evaluate role of P2Y12R in SGC in lingual neuropathic pain. Results The head-withdrawal reflex thresholds to mechanical and heat stimulation of the lateral tongue were significantly decreased in LNC-rats compared to sham-rats. These nocifensive effects were apparent on day 1 after LNC and lasted for 17 days. On days 3, 9, 15 and 21 after LNC, the mean relative number of TG neurons encircled with GFAP-immunoreactive (IR cells significantly increased in the ophthalmic, maxillary and mandibular branch regions of TG. On day 3 after LNC, P2Y12R expression occurred in GFAP-IR cells but not neuronal nuclei (NeuN-IR cells (i.e. neurons in TG. After 3 days of successive administration of the P2Y12R antagonist MRS2395 into TG in LNC-rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly decreased coincident with a significant reversal of the lowered head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue compared to vehicle-injected rats. Furthermore, after 3 days of successive administration of the P2YR agonist 2-MeSADP into the TG in naïve rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly increased and head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue were significantly decreased in a dose-dependent manner compared to vehicle-injected rats

  10. An LPA species (18:1 LPA) plays key roles in the self-amplification of spinal LPA production in the peripheral neuropathic pain model

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    Ma, Lin; Nagai, Jun; Chun, Jerold; Ueda, Hiroshi

    2013-01-01

    Background We previously reported that nerve injury-induced neuropathic pain is initiated by newly produced lysophosphatidic acid (LPA). Results In this study, we developed a quantitative mass spectrometry for detecting LPA species by using Phos-tag. Following nerve injury, the levels of 18:1, 16:0 and 18:0 LPA in the spinal dorsal horn significantly increased at 3 h and declined at 6 h. Among them, 18:1 LPA level was the most abundant. In the same preparation, there were significant elevatio...

  11. Behavioral evidence for the differential regulation of p-p38 MAPK and p-NF-κB in rats with trigeminal neuropathic pain

    OpenAIRE

    Lee Min K; Han Seung R; Park Min K; Kim Min J; Bae Yong C; Kim Sung K; Park Jae S; Ahn Dong K

    2011-01-01

    Abstract Background We investigated the differential regulation of p-p38 MAPK or p-NF-κB in male Sprague-Dawley rats with inferior alveolar nerve injury resulting from mal-positioned dental implants. For this purpose, we characterized the temporal expression of p-p38 MAPK or p-NF-κB in the medullary dorsal horn and examined changes in nociceptive behavior after a blockade of p-p38 MAPK or p-NF-κB pathways in rats with trigeminal neuropathic pain. Results Under anesthesia, the left lower secon...

  12. The up-regulation of IL-6 in DRG and spinal dorsal horn contributes to neuropathic pain following L5 ventral root transection.

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    Wei, Xu-Hong; Na, Xiao-Dong; Liao, Guang-Jie; Chen, Qiu-Ying; Cui, Yu; Chen, Feng-Ying; Li, Yong-Yong; Zang, Ying; Liu, Xian-Guo

    2013-03-01

    Our previous works have shown that pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) plays an important role in neuropathic pain produced by lumber 5 ventral root transection (L5-VRT). In the present work we evaluate the role of interleukin-6 (IL-6), another key inflammatory cytokine, in the L5-VRT model. We found that IL-6 was up-regulated in the ipsilateral L4 and L5 dorsal root ganglian (DRG) neurons and in bilateral lumbar spinal cord following L5-VRT. Double immunofluorescence stainings revealed that in DRGs the increased immunoreactivity (IR) of IL-6 was almost restricted in neuronal cells, while in the spinal dorsal horn IL-6-IR up-regulated in both glial cells (astrocyte and microglia) and neurons. Intrathecal administration of IL-6 neutralizing antibody significantly delayed the induction of mechanical allodynia in bilateral hindpaws after L5-VRT. Furthermore, inhibition of TNF-α synthesis by intraperitoneal thalidomide prevented both mechanical allodynia and the up-regulation of IL-6 in DRGs following L5-VRT. These data suggested that the increased IL-6 in afferent neurons and spinal cord contribute to the development of neuropathic pain following motor fiber injury, and that TNF-α is responsible for the up-regulation of IL-6. PMID:23261764

  13. Effect of TRPV4-p38 MAPK Pathway on Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion

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    Yu-Juan Qu

    2016-01-01

    Full Text Available The aim of this study was to investigate the relationships among TRPV4, p38, and neuropathic pain in a rat model of chronic compression of the dorsal root ganglion. Mechanical allodynia appeared after CCD surgery, enhanced via the intrathecal injection of 4α-phorbol 12,13-didecanoate (4α-PDD, an agonist of TRPV4 and anisomycin (an agonist of p38, but was suppressed by Ruthenium Red (RR, an inhibitor of TRPV4 and SB203580 (an inhibitor of p38. The protein expressions of p38 and P-p38 were upregulated by 4α-PDD and anisomycin injection but reduced by RR and SB203580. Moreover, TRPV4 was upregulated by 4α-PDD and SB203580 and downregulated by RR and anisomycin. In DRG tissues, the numbers of