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)

Many pharmaceutical companies are pursuing the 'holy grail' of an effective pain relief drug that has no harmful side effects. The voltage-gated sodium channel family offers some promising targets.
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PMID:Volts and salts in pain relief. 1239 11

The voltage-gated sodium channel NaV1.8 (SNS, PN3) is thought to be a molecular correlate of the dorsal root ganglion (DRG) tetrodotoxin resistant (TTX-R) Na+ current. TTX-R/NaV1.8 is an attractive therapeutic drug target for inflammatory and neuropathic pain on the basis of its specific distribution in sensory neurones and its modulation by inflammatory mediators. However, detailed analysis of recombinant NaV1.8 has been hampered by difficulties in stably expressing the functional protein in mammalian cells. Here, we show stable expression and functional analysis of rat NaV1.8 (rNaV1.8) in the rat DRG/mouse N18Tg2 neuroblastoma hybridoma cell line ND7-23. Rat NaV1.8 Na+ currents were recorded (789 +/- 89 pA, n=62, over 20-cell passages) that qualitatively resembled DRG TTX-R in terms of gating kinetics and voltage-dependence of activation and inactivation. The local anaesthetic drug tetracaine produced tonic inhibition of rNaV1.8 (mean IC50 value 12.5 microM) and in repeated gating paradigms (2-10 Hz) also showed frequency-dependent block. There was a correlation between the ability of several analogues of the anticonvulsant/analgesic compound lamotrigine to inhibit TTX-R and rNaV1.8 (r=0.72, P<0.001). RT-PCR analysis of wild type ND7-23 cells revealed endogenous expression of the beta1 and beta3 accessory Na+ channel subunits-the possibility that the presence of these subunits assists and stabilises expression of rNaV1.8 is discussed. We conclude that the neuroblastoma ND7-23 cell line is a suitable heterologous expression system for rNaV1.8 Na+ channels in that it allows stable expression of a channel with biophysical properties that closely resemble the native TTX-R currents in DRG neurones. This reagent will prove useful in the search for pharmacological inhibitors of rNaV1.8 as novel analgesics.
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PMID:Heterologous expression and functional analysis of rat Nav1.8 (SNS) voltage-gated sodium channels in the dorsal root ganglion neuroblastoma cell line ND7-23. 1497 98

Vulvodynia is characterised by painful burning sensation, allodynia and hyperalgesia in the region of the vulval vestibulus. While in many patients the cause of vulvodynia remains uncertain, we and others have previously shown increased intraepithelial and papillary innervation in vulvodynia. The vanilloid receptor VR1 (TRPV1) is expressed by nociceptors, and is triggered by capsaicin, noxious heat, protons, and chemicals produced during inflammation. In the present study we show increased papillary VR1 fibres by immunostaining and image analysis in vulvodynia tissues compared to controls (p<0.002). VR1 expression was found to be significantly increased when the percentage area immunostained was expressed as a ratio of VR1 to PGP 9.5, a pan-neuronal marker (P=0.01). VR1-positive fine epidermal fibres also appeared to be increased in vulvodynia tissues, by inspection. Fibres immunoreactive to the voltage-gated sodium channel SNS1/PN3 (Nav1.8), also expressed by nociceptors, were relatively scarce in both vulvodynia and control tissues. We hypothesize that increased expression of VR1 by nociceptors could mediate some of the symptoms in vulvodynia, for which systemic or topical specific VR1 antagonists may provide novel treatment.
Eur J Pain 2004 Apr
PMID:Increased vanilloid receptor VR1 innervation in vulvodynia. 1498 22

The upregulation of voltage-gated sodium channel Na(v)1.3 has been linked to hyperexcitability of axotomized dorsal root ganglion (DRG) neurons, which underlies neuropathic pain. However, factors that regulate delivery of Na(v)1.3 to the cell surface are not known. Contactin/F3, a cell adhesion molecule, has been shown to interact with and enhance surface expression of sodium channels Na(v)1.2 and Na(v)1.9. In this study we show that contactin coimmunoprecipitates with Na(v)1.3 from postnatal day 0 rat brain where this channel is abundant, and from human embryonic kidney (HEK) 293 cells stably transfected with Na(v)1.3 (HEK-Na(v)1.3). Purified GST fusion proteins of the N and C termini of Na(v)1.3 pull down contactin from lysates of transfected HEK 293 cells. Transfection of HEK-Na(v)1.3 cells with contactin increases the amplitude of the current threefold without changing the biophysical properties of the channel. Enzymatic removal of contactin from the cell surface of cotransfected cells does not reduce the elevated levels of the Na(v)1.3 current. Finally, we show that, similar to Na(v)1.3, contactin is upregulated in axotomized DRG neurons and accumulates within the neuroma of transected sciatic nerve. We propose that the upregulation of contactin and its colocalization with Na(v)1.3 in axotomized DRG neurons may contribute to the hyper-excitablity of the injured neurons.
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PMID:Contactin associates with sodium channel Nav1.3 in native tissues and increases channel density at the cell surface. 1531 64

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

NaV1.8 is a voltage-gated sodium channel expressed only in a subset of sensory neurons of which more than 85% are nociceptors. In order to delete genes in nociceptive neurons, we generated heterozygous transgenic mice expressing Cre recombinase under the control of the NaV1.8 promoter. Functional Cre recombinase expression replicated precisely the expression pattern of NaV1.8. Cre expression began at embryonic day 14 in small diameter neurons in dorsal root, trigeminal and nodose ganglia, but was absent in non-neuronal or CNS tissues into adulthood. Sodium channel subtypes were normal in isolated DRG neurons. Pain behaviour in response to mechanical or thermal stimuli, and in acute, inflammatory and neuropathic pain was also normal. These data demonstrate that the heterozygous NaV1.8-Cre mouse line is a useful tool to analyse the effects of deleting floxed genes on pain behaviour.
Pain 2005 Jan
PMID:Nociceptor-specific gene deletion using heterozygous NaV1.8-Cre recombinase mice. 1562 61

