Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0423716 (Neuropathic pain)
 1,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deafferentation pain syndromes developing after peripheral nerve lesions are difficult to treat. According to the follow-up (mean: 39.5 months) of 6 patients suffering from causalgic pain we will present our method of augmentative therapy in chronic neuropathic pain caused by peripheral nerve lesions, i.e., peripheral nerve stimulation (PNS), spinal cord stimulation (SCS) and chronic intrathecal opioid infusion. None of the patients showed intraoperative or follow-up complications. Evaluated by visual analogue scales all patients reported a good to excellent pain relief (75-100%). (1) Regarding the favourable long-term results of PNS, this method should be considered in cases of mononeuropathic pain syndromes. (2) Neuropathic pain syndromes which are not assignable to a singular nerve lesion, can often be managed effectively by SCS. (3) In contrast to the widespread opinion, deafferentation pain syndromes of central or peripheral origin can be treated satisfactorily by intrathecal opiate administration.
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PMID:Augmentative treatment of chronic deafferentation pain syndromes after peripheral nerve lesions. 1079 66

Mechanical allodynia- and hyperalgesia-like behavior which develops in rats after L5 spinal nerve lesion has been suggested to be due to ectopic activity in the lesioned afferent neurons originating at the lesion site and/or in the dorsal root ganglion because it is eliminated by section of the dorsal root. Here we reevaluated the effect of a dorsal rhizotomy in rats after L5 spinal nerve lesion. Using calibrated von Frey hairs, paw withdrawal threshold to single stimuli and paw withdrawal incidence to repetitive stimulation were tested before and after nerve section. Neuropathic pain behavior of similar time course and magnitude also developed after cutting the L5 dorsal root, and L5 spinal nerve lesion-induced abnormal behavior could not be reversed by dorsal rhizotomy. The neuropathic pain behavior elicited by dorsal root section also developed when impulse conduction in the dorsal root axons was blocked during rhizotomy by a local anesthetic, i.e. when the immediate injury discharge was prevented from reaching the spinal cord. These results challenge the widely accepted idea that neuropathic pain behavior developing after spinal nerve lesion is dependent on ectopic activity in the lesioned afferent neurons. However, the present results do not rule out the possibility that after the two nerve lesions the mechanisms generating neuropathic pain behavior are different. After dorsal rhizotomy neuropathic pain behavior may be related to deafferentation whereas after spinal nerve lesion it may be caused by ectopic activity.
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PMID:Dorsal root section elicits signs of neuropathic pain rather than reversing them in rats with L5 spinal nerve injury. 1092 14

Neuropathic pain results from traumatic or disease-related insults to the nervous system. Mechanisms that have been postulated to underlie peripheral neuropathy commonly implicate afferent neurons that have been damaged but still project centrally to the spinal cord, and/or intact neurons that interact with degenerating distal portions of the injured neurons. One pain state that is observed following peripheral nerve injury in the rat is thermal hyperalgesia. The noxious heat-gated ion channel TRPV1 may be responsible for this increased sensitivity, as it is up-regulated in L4 dorsal root ganglion (DRG) neurons following L5 spinal nerve lesion (SpNL). The TRPV1 homologue TRPV2 (or VRL-1) is another member of the TRPV subfamily of TRP ion channels. TRPV2 is a nonselective cation channel activated by high noxious temperatures (>52 degrees C) and is present in a subset of medium- to large-diameter DRG neurons. To establish whether TRPV2 is endogenous to the spinal cord, we examined its expression in the dorsal horn following rhizotomy. We found no significant decrease in TRPV2 immunoreactivity, suggesting that TRPV2 is endogenous to the spinal cord. In order to determine whether TRPV2, like TRPV1, is regulated by peripheral axotomy, we performed L5 SpNL and characterized TRPV2 distribution in the DRG, spinal cord, brainstem, and sympathetic ganglia. Our results show that peripheral axotomy did not regulate TRPV2 in the DRG, spinal cord, or brainstem; however, TRPV2 was up-regulated in sympathetic postganglionic neurons following injury, suggesting a potential role for TRPV2 in sympathetically mediated neuropathic pain.
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PMID:Regulation of TRPV2 by axotomy in sympathetic, but not sensory neurons. 1526 Nov 11

