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

Neuropathic pain may be produced, at least in part, by the increased activity of primary afferent neurons. Studies have suggested that an accumulation of voltage-gated sodium channels at the site of peripheral nerve injury is a primary precursory event for subsequent afferent hyperexcitability. In this study, a human sodium channel (hPN3, SCN10A) has been cloned from the lumbar 4/5 dorsal root ganglia (DRG). Expression of hPN3 in Xenopus oocytes showed that this clone is a functional voltage-gated sodium channel. The amino acid sequence of hPN3 is most closely related to the rat PN3/SNS sodium channels which are expressed primarily in the small neurons of rat DRGs. The homologous relationship between rPN3 and hPN3 is defined by (i) a high level of sequence identity (ii) sodium currents that are highly resistant to tetrodotoxin (TTX) (iii) similar tissue distribution profiles and (iv) orthologous chromosomal map positions. Since rPN3/SNS has been implicated in nociceptive transmission, hPN3 may prove to be a valuable target for therapeutic agents against neuropathic pain.
 ...
PMID:A tetrodotoxin-resistant voltage-gated sodium channel from human dorsal root ganglia, hPN3/SCN10A. 983 20

Neuropathic pain arises as a debilitating consequence of nerve injury. The etiology of such pain is poorly understood, and existing treatment is largely ineffective. We demonstrate here that glial cell line-derived neurotrophic factor (GDNF) both prevented and reversed sensory abnormalities that developed in neuropathic pain models, without affecting pain-related behavior in normal animals. GDNF reduces ectopic discharges within sensory neurons after nerve injury. This may arise as a consequence of the reversal by GDNF of the injury-induced plasticity of several sodium channel subunits. Together these findings provide a rational basis for the use of GDNF as a therapeutic treatment for neuropathic pain states.
 ...
PMID:Potent analgesic effects of GDNF in neuropathic pain states. 1102 95

Neuropathic pain is a debilitating consequence of nerve damage. Existing treatment is largely ineffective. Current models of neuropathic pain recognise the importance of ectopic activity in primary sensory neurones impinging on a sensitised central nervous system. Neurotrophic factors have been shown to be neuroprotective for damaged sensory neurones, providing a rationale for testing their effects in neuropathic pain states. Recent data have demonstrated potent analgesic effects of one factor (glial cell line-derived neurotrophic factor) in animal models of neuropathy, and implicated changes in sodium channel alpha-subunits in the generation of afferent ectopic activity. The new findings provide a rational basis for the use of neurotrophic factors as a novel therapeutic treatment for neuropathic pain states.
 ...
PMID:Neurotrophic factors and neuropathic pain. 1171 38

Neuropathic pain is a debilitating chronic syndrome that often arises from injuries to peripheral nerves. Such pain has been hypothesized to be the result of an aberrant expression and function of sodium channels at the site of injury. Here, we show that intrathecal administration of specific antisense oligodeoxynucleotides (ODN) to the peripheral tetrodotoxin (TTX)-resistant sodium channel, NaV1.8, resulted in a time-dependent uptake of the ODN by dorsal root ganglion (DRG) neurons, a selective "knock-down" of the expression of NaV1.8, and a reduction in the slow-inactivating, TTX-resistant sodium current in the DRG cells. The ODN treatment also reversed neuropathic pain induced by spinal nerve injury, without affecting non-noxious sensation or response to acute pain. These data provide direct evidence linking NaV1.8 to neuropathic pain. As NaV1.8 expression is restricted to sensory neurons, this channel offers a highly specific and effective molecular target for the treatment of neuropathic pain.
 ...
PMID:Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. 1179 Apr 77

