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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, our laboratory has proposed the avulsion of rat brachial plexus as a new and reliable model for the study of neuropathic pain. In this model, the neuropathy can be detected even at distant sites from the injury, both in ipsilateral and contralateral hindpaws. The purpose of this study was to pharmacologically characterise this behavioural model of persistent peripheral neuropathic pain by assessing the effects of several analgesic drugs currently used in clinical practice. For this purpose, the effects of these drugs on the mechanical and cold allodynia were analysed 20-40 days after rat brachial plexus avulsion. Injection of saline, administered by the same route as the other drugs, did not significantly affect the nociceptive threshold either in sham-operated or in neuropathic rats. However, administration of the opioid analgesic morphine (5 mg/kg, s.c.), the alpha2 adrenoceptor agonist clonidine (300 microg/kg, i.p.), the NMDA receptor antagonist ketamine (25 mg/kg, i.p.) or the anticonvulsant drug gabapentin (70 mg/kg, p.o.) consistently reduced both mechanical and cold allodynia following avulsion of rat brachial plexus. The administration of the selective COX-2 inhibitor celecoxib (10 mg/kg, p.o.) blocked mechanical allodynia, but not cold allodynia, whereas the sodium channel blocker lidocaine (40 mg/kg, i.p.) attenuated only cold allodynia. The non-steroidal anti-inflammatory drug diclofenac (100 mg/kg, i.p.), the steroidal anti-inflammatory dexamethasone (1.5 mg/kg, i.p.) and the antidepressant imipramine (10 mg/kg, i.p.) all failed to significantly attenuate both mechanical and cold allodynia in the rats following avulsion of brachial plexus. These findings suggest that avulsion-associated mechanical and cold allodynia, two classic signs of persistent neuropathic pain, were consistently prevented by several analgesics currently available in clinical practice, namely morphine, clonidine, ketamine and gabapentin, and to a lesser extent by celecoxib and lidocaine. Therefore, this new proposed model of persistent nociception seems to be suitable for the study of the underlying mechanisms involved in neuropathic pain and for the identification of potential clinically relevant drugs to treat this aspect of peripheral neuropathy.
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PMID:Pharmacological characterisation of the rat brachial plexus avulsion model of neuropathic pain. 1527 74

In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg.
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PMID:Phenoxyphenyl pyridines as novel state-dependent, high-potency sodium channel inhibitors. 1529 99

Molecular medicine requires the precise definition of drug targets, and tools are now in place to provide genome-wide information on the expression and alternative splicing patterns of any known gene. DNA microarrays were used to monitor transcript levels of the nine well-characterized alpha-subunit sodium channel genes across a broad range of tissues from cynomolgus monkey, a non-human primate model. Alternative splicing of human transcripts for a subset of the genes that are expressed in dorsal root ganglia, SCN8A (Na(v)1.6), SCN9A (Na(v)1.7), and SCN11A (Na(v)1.9) was characterized in detail. Genomic sequence analysis among gene family paralogs and between cross-species orthologs suggested specific alternative splicing events within transcripts of these genes, all of which were experimentally confirmed in human tissues. Quantitative PCR revealed that certain alternative splice events are uniquely expressed in dorsal root ganglia. In addition to characterization of human transcripts, alternatively spliced sodium channel transcripts were monitored in a rat model for neuropathic pain. Consistent down-regulation of all transcripts was observed, as well as significant changes in the splicing patterns of SCN8A and SCN9A.
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PMID:Expression of alternatively spliced sodium channel alpha-subunit genes. Unique splicing patterns are observed in dorsal root ganglia. 1530 75

