Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acid-sensing ion channel 3 (ASIC3), a proton-gated ion channel of the degenerins/epithelial sodium channel (DEG/ENaC) receptor family is expressed predominantly in sensory neurons including nociceptive neurons responding to protons. To study the role of ASIC3 in pain signaling, we generated ASIC3 knockout mice. Mutant animals were healthy and responded normally to most sensory stimuli. However, in behavioral assays for pain responses, ASIC3 null mutant mice displayed a reduced latency to the onset of pain responses, or more pain-related behaviors, when stimuli of moderate to high intensity were used. This unexpected effect seemed independent of the modality of the stimulus and was observed in the acetic acid-induced writhing test (0.6 vs. 0.1-0.5%), in the hot-plate test (52.5 and 55 vs. 50 degrees C), and in tests for mechanically induced pain (tail-pinch vs. von Frey filaments). We postulate that ASIC3 is involved in modulating moderate- to high-intensity pain sensation.
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PMID:A role for ASIC3 in the modulation of high-intensity pain stimuli. 1206 Jul 8

Veratridine, a blocker of inactive gate of sodium channel, was used to perfuse L5 dorsal root ganglion (DRG) topically. Afferent activities of type A single fiber from these DRGs were recorded. It was found that after a 10-min bath of veratridine (1.8-3 micromol/L), some of the primary silent DRG neurons were triggered by touch or pressure on the receptive fields or by electrical stimulation of the sciatic nerve to produce high-frequency firing, which was termed triggered oscillation presenting a U-type of interspike intervals (ISI) or other types of oscillations. The longer the intervals between stimulating pulses, the more stimulating pulses were needed to trigger the oscillation. The oscillation, triggered by electric stimuli with different duration or patterns, had no significant difference in their patterns. The duration of the inhibitory period after a triggered oscillation was generally 30-90 s. It was also observed that this kind of triggered oscillation was induced by afferent pulses of the same neurons. These results suggest that triggered oscillation, which may contribute to the fit of triggered pain, can be produced in primary sensory neurons after application of veratridine.
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PMID:[Triggered oscillations in type A dorsal root ganglion neurons induced by veratridine]. 1207 66

The recently discovered epithelial sodium channel (ENaC)/degenerin (DEG) gene family encodes sodium channels involved in various cell functions in metazoans. Subfamilies found in invertebrates or mammals are functionally distinct. The degenerins in Caenorhabditis elegans participate in mechanotransduction in neuronal cells, FaNaC in snails is a ligand-gated channel activated by neuropeptides, and the Drosophila subfamily is expressed in gonads and neurons. In mammals, ENaC mediates Na+ transport in epithelia and is essential for sodium homeostasis. The ASIC genes encode proton-gated cation channels in both the central and peripheral nervous system that could be involved in pain transduction. This review summarizes the physiological roles of the different channels belonging to this family, their biophysical and pharmacological characteristics, and the emerging knowledge of their molecular structure. Although functionally different, the ENaC/DEG family members share functional domains that are involved in the control of channel activity and in the formation of the pore. The functional heterogeneity among the members of the ENaC/DEG channel family provides a unique opportunity to address the molecular basis of basic channel functions such as activation by ligands, mechanotransduction, ionic selectivity, or block by pharmacological ligands.
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PMID:Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. 1208 34

