UMLS:C0423716 - FACTA Search

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Query: UMLS:C0423716 (Neuropathic pain)
1,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This series of studies has investigated the involvement of the NMDA receptor and the translocation of PKC in the seemingly unrelated phenomena of neuropathic pain and tolerance and dependence to narcotic analgesic drugs. This work has demonstrated that the NMDA receptor and PKC translocation are importantly involved in neuropathic pain and morphine tolerance or dependence and that these phenomena may be importantly interrelated. Neuropathic pain following nerve injury is a major chronic pain syndrome. Utilizing a rat model of painful peripheral mononeuropathy produced by CCI of the sciatic nerve, the authors have investigated central mechanisms of postinjury neuropathic pain. Behavioral and pharmacological studies indicate that thermal hyperalgesia and spontaneous pain behaviors observed in this model are attenuated by treatment with NMDA receptor antagonists. A consequence of NMDA receptor activation is calcium influx, which in turn can result in translocation of PKC from cytosol to membrane. Inhibitors of intracellular PKC translocation and activation block thermal hyperalgesia and spontaneous pain behaviors after CCI and also reduce the elevated spinal cord neural activity in CCI rats. Furthermore, spinal cord levels of membrane-bound PKC reliably increase in CCI rats as a result of translocation of PKC revealed by the [3H]PDBu autoradiographic assay. This increase in membrane-bound PKC is associated with postinjury neuropathic pain behaviors in CCI rats and both pain-related behaviors and membrane-bound PKC are reduced potently by GM1 ganglioside.
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PMID:The association of neuropathic pain, morphine tolerance and dependence, and the translocation of protein kinase C. 874 91

Neuropathic pain following nerve injury is believed to involve excitatory amino acids (EAAs) and Ca2+-mediated neuronal plastic changes in the central nervous system (CNS). This study was designed to investigate the changes in glutamate and aspartate contents in the dorsal half of the spinal cord following chronic constrictive injury (CCI) of the rat common sciatic nerve. We also examined the changes in intracellular calcium ion concentration ([Ca2+]i) of the spinal dorsal horn in transverse spinal slices in the same animal model. Thermal and mechanical hyperalgesia were observed on day 2 and thereafter following CCI (P < 0.0001). In the CCI rats to which 0.5 mg/kg of i.p. MK-801 was given 30 min prior to CCI and subsequently three daily treatments with 0.5 mg/kg of i.p. MK-801, the development of thermal and mechanical hyperalgesia was suppressed for a period of up to 7 days; however, hyperalgesia appeared on day 10 and day 14 (P < 0.001). In CCI rats, significant increases were observed in glutamate and aspartate contents on the ipsilateral side of the dorsal horn to nerve ligation on days 4, 7 and 14 (P < 0.001). Moreover, significant increases in [Ca2+]i in the spinal dorsal horn were also observed in the superficial (lamina I-II) and deep layers (lamina V-VI) on the ipsilateral side to nerve ligation on days 4, 7 and 14 after nerve ligation in the spinal slices (P < 0.0001). The treatment with i.p. MK-801 suppressed the increases in the contents of glutamate and aspartate and in [Ca2+]i on days 4 and 7. However, the ipsilateral contents of glutamate and aspartate significantly increased on day 14 (P < 0.001 and 0.003, respectively); the increased [Ca2+]i was also observed on day 14 (P < 0.001), and the spatial pattern of the increased regions was similar to untreated CCI rats. We interpret these results to indicate that neuropathic hyperalgesia induced by CCI in the rat is associated with an increase in glutamate and aspartate contents and the subsequent activation of NMDA receptors, followed by an increase in [Ca2+]i within dorsal horn of the spinal cord.
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PMID:Involvement of increased excitatory amino acids and intracellular Ca2+ concentration in the spinal dorsal horn in an animal model of neuropathic pain. 925 3

