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

Although it is well established that hyperexcitability and/or increased baseline sensitivity of primary sensory neurons can lead to abnormal burst activity associated with pain, the underlying molecular mechanisms are not fully understood. Early studies demonstrated that, after injury to their axons, neurons can display changes in excitability, suggesting increased sodium channel expression, and, in fact, abnormal sodium channel accumulation has been observed at the tips of injured axons. We have used an ensemble of molecular, electrophysiological, and pharmacological techniques to ask: what types of sodium channels underlie hyperexcitability of primary sensory neurons after injury? Our studies demonstrate that multiple sodium channels, with distinct electrophysiological properties, are encoded by distinct mRNAs within small dorsal root ganglion (DRG) neurons, which include nociceptive cells. Moreover, several DRG neuron-specific sodium channels now have been cloned and sequenced. After injury to the axons of DRG neurons, there is a dramatic change in sodium channel expression in these cells, with down-regulation of some sodium channel genes and up-regulation of another, previously silent sodium channel gene. This plasticity in sodium channel gene expression is accompanied by electrophysiological changes that poise these cells to fire spontaneously or at inappropriate high frequencies. Changes in sodium channel gene expression also are observed in experimental models of inflammatory pain. Thus, sodium channel expression in DRG neurons is dynamic, changing significantly after injury. Sodium channels within primary sensory neurons may play an important role in the pathophysiology of pain.
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PMID:Sodium channels and pain. 1039 72

Alterations in sodium channel expression and function have been suggested as a key molecular event underlying the abnormal processing of pain after peripheral nerve or tissue injury. Although the relative contribution of individual sodium channel subtypes to this process is unclear, the biophysical properties of the tetrodotoxin-resistant current, mediated, at least in part, by the sodium channel PN3 (SNS), suggests that it may play a specialized, pathophysiological role in the sustained, repetitive firing of the peripheral neuron after injury. Moreover, this hypothesis is supported by evidence demonstrating that selective "knock-down" of PN3 protein in the dorsal root ganglion with specific antisense oligodeoxynucleotides prevents hyperalgesia and allodynia caused by either chronic nerve or tissue injury. In contrast, knock-down of NaN/SNS2 protein, a sodium channel that may be a second possible candidate for the tetrodotoxin-resistant current, appears to have no effect on nerve injury-induced behavioral responses. These data suggest that relief from chronic inflammatory or neuropathic pain might be achieved by selective blockade or inhibition of PN3 expression. In light of the restricted distribution of PN3 to sensory neurons, such an approach might offer effective pain relief without a significant side-effect liability.
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PMID:A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. 1039 73

Previous studies have shown that sodium channel alpha-subunit NaN is preferentially expressed in small-diameter sensory neurons of dorsal root ganglia and trigeminal ganglia. These neurons include high-threshold nociceptors that are involved in transduction of pain associated with tissue and nerve injury. In this study, we show that mouse NaN is a 1765-amino-acid peptide that is predicted to produce a current that is resistant to tetrodotoxin (TTX-R). Mouse and rat NaN are 80 and 89% identical at the nucleotide and amino acid levels, respectively. The Scn11a gene encoding this cDNA is organized into 24 exons. Unlike some alpha-subunits, Scn11a does not have an alternative exon 5 in domain I. Introns of the U2 and U12 spliceosome types are present at conserved positions relative to other members of this family. Scn11a is located on mouse chromosome 9, close to the two other TTX-R sodium channel genes, Scn5a and Scn10a. The human gene, SCN11A, was mapped to the conserved linkage group on chromosome 3p21-p24, close to human SCN5A and SCN10A. The colocalization of the three sodium channel genes supports a common lineage of the TTX-R sodium channels.
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PMID:Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN. 1044 32

Following nerve injury, primary sensory neurons (dorsal root ganglion [DRG] neurons, trigeminal neurons) exhibit a variety of electrophysiological abnormalities, including increased baseline sensitivity and/or hyperexcitability, which can lead to abnormal burst activity that underlies pain, but the molecular basis for these changes has not been fully understood. Over the past several years, it has become clear that nearly a dozen distinct sodium channels are encoded by different genes and that at least six of these (including at least three distinct DRG- and trigeminal neuron-specific sodium channels) are expressed in primary sensory neurons. The deployment of different types of sodium channels in different types of DRG neurons endows them with different physiological properties. Dramatic changes in sodium channel expression, including downregulation of the SNS/PN3 and NaN sodium channel genes and upregulation of previously silent type III sodium channel gene, occur in DRG neurons following axonal transection. These changes in sodium channel gene expression are accompanied by a reduction in tetrodotoxin (TTX)-resistant sodium currents and by the emergence of a TTX-sensitive sodium current which recovers from inactivation (reprimes) four times more rapidly than the channels in normal DRG neurons. These changes in sodium channel expression poise DRG neurons to fire spontaneously or at inappropriately high frequencies. Changes in sodium channel gene expression also occur in experimental models of inflammatory pain. These observations indicate that abnormal sodium channel expression can contribute to the molecular pathophysiology of pain. They further suggest that selective blockade of particular subtypes of sodium channels may provide new, pharmacological approaches to treatment of disease involving hyperexcitability of primary sensory neurons.
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PMID:Sodium channels, excitability of primary sensory neurons, and the molecular basis of pain. 1045 12