Voltage-gated sodium channels consist of a pore-forming alpha subunit and two auxiliary beta subunits. Excitable cells express multiple alpha subtypes, designated Na(v)1.1-Na(v)1.9, and three beta subunits, designated beta1, beta2 and beta3. Understanding how the different alpha subtypes, in combination with the various beta subunits, determine sodium channel behavior is important for elucidating the molecular basis of sodium channel functional diversity. In this study, we used whole-cell electrophysiological recording to examine the properties of the human Na(v)1.3 alpha subtype, stably expressed in Chinese hamster ovary cells, and to investigate modulation of Na(v)1.3 function by beta1, beta2 and beta3 subunits. In the absence of beta subunits, human Na(v)1.3 formed channels that inactivated rapidly (tau(inactivation) approximately equals 0.5 ms at 0 mV) and almost completely by the end of 190-ms-long depolarizations. Using an intracellular solution with aspartate as the main anion, the midpoint for channel activation was approximately -12 mV. The midpoint for inactivation, determined using 100-ms conditioning pulses, was approximately -47 mV. The time constant for repriming of inactivated channels at -80 mV was approximately 6 ms. Coexpression of beta1 or beta3 did not affect inactivation time course or the voltage dependence of activation, but shifted the inactivation curve approximately 10 mV negative, and slowed the repriming rate ca. three-fold. beta2 did not affect channel properties, either by itself or in combination with beta1 or beta3. Na(v)1.3 expression is increased in damaged nociceptive peripheral afferents. This change in channel expression levels is correlated with the emergence of a rapidly inactivating and rapidly repriming sodium current, which has been proposed to contribute to the pathophysiology of neuropathic pain. The results of this study support the hypothesis that Na(v)1.3 may mediate this fast sodium current.
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PMID:Functional modulation of human brain Nav1.3 sodium channels, expressed in mammalian cells, by auxiliary beta 1, beta 2 and beta 3 subunits. 1222 May 75

Intraspinal drug delivery represents an important treatment option for the management of chronic pain. Selection of candidates for this type of therapy requires careful evaluation of the patient, possibly including psychological screening. Although determining the efficacy of long-term intraspinal drug therapy has been challenging, several classes of agents have been identified to provide benefits in patients with a variety of pain types. Such agents include opioids, alpha(2)-agonists, sodium channel antagonists, and gamma-aminobutyric acid agonists. In addition, combinations of agents with distinct mechanisms of action may be therapeutically advantageous because many clinical pain states result from more than one mechanism.
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PMID:Treatment options for refractory pain: the role of intrathecal therapy. 1222 Nov 52

Central pain is a particular form of neuropathic pain. Due to lesions in the spinothalamocortical pathways, ectopic neuronal discharges can occur into different neurons of the spinal cord and brain. Functional MRI, and positron emission tomography might be able to visualize ongoing pain activity which is, sometimes the consequence of spinothalamocortical lesions. Sometimes the patient experiences a burning ice-like sensation. This is more frequent in spinal cord lesions than in brain injuries. Some adrenergic, gabergic neurotransmitters, glycine, prostanoids and glutamate may play a role in pain transmission. These transmitters can induce changes in the neuronal membrane potential. Consequently, amitriptyline as an adrenergic reuptake inhibitor and the sodium channel blockers are the drugs of first-choice. A test procedure with placebo, opioids, lignocaine, propofol and ketamine might give some insight into advanced drug treatment. If oral or transdermal drug delivery is not indicated or ineffective, the intrathecal administration route can be attempted with baclofen, clonidine, opioids and midazolam. Invasive electrostimulation is the last treatment option. Thalamic stimulation can be tried in spinal cord injuries, and sensory motor cortex stimulation is sometimes the last resort for brain lesions associated with pain.
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PMID:Central pain: an overview. 1240 Feb 47

Although pain is experienced by many patients with diabetic neuropathy, the pathophysiology of painful diabetic neuropathy is not understood. Substantial evidence indicates that dysregulated sodium channel gene transcription contributes to hyperexcitability of dorsal root ganglion neurons, which may produce neuropathic pain after axonal transection. In this study, we examined sodium channel mRNA and protein expression in dorsal root ganglion neurons in rats with streptozotocin-induced diabetes and tactile allodynia, using in situ hybridization and immunocytochemistry for sodium channels Na(v)1.1, Na(v)1.3, Na(v)1.6, Na(v)1.7, Na(v)1.8, and Na(v)1.9. Our results show that, in rats with experimental diabetes, there is a significant upregulation of mRNA for the Na(v)1.3, Na(v)1.6, and Na(v)1.9 sodium channels and a downregulation of Na(v)1.8 mRNA 1 and 8 weeks after onset of allodynia. Channel protein levels display parallel changes. Our results demonstrate dysregulated expression of the genes for sodium channels Na(v)1.3, Na(v)1.6, Na(v)1.8, and Na(v)1.9 in dorsal root ganglion neurons in experimental diabetes and suggest that misexpression of sodium channels contributes to neuropathic pain associated with diabetic neuropathy.
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PMID:Changes of sodium channel expression in experimental painful diabetic neuropathy. 1244 33