Neuropathic pain, due to peripheral nerve damage, can include allodynia (perception of innocuous stimuli as being painful), hyperalgesia (increased sensitivity to noxious stimuli) and spontaneous pain, often accompanied by sensory deficits. Plasticity in transmission and modulatory systems are implicated in the underlying mechanisms. The Kim and Chung rodent model of neuropathy (Kim and Chung, Pain 50 (1992) 355) employed here involves unilateral tight ligation of two (L5 and L6) of the three (L4, L5, and L6) spinal nerves of the sciatic nerve and reproducibly induced mechanical and cold allodynia in the ipsilateral hindpaw over the 14 day post-operative period. In vivo electrophysiological techniques have then been used to record the response of dorsal horn neurones to innocuous and noxious electrical and natural (mechanical and thermal) stimuli after spinal nerve ligation (SNL). Activation of voltage-dependent calcium channels (VDCCs) is critical for neurotransmitter release and neuronal excitability, and antagonists can be antinociceptive. Here, for the first time, the effect of N- and P-type VDCC antagonists (omega-conotoxin-GVIA and omega-agatoxin-IVA, respectively) on the evoked dorsal horn neuronal responses after neuropathy have been investigated. Spinal omega-conotoxin-GVIA (0.1-3.2 microg) produced prolonged inhibitions of both the electrically- and low- and high-intensity naturally-evoked neuronal responses in SNL and control rats. Spinal omega-agatoxin-IVA (0.1-3.2 microg) also had an inhibitory effect but to a lesser extent. After neuropathy the potency of omega-conotoxin-GVIA was increased at lower doses in comparison to control. This indicates an altered role for N-type but not P-type VDCCs in sensory transmission after neuropathy and selective plasticity in these channels after nerve injury. Both pre- and post-synaptic VDCCs appear to be important.
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PMID:Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy. 1132 45

Neuropathic pain is associated with changes in the electrophysiological and neurochemical properties of injured primary afferent neurons. A mRNA differential display study in rat L(4/5) dorsal root ganglia (DRGs) revealed upregulation of the calcium channel alpha2delta-1 subunit 2 weeks after partial sciatic nerve ligation (Seltzer model of neuropathic pain). The upregulated transcript appeared to represent previously unidentified sequence from the 3'-untranslated region of rat alpha2delta-1 mRNA. In situ hybridization using L(5) DRGs from sham operated rats showed that 73, 40 and 19% of small (<700 microm(2)), medium (700-1100 microm(2)) and large (>1100 microm(2)) neuronal profiles, respectively, expressed alpha2delta-1 mRNA. Two weeks following nerve injury there was a significant ipsilateral increase, both in the percentage of DRG neurons expressing alpha2delta-1 mRNA and in the intensity of the hybridization signal. Comparison of this ipsilateral expression with that in sham animals, revealed that for small, medium and large neurons, respectively, the proportion of neurons labelled increased by 1.2-, 1.8- and 2.7-fold, while the hybridization signal in alpha2delta-1-labelled neurons increased by 2.8-, 2.5- and 3.7-fold. The most intensely labelled neuronal profiles in ipsilateral, sham and contralateral DRGs, were generally those with small cross-sectional areas. The alpha2delta-1 auxiliary subunit is known to modulate calcium channel function in heterologous expression systems via its association with the pore-forming alpha1 calcium channel subunit. Therefore the increased levels of this subunit in the populations of primary afferents described may, via modulation of calcium-dependent processes such as neurotransmitter release and neuronal excitability, influence the processing of sensory information.
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PMID:Dorsal root ganglion neurons show increased expression of the calcium channel alpha2delta-1 subunit following partial sciatic nerve injury. 1168 71

