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

Phoneutria nigriventer (Labidognatha, Ctenidae) is a spider found in the warm regions of South America. Bites by this species cause intense local pain, autonomic dysfunction and paralysis. PhTx2, a neurotoxic fraction of the venom of this species, interferes with the physiology of sodium channel function. The present study describes the morphological changes in mouse phrenic nerve and diaphragm muscle after 15, 30, 45 and 60 min of incubation with 1 microg of PhTx2/ml. Light and transmission electron microscopy showed that PhTx2 caused progressive myonecrosis which involved swelling of the sarcoplasmic reticulum, mitochondrial damage, disorganization of the sarcomeres, zones of hypercontracted myofibrils and rupture of the plasma membrane. The intramuscular fascicles of the phrenic nerve showed vacuolated myelinated axons and Schwann cells. The neuromuscular junctions had vesicle-depleted nerve terminals with swollen mitochondria. The axolema was frequently invaginated and sequestered portions of the axoplasm, or was sometimes interrupted at the site of the synaptic gutter. The post-synaptic junctional folds were shallow and disperse. These morphological alterations in the muscle and nerve fibres were similar to those caused by osmotic disturbances and agree with the ability of PhTx2 to increase the permeability of sodium channels. An increase in sodium influx would probably be accompanied by an influx of water and an elevation in the concentration of cytosolic calcium as a result of calcium release by the sarcoplasmic reticulum and/or mitochondria and the entry of extracellular calcium. The morphological effects caused by PhTx2 were comparable to those seen with Phoneutria nigriventer whole venom which is known to activate and to delay the inactivation of sodium channels. We conclude that PhTx2 is probably the main toxic fraction responsible for such morphological alterations.
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PMID:Toxin 2 (PhTx2), a neurotoxic fraction from Phoneutria nigriventer spider venom, causes acute morphological changes in mouse skeletal muscle. 1069 66

Voltage-gated sodium channel alpha-subunits have been shown to be key mediators of the pathophysiology of pain. The present review considers the role of sodium channel auxiliary beta-subunits in channel modulation, channel protein expression levels, and interactions with extracellular matrix and cytoskeletal signaling molecules. Although beta-subunits have not yet been directly implicated in pain mechanisms, their intimate association with and ability to regulate alpha-subunits predicts that they may be a viable target for therapeutic intervention in the future. It is proposed that multifunctional sodium channel beta-subunits provide a critical link between extracellular and intracellular signaling molecules and thus have the ability to fine tune channel activity and electrical excitability.
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PMID:I. Cellular and molecular biology of sodium channel beta-subunits: therapeutic implications for pain? 1071 53

The identification of compounds that can effectively and safely treat chronic pain is a major challenge of biomedical research. One approach is to optimize currently active analgesic treatments, notably by reducing their side effects. An example of this approach is the recent development of a novel class of nonsteroidal antiinflammatory drugs (NSAIDs), the cyclo-oxygenase 2 inhibitors, that lack the limiting gastrointestinal side effects of the traditional NSAIDs. Another approach, based on the recent development of molecular biology, is to develop analgesic compounds acting on new targets. These include notably ion channel blockers (TTX-resistant sodium channel blockers specific for nociceptors, N-type calcium channel blockers), nicotine receptor agonists, peptide receptor antagonists, N-methyl-D-aspartate (NMDA) receptor antagonists, vanilloids, new opioid compounds, cannabinoids, selective alpha2-adrergic agonists, purinergic modulators. Most of these compounds are currently in preclinical or early clinical investigation. However, the development of more predictable in vitro and in vivo tests and the broadening use of clinical models of experimental pain, will hopefully help increase the proportion of drugs that will become successful analgesics in clinical practice.
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PMID:[Recent pharmacologic approaches to pain]. 1079 Jun 5