Microglia play an important role as immune cells in the central nervous system (CNS). Microglia are activated in threatened physiological homeostasis, including CNS trauma, apoptosis, ischemia, inflammation, and infection. Activated microglia show a stereotypic, progressive series of changes in morphology, gene expression, function, and number and produce and release various chemical mediators, including proinflammatory cytokines that can produce immunological actions and can also act on neurons to alter their function. Recently, a great deal of attention is focusing on the relation between activated microglia through adenosine 5'-triphosphate (ATP) receptors and neuropathic pain. Neuropathic pain is often a consequence of nerve injury through surgery, bone compression, diabetes, or infection. This type of pain can be so severe that even light touching can be intensely painful and it is generally resistant to currently available treatments. There is abundant evidence that extracellular ATP and microglia have an important role in neuropathic pain. The expression of P2X4 receptor, a subtype of ATP receptors, is enhanced in spinal microglia after peripheral nerve injury model, and blocking pharmacologically and suppressing molecularly P2X4 receptors produce a reduction of the neuropathic pain. Several cytokines such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in the dorsal horn are increased after nerve lesion and have been implicated in contributing to nerve-injury pain, presumably by altering synaptic transmission in the CNS, including the spinal cord. Nerve injury also leads to persistent activation of p38 mitogen-activated protein kinase (MAPK) in microglia. An inhibitor of this enzyme reverses mechanical allodynia following spinal nerve ligation (SNL). ATP is able to activate MAPK, leading to the release of bioactive substances, including cytokines, from microglia. Thus, diffusible factors released from activated microglia by the stimulation of purinergic receptors may have an important role in the development of neuropathic pain. Understanding the key roles of ATP receptors, including P2X4 receptors, in the microglia may lead to new strategies for the management of neuropathic pain.
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PMID:The function of microglia through purinergic receptors: neuropathic pain and cytokine release. 1616 95

Microglia, activated when physiological homeostasis is threatened, play an important role as immune cells in the CNS. Activated microglia show a progressive series of changes in morphology, gene expression, function and number, and produce and release various chemical mediators, including proinflammatory cytokines that can produce immunological actions and modify neuronal function. Recently, accumulating evidence has indicated an important role for ATP receptors of activated microglia in neuropathic pain. Neuropathic pain is often a consequence of nerve injury through surgery, bone compression, cancer, diabetes or infection. The expression of the P2X4 receptor, a subtype of ATP receptors, is enhanced in spinal microglia in a peripheral nerve injury model, and blocking pharmacologically and suppressing molecularly P2X4 receptors produces a reduction of the neuropathic pain. Several cytokines such as interleukin 6 (IL6) and tumour necrosis factor alpha (TNFalpha) in the dorsal horn are also increased after nerve lesion and have been implicated in contributing to nerve-injury pain. ATP can activate mitogen-activated protein kinase (MAPK) leading to the release of bioactive substances including cytokines from microglia. Thus, diffusible factors released from activated microglia by the stimulation of purinergic receptors may have an important role in the development of neuropathic pain.
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PMID:ATP receptors of microglia involved in pain. 1680 36