Lamotrigine, a sodium channel blocker that selectively inhibits the neuronal release of glutamate, has been shown to produce analgesia in acute and chronic pain models in rats without causing noticeable sedation. After oral administration it also reduces pain scores, as assessed by the cold pain test, in volunteers. The purpose of this study was to determine the analgesic effect of lamotrigine given by mouth to healthy volunteers as evidenced by alterations in chemo-somatosensory evoked potentials. The following factors were measured: latency to N1 and P100 peak (ms); amplitude between the N1 and P100 peak (microV); visual analogue pain intensity scores. A double-blind, randomised and crossover design was used in which 12 volunteers received either placebo or lamotrigine 300 mg on separate occasions as determined by the randomisation schedule. Volunteers were tested before and 2 h after the treatment. The plasma lamotrigine concentration was measured immediately after the end of the experimental sessions. Lamotrigine produced a significantly higher latency to P100 values at 2 h postdrug than placebo (p < 0.05) but had no significant effects on the other factors. Although plasma concentrations were similar to those observed in the cold pain test, we conclude that lamotrigine 300 mg by mouth had no analgesic effect in this acute pain model.
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PMID:Effects of lamotrigine on pain-induced chemo-somatosensory evoked potentials. 1046 May 30

Adenosine 5'-triphosphate (ATP) is a purine nucleotide found in every cell of the human body. In addition to its well established role in cellular metabolism, extracellular ATP and its breakdown product adenosine, exert pronounced effects in a variety of biological processes including neurotransmission, muscle contraction, cardiac function, platelet function, vasodilatation and liver glycogen metabolism. These effects are mediated by both P1 and P2 receptors. A cascade of ectonucleotidases plays a role in the effective regulation of these processes and may also have a protective function by keeping extracellular ATP and adenosine levels within physiological limits. In recent years several clinical applications of ATP and adenosine have been reported. In anaesthesia, low dose adenosine reduced neuropathic pain, hyperalgesia and ischaemic pain to a similar degree as morphine or ketamine. Postoperative opioid use was reduced. During surgery, ATP and adenosine have been used to induce hypotension. In patients with haemorrhagic shock, increased survival was observed after ATP treatment. In cardiology, ATP has been shown to be a well tolerated and effective pulmonary vasodilator in patients with pulmonary hypertension. Bolus injections of ATP and adenosine are useful in the diagnosis and treatment of paroxysmal supraventricular tachycardias. Adenosine also allowed highly accurate diagnosis of coronary artery disease. In pulmonology, nucleotides in combination with a sodium channel blocker improved mucociliary clearance from the airways to near normal in patients with cystic fibrosis. In oncology, there are indications that ATP may inhibit weight loss and tumour growth in patients with advanced lung cancer. There are also indications of potentiating effects of cytostatics and protective effects against radiation tissue damage. Further controlled clinical trials are warranted to determine the full beneficial potential of ATP, adenosine and uridine 5'-triphosphate.
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PMID:Adenosine triphosphate: established and potential clinical applications. 1047 17

Although hyperexcitability and/or increased baseline sensitivity of primary sensory neurons following nerve injury can lead to abnormal burst activity associated with pain, the molecular mechanisms that contribute to it are not fully understood. Early studies demonstrated that, following axonal injury, neurons can display changes in excitability suggesting increased sodium channel expression. Consistent with this, abnormal accumulations of sodium channels have been observed at the tips of injured axons. But we now know that nearly a dozen distinct sodium channels are encoded by different genes, raising the question, what types of sodium channels underlie hyperexcitability of primary sensory neurons following injury? My laboratory has used molecular, electrophysiological, and pharmacological techniques to answer this question. Our studies have demonstrated that multiple sodium channels, with distinct physiological properties, are expressed within small dorsal root ganglion (DRG) neurons, which include nociceptive cells. Several DRG and trigeminal neuron-specific sodium channels have now been cloned and sequenced. There is a dramatic change in sodium channel expression in DRG neurons, with down-regulation of the SNS/PN3 and NaN sodium channel genes and up-regulation of previously silent Type III sodium channel gene, following injury to the axons of these cells. These changes in sodium channel gene expression can produce electrophysiological changes in DRG neurons which poise them to fire spontaneously or at inappropriate high frequencies. We have also observed changes in sodium channel gene expression in experimental models of inflammatory pain. The dynamic nature of sodium channel gene expression in DRG neurons, and the changes which occur in sodium channel and sodium current expression in these cells following axonal injury and in inflammatory pain models, suggest that abnormal expression of sodium channels contributes to the molecular pathophysiology of pain.
Pain 1999 Aug
PMID:The molecular pathophysiology of pain: abnormal expression of sodium channel genes and its contributions to hyperexcitability of primary sensory neurons. 1049 82