Neuropathic pain, whether of peripheral or central origin, is characterized by a neuronal hyperexcitability in damaged areas of the nervous system. In peripheral neuropathic pain, damaged nerve endings exhibit abnormal spontaneous and increased evoked activity, partly due to an increased and novel expression of sodium channels. In central pain, although not explored in detail, the spontaneous pain and evoked allodynia are also best explained by a neuronal hyperexcitability. The peripheral hyperexcitability is due to a series of molecular changes at the level of the peripheral nociceptor, in dorsal root ganglia, in the dorsal horn of the spinal cord, and in the brain. These changes include abnormal expression of sodium channels, increased activity at glutamate receptor sites, changes in gamma-aminobutyric acid (GABA-ergic) inhibition, and an alteration of calcium influx into cells. The neuronal hyperexcitability and corresponding molecular changes in neuropathic pain have many features in common with the cellular changes in certain forms of epilepsy. This has led to the use of anticonvulsant drugs for the treatment of neuropathic pain. Carbamazepine and phenytoin were the first anticonvulsants to be used in controlled clinical trials. Studies have shown these agents to relieve painful diabetic neuropathy and paroxysmal attacks in trigeminal neuralgia. Subsequent studies have shown the anticonvulsant gabapentin to be effective in painful diabetic neuropathy, mixed neuropathies, and postherpetic neuralgia. Lamotrigine, a new anticonvulsant, is effective in trigeminal neuralgia, painful peripheral neuropathy, and post-stroke pain. Other anticonvulsants, both new and old, are currently undergoing controlled clinical testing. The most common adverse effects of anticonvulsants are sedation and cerebellar symptoms (nystagmus, tremor and incoordination). Less common side-effects include haematological changes and cardiac arrhythmia with phenytoin and carbamazepine. The introduction of a mechanism-based classification of neuropathic pain, together with new anticonvulsants with a more specific pharmacological action, may lead to more rational treatment for the individual patient with neuropathic pain.
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PMID:Anticonvulsants in neuropathic pain: rationale and clinical evidence. 1188 43

Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral pain signaling pathway, has become an area of intense research activity--largely because it represents a disorder with high unmet medical need. It is not a single disease entity, but rather includes a range of heterogeneous conditions that differ in etiology, location and initiating cause. Despite this diversity, the clinical presentation is frequently surprisingly similar, which suggests a common biological basis. Until recently, little was known of the mechanisms underlying the various neuropathic pain conditions, making the directed development of novel therapies almost impossible. However, the steady increase in our understanding of the anatomical, cellular and molecular basis of neuropathic pain, coupled with the advent of a number of experimental models of neuropathy, has permitted relatively rapid progress, and the prospects for the emergence of new, more effective therapies look very good. Gabapentin (Pfizer), which appears to act by blocking calcium channels, is the first drug to acquire widespread regulatory approval for the treatment of neuropathic pain. The Society for Medicines Research symposium held June 26, 2003, considered this treatment modality alongside other approaches to therapy, such as N-methyl-D-aspartate receptor antagonists and cannabinoid receptor agonists. The whole meeting provided an excellent description of the challenges facing neuropathic pain drug discovery--at both the research and the development phases of the value chain.
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PMID:Pharmacotherapy for neuropathic pain: progress and prospects. 1470 44

Neuropathic pain is caused by functional abnormalities of structural lesions in the peripheral or central nervous system, and occurs without peripheral nociceptor stimulation. Many common diseases, such as postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, spinal cord injury, cancer, stroke, and degenerative neurological diseases may produce neuropathic pain. Recently, theories have been proposed that state there are specific cellular and molecular changes that affect membrane excitability and induce new gene expression after nerve injury, thereby allowing for enhanced responses to future stimulation. In addition, the ectopic impulses of neuroma, changes of sodium and calcium channels in injured nerves, sympathetic activation, and deficient central inhibitory pathway contribute to the mechanisms of neuropathic pain. Currently, treatment of neuropathic pain is still a challenge. Pharmacotherapies (antidepressants, antiepileptics) remain the basis of Dr. Long-Sun Ro neuropathic pain management. However, patient satisfaction in the results of the treatment of neuropathic pain is still disappointing. Since it has been established that intense noxious stimulation produces a sensitization of central nervous neurons, it may be possible to direct treatments not only at the site of peripheral nerve injury, but also at the target of central changes. In order to provide better pain control, the mechanism-based approach in treating neuropathic pain should be familiar to physicians. In the future, it is hoped that a combination of new pharmacotherapeutic developments, careful clinical trials, and an increased understanding of the contribution and mechanisms of neuroplasticity will lead to an improvement in the results of clinical treatments and prevention of neuropathic pain.
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PMID:Neuropathic pain: mechanisms and treatments. 1632 50