A new series of voltage-gated sodium channel blockers with potential for treatment of chronic pain is reported. Systematic structure-activity relationship studies, starting with compound 1, led to identification of potent analogs that displayed use-dependent block of sodium channels, were efficacious in pain models in vivo, and most importantly, were devoid of activity against the cardiac potassium channel hERG.
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PMID:Discovery of potent and use-dependent sodium channel blockers for treatment of chronic pain. 1587 74

A multitude of voltage-gated sodium channel subtypes (NaV1) are expressed in primary sensory neurons where they influence excitability via their role in the generation and propagation of action potentials. Peripheral nerve injury alters the expression of several NaV1subtypes, but among these only NaV1.3 is up-regulated in dorsal root ganglia (DRG) neurons. The increased expression of NaV1.3 implicates this subtype in the development and maintenance of neuropathic pain, but its contribution to neuropathic pain behavior has not been examined. Using the spared nerve injury (SNI) model, we found that peripheral nerve lesion increased NaV1.3-like immunoreactivity (-LI) in DRG neurons and that mechanical allodynia was partially alleviated following oral administration of two NaV1 blockers, mexiletine (30 and 100 mg/kg, p.o.) and lamotrigine (30 and 100 mg/kg, p.o.). Intrathecal administration of antisense oligonucleotides (4 days) selective for NaV1.3 decreased NaV1.3 immunostaining in the DRG by 50% in the SNI model, but did not attenuate mechanical or cold allodynia. Moreover, we found that only 18% of NaV1.3 positive neurons also expressed activated transcription factor-3 (ATF3), a marker of injured neurons. We then selectively axotomized a cutaneous nerve (sural) and a muscle nerve (gastrocnemius) in order to identify if NaV1.3 up-regulation is dependent on cutaneous and/or muscle afferent activation and found that the numbers of neurons expressing NaV1.3 was proportional to the magnitude of the injury, but independent of the nature of innervation. These results suggest that NaV1.3 increases in primary sensory neurons that are not directly damaged in response to injury. Thus, although NaV1.3 is up-regulated in a subpopulation of DRG neurons after injury, reduction in the expression of NaV1.3 subtype alone is not sufficient to influence the NaV1-dependent behavioral hypersensitivity associated with nerve injury.
Pain 2005 Sep
PMID:Relationship between sodium channel NaV1.3 expression and neuropathic pain behavior in rats. 1606 26

Spinal cord contusion injury (SCI) is known to induce pain-related behaviour, as well as hyperresponsiveness in lumbar dorsal horn nociceptive neurons associated with the aberrant expression of Na(v)1.3, a rapidly repriming voltage-gated sodium channel. Many of these second-order dorsal horn neurons project to third-order neurons in the ventrobasal complex of the thalamus. In this study we hypothesized that, following SCI, neurons in the thalamus undergo electrophysiological changes linked to aberrant expression of Na(v)1.3. Adult male Sprague-Dawley rats underwent contusion SCI at the T9 thoracic level. Four weeks post-SCI, Na(v)1.3 protein was upregulated within thalamic neurons in ventroposterior lateral (VPL) and ventroposterior medial nuclei, where extracellular unit recordings revealed increased spontaneous discharge, afterdischarge, hyperresponsiveness to innocuous and noxious peripheral stimuli, and expansion of peripheral receptive fields. Altered electrophysiological properties of VPL neurons persisted after interruption of ascending spinal barrage by spinal cord transection above the level of the injury. Lumbar intrathecal administration of specific antisense oligodeoxynucleotides generated against Na(v)1.3 caused a significant reduction in Na(v)1.3 expression in thalamic neurons and reversed electrophysiological alterations. These results show, for the first time, a change in sodium channel expression within neurons in the thalamus after injury to the spinal cord, and suggest that these changes contribute to altered processing of somatosensory information after SCI.
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PMID:Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury. 1610 50

We recently showed that spinal cord contusion injury (SCI) at the thoracic level induces pain-related behaviors and increased spontaneous discharges, hyperresponsiveness to innocuous and noxious peripheral stimuli, and enlarged receptive fields in neurons in the ventral posterolateral (VPL) nucleus of the thalamus. These changes are linked to the abnormal expression of Na(v)1.3, a rapidly repriming voltage-gated sodium channel. In this study, we examined the burst firing properties of VPL neurons after SCI. Adult male Sprague-Dawley rats underwent contusion SCI at the T9 level. Four weeks later, when Na(v)1.3 protein was upregulated within VPL neurons, extracellular unit recordings were made from VPL neurons in intact animals, those with SCI, and in SCI animals after receiving lumbar intrathecal injections of Na(v)1.3 antisense or mismatch oligodeoxynucleotides for 4 days. After SCI, VPL neurons with identifiable peripheral receptive fields showed rhythmic oscillatory burst firing with changes in discrete burst properties, and alternated among single-spike, burst, silent, and spindle wave firing modes. Na(v)1.3 antisense, but not mismatch, partially reversed alterations in burst firing after SCI. These results demonstrate several newly characterized changes in spontaneous burst firing properties of VPL neurons after SCI and suggest that abnormal expression of Na(v)1.3 contributes to these phenomena.
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PMID:Alterations in burst firing of thalamic VPL neurons and reversal by Na(v)1.3 antisense after spinal cord injury. 1648 57


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