A spinal cord injury (SCI) was produced in adult rats by complete spinal cord transection at L6-S1. Neuropathic pain behaviors similar to the chronic central pain (CCP) syndrome in human, such as thermal hyperalgesia, mechanical allodynia and autotomy, were present in these rats after spinal cord injury. Meanwhile, wide dynamic range (WDR) neurons recorded in the spinal dorsal horn rostral to the lesion responded as high frequency of spontaneous activities, long duration of after-discharges to noxious electrical stimuli and an augmented wind-up to 0.5 Hz stimuli. By using bupivacaine powder, a sodium channel blocker, at the locus of transection immediate after nerve injury, the chronic pain behaviors were prevented; the hyperexcitability of WDR neurons was also substantially reduced. It is suggested that spinal cord transection induces the CCP syndromes, which may be evoked and maintained by the hyperexcitability in WDR neurons rostrally. Reducing the neuronal activity at the site of lesion following injury may prevent the development of CCP after SCI.
 ...
PMID:Spinal cord injury triggers sensitization of wide dynamic range dorsal horn neurons in segments rostral to the injury. 1608 64

Neuropathic pain has been hypothesized to be the result of aberrant expression and function of sodium channels at the site of injury. To investigate the effects of NaV1. 8 antisense oligonucleotide on the expression of sodium channel mRNA in dorsal root ganglion (DRG) neurons in chronic neuropathic pain. 24 Sprague-Dawley rats weighing 200-260 g were anesthetized with the intraperitoneal injection of 300 mg x kg(-1) choral hydrate. The CCI model was made by loose ligation of sciatic nerve trunk by 4-0 chromic gut. The mechanical and thermal pain threshold were measured before operation and 1, 3, 5, 7, 9, 11, 13 days after operation. A PE-10 catheter was implanted in subarachnoid space at lumbar region. On the 7th postoperative day the animals were randomly divided into 4 groups. The drugs were injected intrathecally twice a day for 5 consecutive days in group 2-4. The animals were decapitated 14 days after the surgery. The L4-L6 DRG of the operated side was removed and crushed, and total RNA was extracted with Trizol reagent. The contralateral side was used as control. The change of NaV1. 8 sodium channel transcripts was determined by RT-PCR. Pain threshold was significantly lowered after CCI as compared with that in control group and was elevated 3 days after antisense oligonucleotide injection. Sensory neuron specific TTX-R sodium channel NaV1. 8 transcript was down-regulated after antisense oligonucleotide injection at the dosage of 45 microg as compared with that in CCI group (P < 0.01), and it was even greater at the dosage of 90 microg. The intrathecally injected NaV1. 8 antisense oligonucleotide can reduce the mechanical allodynia and thermal hyperalgesia partially by downregulating the SNS transcript expression.
 ...
PMID:Effects of intrathecally administerd NaV1. 8 antisense oligonucleotide on the expression of sodium channel mRNA in dorsal root ganglion. 1669 29

Neuropathic pain remains a large unmet medical need. A number of therapeutic options exist, but efficacy and tolerability are less than satisfactory. Based on animal models and limited data from human patients, the pain and hypersensitivity that characterize neuropathic pain are associated with spontaneous discharges of normally quiescent nociceptors. Sodium channel blockers inhibit this spontaneous activity, reverse nerve injury-induced pain behavior in animals and alleviate neuropathic pain in humans. Several sodium channel subtypes are expressed primarily in sensory neurons and may contribute to the efficacy of sodium channel blockers. In this report, the authors review the current understanding of the role of sodium channels and of specific sodium channel subtypes in neuropathic pain signaling.
 ...
PMID:Blocking sodium channels to treat neuropathic pain. 1729 89

Pain serves a crucial physiological function, warning the body of impending or actual tissue damage, preventing further damage and aiding the healing process. Neuropathic pain, resulting from nervous system injury or dysfunction, can be a serious medical problem and especially difficult to treat. Although sodium channel blockers are clinically useful for treating pain, they often provide only partial relief and adverse effects associated with nonspecific actions can limit their use. Research on the roles of sodium channels in neuronal excitability and pain shows that specific sodium channel isoforms are crucial determinants of nociception and neuropathic pain, indicating that it should be possible to develop sodium channel blockers with lower toxicity and enhanced efficacy for treating neuropathic pain.
 ...
PMID:Voltage-gated sodium channel blockers for the treatment of neuropathic pain. 1799 6