There are various types of pain: acute, inflammatory, and neuropathic. The latter starts with a nerve injury, which could be secondary to an inflammatory reaction. Neuropathic pain often remains even after the original injury has healed and sometimes becomes chronic. It has recently been proposed that activated astrocytes and microglial cells could be the generators maintaining neuropathic pain. As astrocytes exhibit gap junction coupled networks, glia may be involved in spreading of pain sensations in form of Ca2+ oscillations or waves. Astrocytic Ca2+ oscillations induce ATP release which in turn stimulates both microglial cells and those monocytes that have crossed the blood-brain barrier, and also stimulates distant astrocyte networks and microglial cells. These activated cells release pro-inflammatory cytokines. One theory is that the Ca2+ oscillations by their induction and release of growth factors, give rise to new synapses, thereby establishing new neuronal contacts for maintaining and spreading pain sensation.
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PMID:[Can chronic pain and spreading of pain be induced via glial mechanisms? New hypotheses on the generators maintaining protracted pain conditions]. 1640 93

Neuropathic pain might best be considered as a collection of various pain states with a common feature, that being symptoms suggestive of dysfunction of peripheral nerves. The development of therapeutic options for the treatment of neuropathic pain is complicated significantly by several factors. Neuropathic pain may arise from widely diverse etiologies such as physical trauma, disease, infection, or chemotherapy. Symptoms indicative of neuropathic pain may also arise in individuals with no evidence of any type of nerve trauma (idiopathic). Although neuropathic pain is a substantial health care issue, it is relatively uncommon and only occurs in a small fraction (<10%) of individuals with these initiating factors. Moreover, the efficacy of treatment protocols, even against the same type of symptoms, differ depending on the underlying initiating cause of the neuropathy. Although these observations strongly suggest that there are predisposing factors that may impart susceptibility to the development of neuropathic pain, no common predisposing factors or genetic markers have been satisfactorily identified. Because of these vagaries, treatment of neuropathic pain has been based on trial and error. However, recent progress in the understanding of neurophysiologic changes that accompany peripheral nerve dysfunction indicate that regulation of ion channels that maintain membrane potentials or generate action potentials may provide an important therapeutic approach. Neuropathic pain is accompanied by increased activity of peripheral nociceptors, which is produced in part by changes in levels of specific calcium and sodium channels. The identification of sodium and/or calcium channels subtypes that are expressed almost exclusively on nociceptors may provide a way of regulating the activity of exaggerated nociceptor function without altering other sensory modalities. Thus, the selective targeting of ion channels may represent a viable therapeutic target for the management of the neuropathic pain state, regardless of etiology.
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PMID:Challenges in the development of novel treatment strategies for neuropathic pain. 1648 72

Neuropathic pain is a condition affecting a significant proportion of the world's population. Many therapeutic drugs have been used. They achieve less than satisfactory results and are associated to common side effects that affect the daily life of patients. Pregabalin is a new drug that has been shown to be effective for treating partial epilepsy and peripheral neuropathic pain in clinical trials. It is a structural, but not functional, analogue of GABA. It acts as a ligand of the alpha2-delta subunit, a protein associated to the voltage-dependent calcium channels. Modulation of these channels decreases calcium entry into nerve endings, resulting in a decreased release of several excitatory neurotransmitters. Pregabalin had a linear pharmacokinetics with little variability between the different subjects. It does not bind to plasma proteins, has no liver metabolism, and is excreted trough the kidneys. Few interactions with other drugs may be expected based on these characteristics. In clinical trials, pregabalin has been shown to be effective in postherpetic neuralgia and painful diabetic neuropathy at doses ranging from 150-600 mg/day. The analgesic effects of pregabalin occur in the first few days of treatment and are sustained over time. Side effects are few; most are transient and well-tolerated by patients, and the treatment discontinuation rate is minimal.
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PMID:[Pregabalin. A new treatment for neuropathic pain]. 1652 16

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