The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat

Background and purpose: Agonists selective for the α7 nicotinic acetylcholine (nACh) receptor 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 recognized as a potential strategy to obtain desired efficacy in the absence of the putative adverse effects associated with agonist activation.

Experimental approach: We compared the anti-hyperalgesic and anti-inflammatory effects of the α7 nACh receptor agonist compound B with the positive allosteric modulator (PAM) PNU-120596 and the standard non-steroidal anti-inflammatory drug (NSAID), diclofenac, in rats with hind paw inflammation induced by either formalin, carrageenan or complete Freund's adjuvant (CFA).

Key results: When administered before carrageenan, both diclofenac (30 mg·kg(-1) ) and PNU-120596 (30 mg·kg(-1) ) significantly reduced mechanical hyperalgesia and weight-bearing deficits for up to 4 h. Compound B (30 mg·kg(-1) ) also attenuated both measures of pain-like behaviour, albeit less robustly. Whereas compound B and PNU-120596 attenuated the carrageenan-induced increase in levels of TNF-α and IL-6 within the hind paw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by carrageenan or CFA was also partially reversed by compound B and PNU-120596. However, diclofenac was considerably more efficacious. Formalin-induced nocifensive behaviours were only reversed by compound B, albeit at doses which disrupted motor performance.

Conclusions and implications: α7 nACh receptor PAMs could prove to be useful in the treatment of inflammatory pain conditions, which respond poorly to NSAIDs or in situations where NSAIDs are contra-indicated.