Neuropathic pain is generally resistant to "classical" analgesic drugs, including opioids, and there is still an urgent need for really effective treatments to alleviate pain caused by lesions of the peripheral and/or central nervous system. The pathophysiological mechanisms underlying neuropathic pain are still poorly known, and treatments are mainly empirical. Antidepressant drugs are generally prescribed first, with positive but limited results in a significant proportion of patients. Anticonvulsant drugs (carbamazepine, phenytoin, lamotrigine) are also used but are often poorly tolerated. Clinical studies and preclinical investigations support the idea that the nature of neuropathic pain, and the underlying mechanisms, are different in the cephalic (trigeminal) territories and the extracephalic (spinal) territories. In order to further investigate these regional differences, we used rat nerve ligature models. Comparison of allodynia/hyperalgesia in the vibrissal territory caused by unilateral ligature of the infraorbital nerve (2nd branch of the trigeminal nerve) with those in the hindpaw ipsilateral to unilateral ligature of the sciatic nerve revealed marked differences in their responses to sodium channel blockers (such as tetrodotoxin), serotonin (5-HT) receptor agonists and calcitonin gene-related peptide (CGRP) receptor antagonists. In particular, 5-HT7 receptor agonists were particularly effective at reducing allodynia in sciatic nerve-ligated rats, but were completely ineffective in infraorbital nerve-ligated rats. Conversely, triptans (5-HT1B/1D receptor agonists) and CGRP-receptor antagonists markedly inhibited cephalic allodynia in infraorbital nerve-ligated rats but failed to relieve neuropathic pain in sciatic nerve-ligated animals. Interestingly, ligature-induced expression of the proinflammatory cytokine interleukin-6 in central tissues showed marked differences in sciatic nerve- and infraorbital nerve-ligated rats, providing direct evidence of differences in the mechanisms underlying extra-cephalic- and cephalic neuropathic pain. Such preclinical studies should contribute to the design of innovative strategies for more effective and well-tolerated treatments for neuropathic pain in cephalic and extra-cephalic territories.
 ...
PMID:[Neuropathic pain. Physiopathological mechanisms and therapeutic perspectives]. 1923 82

Axonal excitability testing can provide new insights into the ionic mechanisms underlying the pathophysiology of hyperexcitability of motor and sensory axons in human neuropathies. Threshold tracking was developed in the 1990's to non-invasively measure a number of axonal excitability indices that depend on sodium and potassium channel function, and this makes it possible to monitor the effects of pharmacologic intervention with ion channel modulators. This paper reviews recent advances in ionic-pathophysiological studies in humans. (1) Neuropathic pain or muscle cramp/fasciculation is partly caused by hyperexcitability of the injured axons. The enhanced excitability can result from altered ion channel function; such as an increase in persistent sodium currents. Persistent sodium currents can be reliably estimated using threshold tracking. In peripheral neuropathy, persistent sodium currents usually increase possibly due to over-expression of sodium channels associated with axonal regeneration, and could be responsible for ectopic firings. Administration of sodium channel blockers such as mexiletine, results in marked alleviation of muscle cramping in parallel with a decrease in nodal persistent sodium currents. (2) In diabetic neuropathy, the activation of the polyol pathway mediated by an enzyme, aldose reductase, leads to reduced Na(+)/K(+) pump activity, and intra-axonal sodium accumulation; sodium currents are reduced presumably due to decreased trans-axonal sodium gradient. Aldose reductase inhibitiors improve nodal sodium currents, as well as nerve conduction, and this can be objectively assessed by threshold tracking. Studies of ion-channel pathophysiology in human subjects have recently begun. Investigating ionic mechanisms by monitoring the corresponding ionic currents. is of clinical relevance, because once a specific ionic conductance is identified, pharmacologic blocking or modulation could provide a new therapeutic option.
 ...
PMID:Pharmacologic intervention in axonal excitability: in vivo assessment of nodal persistent sodium currents in human neuropathies. 2002 24


1 2 Next >>