Articles: hyperalgesia.
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The function of the isolectin B4 (IB4+)-binding and GDNF-dependent Ret (Ret+)-expressing non-peptidergic subpopulation of nociceptors remain poorly understood. We demonstrate that acute administration of GDNF sensitizes nociceptors and produces mechanical hyperalgesia in the rat. Intrathecal IB4-saporin, a selective toxin for IB4+/Ret+-nociceptors, attenuates GDNF but not NGF hyperalgesia. ⋯ Intrathecal administration of antisense oligodeoxynucleotides targeting mRNA for versican, the molecule that renders the Ret-expressing nociceptors IB4-positive (+), also attenuated GDNF but not NGF hyperalgesia, as did ADAMTS-4, a matrix metalloprotease known to degrade versican. Finally, inhibitors for all five signaling pathways known to be activated by GDNF at GFRa1/Ret: PLCc, CDK5, PI3K,MAPK/ERK and Src family kinases, attenuated GDNF hyperalgesia. Our results demonstrate a role of the non-peptidergic nociceptors in pain produced by the neurotrophin GDNF and suggest that the IB4-binding protein versican functions in the expression of this phenotype.
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Randomized Controlled Trial Controlled Clinical Trial
Effects of NGF-induced muscle sensitization on proprioception and nociception.
Temporomandibular disorders (TMDs) are associated with perturbation of proprioceptive and nociceptive function. Recent studies have shown that injection of the neurotrophic protein nerve growth factor (NGF) into the masseter muscle causes sensitization to mechanical pressure stimuli; however, it is not clear if vibration sense and jaw stretch reflexes as measures of proprioceptive function as well as glutamate-evoked pain are also altered. We tested the hypothesis that NGF-induced mechanical sensitization would be associated with changes in vibration sense and stretch reflex sensitivity as well as facilitation of glutamate-evoked pain responses. ⋯ In conclusion, this study confirms that masseter muscle injection of NGF is associated with a distinct and prolonged sensitization to mechanical stimuli, but without an effect on large-diameter mechanoreceptive and the muscle spindle afferents. Additional challenge of the NGF pretreated muscle with glutamate did not indicate a conspicuous sensitization to noxious chemical stimuli. These findings are discussed in terms of the concept of "proprioceptive allodynia".
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Voltage-gated sodium channels play an essential role in regulating the excitability of nociceptive primary afferent neurones. In particular the tetrodotoxin-sensitive (TTX-S) Na(V)1.7 and the tetrodotoxin-resistant (TTX-R) Na(V)1.8 and Na(V)1.9 channels have been suggested to play a role in inflammatory pain. Previous work has revealed acute administration of inflammatory mediators, such as Freund's complete adjuvant (FCA) or carrageenan caused an upregulation in the levels of Na(V)1.7 and Na(V)1.8 protein in DRG (dorsal root ganglia) tissue up to 4 days post-insult. ⋯ The results demonstrate that, following FCA injection, Na(V)1.9 expression is upregulated at days 14, 21 and 28 post-FCA, with Na(V)1.7 and Na(V)1.8 showing increased channel expression at days 14 and 28. These observations are accompanied by a unilateral joint hypersensitivity in the FCA-injected knee indicated by a behavioural shift in weight distribution measured using an incapacitance tester. The increased presence of these channels suggests that Na(V)1.7, Na(V)1.8 and Na(V)1.9 play a role, at least in part, in the maintenance of chronic inflammatory pain several weeks after the initial insult.
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Because of its severity, chronicity, resistance to usual therapy and its consequences on quality of life, neuropathic pain represents a real clinical challenge. Fundamental research on this pathology uses metabolic, pharmacological or traumatic models in rodents that reproduce the characteristic human pain symptoms. In 1996, Mosconi and Kruger morphologically described a model of peripheral neuropathy in which a cuff of polyethylene tubing was placed around the sciatic nerve in rats. ⋯ The analysis of video recordings revealed that most aspects of spontaneous behavior remained unaffected on the long term, excepted for a decrease in the time spent at social interaction for the neuropathic mice. Using the elevated plus-maze and the marble-burying test, we also showed that neuropathic mice develop an anxiety phenotype. Our data indicate that sciatic nerve cuffing in mice is a pertinent model for the study of nociceptive and emotional consequences of sustained neuropathic pain.
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Am. J. Physiol. Regul. Integr. Comp. Physiol. · Jul 2008
Blockade of NGF and trk receptors inhibits increased peripheral mechanical sensitivity accompanying cystitis in rats.
Visceral inflammation, including that arising from bladder inflammation, reduces the threshold to sensation of innocuous or noxious stimuli applied to peripheral structures (referred hyperalgesia). Cystitis may induce transient or persistent plastic changes mediated by neurotrophins, particularly nerve growth factor (NGF), which contribute to increased nociceptive input. In this study, acute or subacute cystitis was induced in female rats by one or three (at 72-h intervals) 400-microl intravesical instillations of 1 mM acrolein. ⋯ Systemic treatment with NGF-neutralizing antiserum before instillation of acrolein suppressed subsequent mechanical referred hyperalgesia. Expression of NGF was increased within the bladder by acute or subacute cystitis and in L6/S1 dorsal root ganglia by subacute cystitis. These results suggest that the bladder-derived NGF acting via trk receptors at least partially mediates peripheral sensitization to mechanical stimuli associated with acute and subacute acrolein-induced cystitis.