The Nav1.8 sodium channel isoform, expressed in sensory neurons and implicated in pain responses, is known to be upregulated in Xenopus oocytes by agents that activate protein kinase A. In the absence of exogenous modulators, Nav1.8 channels expressed in oocytes exhibited spontaneous downregulation, so that the amplitudes of peak sodium currents at the end of a 30-min recording period were reduced to 58% of those at the outset of recording with no change in the properties of the expressed channels. Perfusion of oocytes with either cyclosporin A or deltamethrin, considered to be diagnostic inhibitors of the protein phosphatase calcineurin, at 10 microM blocked spontaneous downregulation. These results identify endogenous calcineurin as the mediator of Nav1.8 sodium channel downregulation in oocytes. The use of a calcineurin inhibitor such as cyclosporin A provides an effective means of stabilizing the expression of Nav1.8 sodium channels in oocytes for functional and pharmacological studies.
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PMID:Cyclosporin A and deltamethrin block the downregulation of Nav1.8 sodium channels expressed in Xenopus oocytes. 1533 72

Acute, inflammatory, and neuropathic pain can all be attenuated or abolished by local treatment with sodium channel blockers such as lidocaine. The peripheral input that drives pain perception thus depends on the presence of functional voltage-gated sodium channels. Remarkably, two voltage-gated sodium channel genes (Nav1.8 and Nav1.9) are expressed selectively in damage-sensing peripheral neurons, while a third channel (Nav1.7) is found predominantly in sensory and sympathetic neurons. An embryonic channel (Nav1.3) is also upregulated in damaged peripheral nerves and associated with increased electrical excitability in neuropathic pain states. A combination of antisense and knock-out studies support a specialized role for these sodium channels in pain pathways, and pharmacological studies with conotoxins suggest that isotype-specific antagonists should be feasible. Taken together, these data suggest that isotype-specific sodium channel blockers could be useful analgesics.
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PMID:Voltage-gated sodium channels and pain pathways. 1536 53

An open label study of topical lidocaine 5% patches was conducted for myofascial pain management based on the hypothesis that electrical dysfunction is a component of myofascial pain and therefore sodium channel blockade may be useful in managing myofascial pain. The efficacy of topical lidocaine patch therapy for myofascial pain impact of the therapy on associated quality of life were investigated in the one-month trial. Principal outcome measures were Brief Pain Inventory- Short Form for pain intensity and quality of life score changes. Twenty-seven patients with moderate-severe myofascial pain were enrolled. Eighteen had low back pain. Two patients reported complete pain relief and 3 reported a lot of relief. Mean improvements for average pain intensity (7, 14, and 28 days), general activity (7 and 28 days), mood and sleep (7, 14, and 28 days), walking (14 and 28 days), and ability to work, relationships, and enjoyment of life (28 days) were significant (P < 0.05). These results suggest lidocaine patches may be useful in the management of myofascial pain.
J Pain Palliat Care Pharmacother 2004
PMID:Topical lidocaine patch therapy for myofascial pain. 1536 29

Inflammation caused by tissue damage results in pain, reflecting an increase in excitability of the primary afferent neurons innervating the area. There is some evidence to suggest that altered function of voltage-gated sodium channels is responsible for the hyperexcitability produced by inflammatory agents, possibly acting through G-proteins, but the role of different channel subtypes has not been fully explored. The tetrodotoxin-resistant (TTX-R) sodium channel Na(v)1.9 is expressed selectively in C- and A-fibre nociceptive-type units and is upregulated by G-protein activation. In this study, we examined the effects of the inflammatory agent prostaglandin-E(2) (PGE(2)) on Na(v)1.9 current in both Na(v)1.8-null and wild-type (WT) mice and explored the role of specific G-proteins in modulation. PGE(2) caused a twofold increase in Na(v)1.9 current (p<0.05) in both systems. Steady-state activation was shifted in a hyperpolarizing direction by 6-8 mV and availability of channels by 12 mV. No differences in the activation and inactivation kinetics could be detected. The increase in current was blocked by pertussis toxin (PTX) but not cholera toxin (CTX), showing involvement of G(i/o) but not G(s) subunits. Our data indicate that Na(v)1.9 current can be increased during inflammation via a G-protein dependent mechanism and suggest that this could contribute to the regulation of electrogenesis in dorsal root ganglia (DRG) neurons.
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PMID:PGE2 increases the tetrodotoxin-resistant Nav1.9 sodium current in mouse DRG neurons via G-proteins. 1537 52