Neuropathic pain syndromes-pain after a lesion or disease of the peripheral or central nervous system-are clinically characterized by spontaneous and evoked types of pain, which are underpinned by various distinct pathophysiological mechanisms in the peripheral and central nervous systems. In some patients, the nerve lesion triggers molecular changes in nociceptive neurons, which become abnormally sensitive and develop pathological spontaneous activity. Inflammatory reactions of the damaged nerve trunk can induce ectopic nociceptor activity, causing spontaneous pain. The hyperactivity in nociceptors induces secondary changes in processing neurons in the spinal cord and brain, so that input from mechanoreceptive A-fibers is perceived as pain. Neuroplastic changes in the central pain modulatory systems can lead to further hyperexcitability. The treatment of neuropathic pain is still unsatisfactory, and a new hypothetical concept has been proposed, in which pain is analyzed on the basis of underlying mechanisms. The increased knowledge of pain-generating mechanisms and their translation into symptoms and signs might eventually allow a dissection of the mechanisms that operate in each patient. If a precise clinical phenotypic characterization of the neuropathic pain is combined with a selection of drugs that act on those mechanisms, it should ultimately be possible to design optimal treatments for individuals. This review discusses the conceptual framework of the novel mechanism-based classification, encouraging the reader to see neuropathic pain as a clinical entity rather than a compilation of single disease states.
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PMID:Mechanisms of disease: neuropathic pain--a clinical perspective. 1693 31

Neuropathic pain can be caused by a variety of nerve lesions and it is unsettled whether it should be categorised into distinct clinical subtypes depending on aetiology or type of nerve lesion or individualised as a specific group, based on common symptomatology across aetiologies. In this study, we used a multivariate statistical method (multiple correspondence analyses) to investigate associations between neuropathic positive symptoms (assessed with a specific questionnaire, the Neuropathic Pain Symptom Inventory [NPSI]) and aetiologies, types of nerve lesion and pain localisations. We also examined the internal structure of the NPSI and its relevance to evaluation of symptoms of evoked pains by exploring their relationships with clinician-based quantified measures of allodynia and hyperalgesia. This study included 482 consecutive patients (53% men; mean age: 58+/-15 years) with pain associated with peripheral or central lesions. Factor analysis showed that neuropathic symptoms of the NPSI can be categorised into five dimensions. Spearman correlation coefficients indicated that self-reported pain evoked by brush, pressure and cold stimuli strongly correlated to allodynia/hyperalgesia to brush, von Frey hairs and cold stimuli (p<0.0001, n=90). Multiple correspondence analyses indicated few associations between symptoms (or dimensions) and aetiologies, types of lesions, or pain localisations. Exceptions included idiopathic trigeminal neuralgia and postherpetic neuralgia. We found that there are more similarities than differences in the neuropathic positive symptoms associated with a large variety of peripheral and central lesions, providing rationale for subgrouping aetiologically diverse neuropathic patients into a specific multidimensional category for therapeutic management.
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PMID:Neuropathic pain: are there distinct subtypes depending on the aetiology or anatomical lesion? 1828 91

Neuropathic pain that typically develops when peripheral nerves are damaged through surgery, bone compression in cancer, diabetes, or infection is a major factor causing impaired quality of life in millions of people worldwide. Recently, there has been a rapidly growing body of evidence indicating that spinal glia play a critical role in the pathogenesis of neuropathic pain. Accumulating findings also indicate that nucleotides play an important role in neuron-glia communication through P2 purinoceptors. Damaged neurons release or leak nucleotides including ATP and UTP to stimulate microglia through P2 purinoceptors expressing on microglia. It was shown in an animal model of neuropathic pain that microglial P2X(4) and P2X(7) receptors are crucial in pain signaling after peripheral nerve lesion. In this review, we describe the modification of neuropathic pain sensation through microglial P2X(4) and P2X(7), with the possibility of P2Y(6) and P2Y(12) involvement.
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PMID:Modification of neuropathic pain sensation through microglial ATP receptors. 1840 44