The effectiveness of systemic lidocaine in relieving acute and chronic pain has been recognized for over 35 years. In particular, systemic lidocaine has been utilized both as a diagnostic and therapeutic tool for intractable neuropathic pain during the last decade. The introduction of oral lidocaine congeners such as mexiletine has significantly extended the usage of lidocaine therapy in chronic pain settings. However, a number of clinical issues remain to be addressed including (1) an effective, meaningful dose range for the clinical lidocaine test, (2) the predictive value of the lidocaine test for an oral trial of lidocaine congeners, (3) identification of pain symptoms and signs relieved by systemic lidocaine, (4) comparisons of therapeutic effects between systemic lidocaine and its oral congeners, and (5) long-term outcomes of systemic lidocaine and its oral congeners. Mechanisms of neuropathic pain relief from lidocaine therapy are yet to be understood. Both central and peripheral mechanisms have been postulated. Systemic lidocaine is thought to have its suppressive effects on spontaneous ectopic discharges of the injured nerve without blocking normal nerve conduction. However, there remain inconsistencies in the scientific basis underlying the clinical application of lidocaine therapy. Recent demonstration of changes in tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels following nerve injury and their link to certain neuropathic pain symptoms may lead to the development of subtype-specific sodium channel blockers. The thoughtful use of lidocaine therapy and the potential application of subtype-specific sodium channel blockers could provide better management of distinctive neuropathic pain symptoms.
Pain 2000 Jul
PMID:Systemic lidocaine for neuropathic pain relief. 1086 41

Despite the availability of different pharmacologic agents for the treatment of various chronic neuropathic pain syndromes, complete symptom reduction and/or complete functional restoration is rarely achieved. New, safe, and effective treatments for chronic neuropathic pain, therefore, must be developed. One such agent, the lidocaine patch (Lidoderm, Endo Pharmaceuticals, Inc., Chadds Ford, PA), has been approved recently by the US Food and Drug Administration for the treatment of postherpetic neuralgia. Like other local anesthetics, the lidocaine patch results in sodium channel blockade, dampening, both peripheral nociceptor sensitization and, ultimately, central nervous system hyperexcitability. The Lidoderm patch is a topical agent and, consequently, insignificant serum levels are achieved even with chronic use. This fact enhances its safety. Recent studies have suggested that the lidocaine patch may be effective for chronic neuropathic pain conditions other than postherpetic neuralgia as well.
Clin J Pain 2000 Jun
PMID:New analgesics for neuropathic pain: the lidocaine patch. 1087 Jul 42

Several lines of evidence developed in preclinical models suggest that both spontaneous and evoked pain are mediated in part by voltage-sensitive sodium and calcium channels, which are in abundance in both the peripheral and the central nervous system. There is an abundance of research, both preclinical and clinical, on the effects of the sodium and calcium channel antagonists on nociceptive processing. Clinical studies on the efficacy of the sodium channel antagonists in the treatment of acute and chronic pain have had mixed results. Preliminary studies of the N-type calcium channel antagonists for the treatment of acute and chronic pain are promising but too early to enable researchers to make firm conclusions. This review summarizes the current literature on the effects of the sodium and calcium channel antagonists on acute nociceptive processing, facilitated pain, and neuropathic pain.
Clin J Pain 2000 Jun
PMID:Calcium and sodium channel antagonists for the treatment of pain. 1087 Jul 45