Previous studies have shown that transection of the sciatic nerve induces dramatic changes in sodium currents of axotomized dorsal root ganglion (DRG) neurons, which are paralleled by significant changes in the levels of transcripts of several sodium channels expressed in these neurons. Sodium currents that are resistant to tetrodotoxin (TTX-R) and the transcripts of two TTX-R sodium channels are significantly attenuated, while a rapidly repriming tetrodotoxin-sensitive (TTX-S) current emerges and the transcripts of alpha-III sodium channel, which produce a TTX-S current when expressed in oocytes, are up-regulated. We report here on changes in sodium currents and sodium channel transcripts in DRG neurons in the chronic constriction injury (CCI) model of neuropathic pain. CCI-induced changes in DRG neurons, 14 days post-surgery, mirror those of axotomy. Transcripts of NaN and SNS, two sensory neuron-specific TTX-R sodium channels, are significantly down-regulated as is the TTX-R sodium current, while transcripts of the TTX-S alpha-III sodium channel and a rapidly repriming TTX-S Na current are up-regulated in small diameter DRG neurons. These changes may provide at least a partial basis for the hyperexcitablity of DRG neurons that contributes to hyperalgesia in this model.
Pain 1999 Dec
PMID:Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain. 1056 68

Tachyphylaxis to local anesthetics is defined as a decrease in duration, segmental spread or intensity of a regional block despite repeated constant dosages. However, there is disagreement about the incidence of tachyphylaxis. In contrast to tachyphylaxis, pseudotachyphylaxis denotes time dependent variations in pain or circadian changes in the duration of local anesthetic action. Tachyphylaxis appears neither to be linked to structural or pharmacological properties of the local anesthetics nor to the technique or mode of their administration. The mechanisms underlying tachyphylaxis are open to debate and include changes in pharmacokinetics or pharmacodynamics. Considering pharmacokinetics, local edema, an increased epidural protein concentration, changes in local anesthetic distribution in the epidural space or a decrease of perineural pH could result in decreased diffusion of the local anesthetics from the epidural space to their binding sites at the sodium channel. Increased clearance of local anesthetics from the epidural space may be caused both by increased epidural blood flow or increased local metabolism. Considering pharmacodynamics, antagonistic effects of nucleotides or increased sodium concentration, increased afferent input from nociceptors or receptor down regulation of the sodium channels have been implicated. However, none of these theoretical considerations is supported strongly enough by data to explain tachyphylaxis. A new possibility to maintain for a longer time neural blockade is the design of new ultralong-acting local anesthetics. Liposomal formulations of local anesthetics also appear suitable to provide longer lasting regional anesthesia. The recent observation that NMDA-antagonists as well as NO-synthase-inhibitors prevent the development of tachyphylaxis suggests involvement of the nitric oxide pathway in the development of tachyphylaxis. Accordingly, NMDA-antagonists or NO-synthase-inhibitors may prevent tachyphylaxis.
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PMID:[Mechanisms of tachyphylaxis in regional anesthesia of long duration]. 1066 8

While sensory loss in leprosy skin is the consequence of invasion by M. leprae of Schwann cells related to unmyelinated fibres, early loss of cutaneous pain sensation, even in the presence of nerve fibres and inflammation, is a hallmark of leprosy, and requires explanation. In normal skin, nerve growth factor (NGF) is produced by basal keratinocytes, and acts via its high affinity receptor (trk A) on nociceptor nerve fibres to increase their sensitivity, particularly in inflammation. We have therefore studied NGF- and trk A-like immunoreactivity in affected skin and mirror-site clinically-unaffected skin from patients with leprosy, and compared these with non-leprosy, control skin, following quantitative sensory testing at each site. Sensory tests were within normal limits in clinically-unaffected leprosy skin, but markedly abnormal in affected skin. Sub-epidermal PGP 9.5- and trk A- positive nerve fibres were reduced only in affected leprosy skin, with fewer fibres contacting keratinocytes. However, NGF-immunoreactivity in basal keratinocytes, and intra-epidermal PGP 9.5-positive nerve fibres, were reduced in both sites compared to non-leprosy controls, as were nerve fibres positive for the sensory neurone specific sodium channel SNS/PN3, which is regulated by NGF, and may mediate inflammation-induced hypersensitivity. Keratinocyte trk A expression (which mediates an autocrine role for NGF) was increased in clinically affected and unaffected skin, suggesting a compensatory mechanism secondary to reduced NGF secretion at both sites. We conclude that decreased NGF- and SNS/PN3-immunoreactivity, and loss of intra-epidermal innervation, may be found without sensory loss on quantitative testing in clinically-unaffected skin in leprosy; this appears to be a sub-clinical change, and may explain the lack of cutaneous pain with inflammation. Sensory loss occurred with reduced sub-epidermal nerve fibres in affected skin, but these still showed trk A-staining, suggesting NGF treatment may restore pain sensation.
Pain 2000 Mar
PMID:Do nerve growth factor-related mechanisms contribute to loss of cutaneous nociception in leprosy? 1069 23


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