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The ?7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-12596 both alleviate inflammatory hyperalgesia and cytokine release in the rat


, : The ?7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-12596 both alleviate inflammatory hyperalgesia and cytokine release in the rat.

Agonists selective for the ?7 nicotinic acetylcholine receptor (nAChR) produce anti-hyperalgesic effects in rodent models of inflammatory pain, via direct actions on spinal pain circuits and possibly via attenuated release of peripheral pro-inflammatory mediators. Increasingly, allosteric modulation of ligand-gated receptors is recognised as a potential strategy to obtain desired efficacy in the absence of putative adverse effects associated with agonist activation. Experimental approach: We have compared the anti-hyperalgesic and anti-inflammatory effects of the ?7 nAChR agonist compound B with the positive allosteric modulator (PAM) PNU-12596 and the standard NSAID, diclofenac, in rats with hindpaw inflammation induced by either formalin, carrageenan or complete Freund's adjuvant (CFA).Key results: When administered prior to carrageenan, both diclofenac (3 mgkg-1) and PNU-12596 (3 mgkg-1) significantly blunted mechanical hyperalgesia and weight bearing deficits for up to 4 h. Compound B (3 mgkg-1) also attenuated both measures of pain-like behaviour, albeit less robustly. Whereas compound B and PNU-12596 attenuated the carrageenan-induced increase in levels of TNF-? and IL-6 within the hindpaw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by carrageenan or CFA was also partially reversed by compound B and PNU-12596. However, diclofenac was considerably more efficacious. Formalin-induced nocifensive behaviours were only reversed by compound B, albeit at doses which disrupted motor performance. and implications: ?7 nAChR PAMs could prove to be useful in the treatment of inflammatory pain conditions which respond poorly to NSAIDs or in situations when NSAIDs are contraindicated.

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DOI: 10.1111/j.1476-5381.2012.02003.x


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