The inferior alveolar nerve is a sensory branch of the trigeminal nerve that is frequently damaged, and such nerve injuries can give rise to persistent paraesthesia and dysaesthesia. The mechanisms behind neuropathic pain following nerve injury is poorly understood. However, remodeling of voltage-gated sodium channels in the neuronal membrane has been proposed as one possible mechanism behind injury-induced ectopic hyperexcitability. The TTX-resistant sodium channel SNS/PN3 has been implicated in the development of neuropathic pain after spinal nerve injury. We here study the effect of chronic axotomy of the inferior alveolar nerve on the expression of SNS/PN3 mRNA in trigeminal sensory neurons. The organization of sodium channels in the neuronal membrane is maintained by binding to ankyrin, which help link the sodium channel to the membrane skeleton. Ankyrin(G), which colocalizes with sodium channels in the initial segments and nodes of Ranvier, and is necessary for normal neuronal sodium channel function, could be essential in the reorganization of the axonal membrane after nerve injury. For this reason, we here study the expression of ankyrin(G) in the trigeminal ganglion and the localization of ankyrin(G) protein in the inferior alveolar nerve after injury. We show that SNS/PN3 mRNA is down-regulated in small-sized trigeminal ganglion neurons following inferior alveolar nerve injury but that, in contrast to the persistent loss of SNS/PN3 mRNA seen in dorsal root ganglion neurons following sciatic nerve injury, the levels of SNS/PN3 mRNA appear to normalize within a few weeks. We further show that the expression of ankyrin(G) mRNA also is downregulated after nerve lesion and that these changes persist for at least 13 weeks. This decrease in the ankyrin(G) mRNA expression could play a role in the reorganization of sodium channels within the damaged nerve. The changes in the levels of SNS/PN3 mRNA in the trigeminal ganglion, which follow the time course for hyperexcitability of trigeminal ganglion neurons after inferior alveolar nerve injury, may contribute to the inappropriate firing associated with sensory dysfunction in the orofacial region.
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PMID:Expression of sodium channel SNS/PN3 and ankyrin(G) mRNAs in the trigeminal ganglion after inferior alveolar nerve injury in the rat. 1091 77

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.
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PMID:Potent analgesic effects of GDNF in neuropathic pain states. 1102 95

First, the fundamentals of impulse transmission and pain perception are revised. The role of the primary afferent nociceptors is explained. Dental pain is described as a form of acute pain and the mechanism of nociception is fundamental. Peripheral and central sensitization can evolve. The second part covers the pharmacological aspects. Local anesthetics reduce impulse transmission by interfering with the mechanism of normal depolarisation. Binding to specific receptors located at the nerve membrane, more specifically on the sodium channel, results in decreased or eliminated permeability to sodium ions and leads to interruption of nerve conduction. The different types of local anesthetics used in dentistry are discussed in more detail with respect to their physico-chemical characteristics and analgetic properties. The importance of factors such as lipophilicity, degree of protein binding and dissociation constant pKa are explained together with the clinical implications of pH and possible toxic effects. Failure of local anesthesia can be the result of problems with the administration of the product or can have a pharmacological basis. Injection of the anesthetic should take place in amounts large enough, with suitable volume and as close as possible to the nerve. When infection and inflammation are present, the intravascular resorption of the anesthetic will accelerate and the lowered pH influences diffusion negatively. Repetitive administration can induce the phenomenon of tachyfylaxis (decreased anesthetic effect).
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PMID:[Pain perception, mechanisms of action of local anesthetics and possible causes of failure]. 1103 81

Tricyclic antidepressants and anticonvulsants have become the mainstay in the treatment of pain in polyneuropathy. Within the last decade, controlled trials have shown that numerous other drugs relieve such pain. To estimate the efficacy of the different treatments, the authors identified all placebo-controlled trials and calculated numbers needed to treat (NNT) to obtain one patient with more than 50% pain relief. The NNT was 2.6 for tricyclic antidepressants, 6.7 for selective serotonin reuptake inhibitors, 2.5 for anticonvulsant sodium channel blockers, 4.1 for the anticonvulsant calcium channel blocker gabapentin, and 3.4 for the mixed opioid and monoaminergic drug tramadol, as calculated from a sufficiently large number of patients. Favorable point estimates of NNT of 1.9 for the NMDA-antagonist dextromethorphan and 3.4 for L-dopa were determined from a limited number of data. For capsaicin, the NNT calculated from many exposed patients was 5.9, but most of the data are controversial owing to trial methodology. Finally, the NNT for the antiarrhythmic sodium channel blocker mexiletine was 38, but this value may be biased because of a lack of dichotomous data in several positive trials. Tricyclic antidepressants are at the moment still the drugs of first choice, and drugs such as gabapentin, carbamazepine, and tramadol may be tried if contraindications or tolerability problems are encountered with the tricyclics.
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PMID:Pharmacologic treatment of pain in polyneuropathy. 1132 Feb


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