The underlying mechanisms of neuropathic pain are poorly understood, and existing treatments are mostly ineffective. We recently demonstrated that antisense mediated "knock-down" of the sodium channel isoform, Na(V)1.8, reverses neuropathic pain behavior after L5/L6 spinal nerve ligation (SNL), implicating a critical functional role of Na(V)1.8 in the neuropathic state. Here we have investigated mechanisms through which Na(V)1.8 contributes to the expression of experimental neuropathic pain. Na(V)1.8 does not appear to contribute to neuropathic pain through an action in injured afferents because the channel is functionally downregulated in the cell bodies of injured neurons and does not redistribute to injured terminals. Although there was little change in Na(V)1.8 protein or functional channels in the cell bodies of uninjured neurons in L4 ganglia, there was a striking increase in Na(V)1.8 immunoreactivity along the sciatic nerve. The distribution of Na(V)1.8 reflected predominantly the presence of functional channels in unmyelinated axons. The C-fiber component of the sciatic nerve compound action potential (CAP) was resistant (>40%) to 100 microm TTX after SNL, whereas both A- and C-fiber components of sciatic nerve CAP were blocked (>90%) by 100 microm TTX in sham-operated rats or the contralateral sciatic nerve of SNL rats. Attenuating expression of Na(V)1.8 with antisense oligodeoxynucleotides prevented the redistribution of Na(V)1.8 in the sciatic nerve and reversed neuropathic pain. These observations suggest that aberrant activity in uninjured C-fibers is a necessary component of pain associated with partial nerve injury. They also suggest that blocking Na(V)1.8 would be an effective treatment of neuropathic pain.
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PMID:Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. 1251 12

BIII-890-CL is a non-orally active sodium channel blocker under development by Boehringer Ingelheim Corp for the potential treatment of thromboembolic stroke. By April 2001, the compound was in phase II clinical trials for this indication, with trials ongoing in June 2002. The compound is also under investigation for its potential use in the treatment of pain.
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PMID:BIII-890-CL. Boehringer Ingelheim. 1252 8

Sixty percent of patients with posttraumatic para- or tetraplegia suffer from severe, continuous burning and/or lancinating pain. Multiple sclerosis produces pain in more than 30%. This pain can be as important as the absent mobility or sexual function as a cause of lowered quality of life. Two unique types of longstanding neuropathic pain can be recognized in persons with spinal cord injury: (1). segmentally distributed pain at the lesion; and (2). pain in the body below the lesion, often with late onset. The first type could be produced by nerve root entrapment or by direct segmental deafferentation. The second type probably contains several forms of central pain, evoked either by the original spinal lesion, by an expanding syrinx in the spinal cord or by secondary changes at higher levels of the somatosensory systems. Patients with central pain almost always have stimulus-independent pain. Its intensity may vary independently, be related to the presence of visceral activity/inflammation or be constant. In addition, stimulus-dependent pain is sometimes present, usually because skin areas or viscera below the lesion are allodynic. Partial spinal lesions, especially centrally in the cervical spinal cord, may be more prone to produce pain than are complete lesions. There is limited analgesic effectiveness in controlled studies of serotonin reuptake inhibitors, of sodium channel blockers (lidocaine, tetracaine), of the GABA receptor agonist baclofen (one study) and of the NMDA-receptor antagonist ketamine (one study). There are anecdotal reports on oral carbamazepine, on gabapentin, on intrathecal opiates and also on the alpha(2)-agonist clonidine, being effective in central neuropathic pain. Neurostimulation is effective only if it evokes paraesthesia in the painful area; hence TENS may give relief of segmental pain. Neurodestructive procedures and central neurostimulation have been largely unsuccessful. As in other longstanding pain, improved coping through cognitive-behavioural rehabilitation may be helpful for the clinical outcome.
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PMID:Pain and rehabilitation after spinal cord injury: the case of sensory spasticity? 1258 23


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