Neuropathic pain syndromes, i.e., pain after a lesion or disease of the peripheral or central nervous system, are clinically characterized by spontaneous pain (ongoing, paroxysms) and evoked types of pain (hyperalgesia, allodynia). A variety of distinct pathophysiological mechanisms in the peripheral and central nervous system operate in concert: In some patients the nerve lesion triggers molecular changes in nociceptive neurons that become abnormally sensitive and develop pathological spontaneous activity (upregulation of sodium channels and receptors, e.g., vanilloid TRPV1 receptors, menthol-sensitive TRPM8 receptors, or alpha-receptors). These phenomena may lead to spontaneous pain, shooting pain sensations, as well as heat hyperalgesia, cold hyperalgesia, and sympathetically maintained pain. Spontaneous activity in damaged large nonnociceptive A-fibers may lead to paresthesias. All these changes may also occur in uninjured neurons driven by substances released by adjacent dying cells and should receive more attention in the future. The hyperactivity in nociceptors in turn induces secondary changes (hyperexcitability) in processing neurons in the spinal cord and brain. This central sensitization causes input from mechanoreceptive A-fibers to be perceived as pain (mechanical allodynia). Neuroplastic changes in the central descending pain modulatory systems (inhibitory or facilitatory) may lead to further hyperexcitability. Neuropathic pain represents a major neurological problem and treatment of patients with such pain has been largely neglected by neurologists in the past. The medical management of neuropathic pain consists of five main classes of oral medication (antidepressants with reuptake blocking effect, anticonvulsants with sodium-blocking action, anticonvulsants with calcium-modulating actions, tramadol, and opioids) and several categories of topical medications for patients with cutaneous allodynia and hyperalgesia (capsaicin and local anesthetics). In many cases an early combination of compounds effecting different mechanisms is useful. At present existing trials only provide general pain relief values for specific causes, which in part may explain the failure to obtain complete pain relief in neuropathic pain conditions. In general, the treatment of neuropathic pain is still unsatisfactorily. Therefore, a new hypothetical concept was proposed in which pain is analyzed on the basis of underlying mechanisms. The increased knowledge of pain-generating mechanisms and their translation into symptoms and signs may in the future allow a dissection of the mechanisms that operate in each patient. If a systematic clinical examination of the neuropathic pain patient and a precise phenotypic characterization is combined with a selection of drugs acting against those particular mechanisms, it should ultimately be possible to design optimal treatments for the individual patient.
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PMID:Neuropathic pain: a clinical perspective. 1965 3

Neuropathic pain after peripheral nerve injury, associated with local neuroinflammation in the spinal cord, is a severe incapacitating condition with which clinical treatment remains challenging. Inflammatory molecules signal through various intracellular transduction pathways, activation of which may amplify and cause spreading of the inflammatory response. We showed recently that spinal nerve lesion leads to rapid activation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signal transduction pathway in dorsal spinal cord microglia in relation with enhanced levels of spinal interleukin-6 (IL-6) protein. Here, we selectively inactivated JAK/STAT3 signaling in rat dorsal spinal cord glia through local, lentiviral-mediated production of the suppressor of cytokine signaling SOCS3, a physiologic inhibitory protein of JAK/STAT3, and analyzed its consequences in a preclinical model of neuropathic pain. The targeted blockade of JAK/STAT3 activity prevented the abnormal expression of IL-6, CC chemokine ligand CCL2, and activating transcription factor ATF3 induced in the spinal cord by chronic constriction injury of the sciatic nerve (CCI) and substantially attenuated mechanical hypersensitivity (allodynia) in rats. In naive rats, intrathecal administration of a proalgesic cytokine IL-6 rapidly activated microglial JAK/STAT3 and induced downstream changes closely resembling CCI-evoked alterations. We identified downstream mechanisms through which JAK/STAT3 pathway activation leads to the spreading of neuroinflammation. Our findings reveal that JAK/STAT3 signaling plays a major role in spinal cord plasticity and mechanical allodynia associated with peripheral nerve injury.
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PMID:SOCS3-mediated blockade of JAK/STAT3 signaling pathway reveals its major contribution to spinal cord neuroinflammation and mechanical allodynia after peripheral nerve injury. 2041 Jan 27


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