Tri-cyclic antidepressants (TCAs) have been widely used in treating major depressive disorders. Recent studies further demonstrated that TCAs have potent sodium channel blocking effect, and amitriptyline, one of the TCAs, has a potent spinal anesthetic effect. The aim of the study was to evaluate the spinal anesthetic effect of various TCAs and to see whether these TCAs could likewise act as local anesthetics after a single intrathecal injection. Bupivacaine, a potent and long-acting traditional local anesthetic, acted as control. The spinal anesthetic effect of nine TCAs (amitriptyline, doxepin, imipramine, trimipramine, clomipramine, protriptyline, desipramine, nortriptyline, and amoxapine) and three traditional local anesthetics (bupivacaine, lidocaine, and mepivacaine) was evaluated in rats and so were dose-response studies of amitriptyline, bupivacaine, and lidocaine. Under a given concentration of 5mM, bupivacaine had the most potent spinal blockade of motor, propioception, and nociception (P<0.001) and the longest duration of action of nociception (P<0.01) among the three traditional local anesthetics. Under this concentration, amitriptyline had a similar potency but longer duration of spinal blockade of motor, propioception, and nociception (P<0.001) than did bupivacaine, whereas several other TCAs had similar or less potencies of spinal blockade than did bupivacaine. In dose-response studies, amitriptyline had a more potent (P<0.005) and longer duration (P<0.001) of spinal blockade than did bupivacaine. We concluded that intrathecal amitriptyline had a more potent and longer duration of spinal anesthetic effect than did bupivacaine, whereas several other TCAs had similar or less potencies than did bupivacaine.
Pain 2004 Nov
PMID:Intrathecal tri-cyclic antidepressants produce spinal anesthesia. 1549 90

Voltage-gated sodium channels are highly specialized molecular transducers that play a significant role in the creation and transmission of electrical activity throughout the neuraxis. These ion channels are fundamentally involved in sensory neuron physiology and pathophysiology; a complete but localized suspension of their normal function can prevent all sensation--including that perceived as pain. Soft-tissue injuries that result in inflammation or direct damage to nerve fibers have each been shown to result in abnormal sodium channel function and, in many cases, to lead to pathological hyperexcitability in the sensory afferent nerves that innervate the injured dermatome or visceral organ. Abrogating abnormal activity whilst leaving normal sensation unaffected would represent a powerful approach to pain relief. This article reviews the evidence supporting abnormal sodium channel biology in various pathological contexts, the opportunities that this presents for novel therapeutics and progress towards realizing this goal.
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PMID:Voltage-gated sodium channels and pain. 1557 63

Sodium channels underlie propagated electrical signalling in most excitable cells, including neurons and the myocytes of skeletal muscle and heart. These proteins are targeted by a variety of current therapeutic drugs to combat such maladies as pain, myotonias, epilepsies and cardiac arrhythmias. Typically, these problems are associated with overactivity of sodium channels leading to hyperexcitability in the relevant tissue. More than ten distinct but closely related molecular isoforms of mammalian sodium channel are now known to be specifically expressed in different cell types and tissues. Therapeutic attenuation of sodium channel activity must be effected with great precision in both targeting and the degree of reduction in channel activity if a malfunction is to be corrected without introducing deleterious or even catastrophic side effects. Numerous natural toxins have evolved to target sodium channels, either by blocking current through the pore or by modifying channel gating. Among the well studied toxins, the peptide conotoxins from cone snail venoms show a remarkable ability to discriminate among closely related forms of sodium channel, as well as exhibiting a variety of modes of action. Here, we examine the molecular basis of action of different Na channel targeted conotoxins and explore their potential as models for the future design of more specifically targeted drugs.
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PMID:Sodium channel toxins--receptor targeting and therapeutic potential. 1557 99


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