The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-alpha represents a new antinociceptive signaling pathway in mice

Recently, alpha 7 nicotinic acetylcholine receptors (nAChRs), primarily activated by binding of orthosteric agonists, represent a target for anti-inflammatory and analgesic drug development. These receptors may also be modulated by positive allosteric modulators (PAMs), ago-allosteric ligands (ago-PAMs), and alpha 7-silent agonists. Activation of 00 nAChRs has been reported to increase the brain levels of endogenous ligands for nuclear peroxisome proliferator-activated receptors type-alpha (PPAR-alpha), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in a Ca2+-dependent manner. Here, we investigated potential crosstalk between alpha 7 nAChR and PPAR-alpha, using the formalin test, a mouse model of tonic pain. Using pharmacological and genetic approaches, we found that PNU282987, a full alpha 7 agonist, attenuated formalin-induced nociceptive behavior in alpha 7 -dependent manner. Interestingly, the selective PPAR-alpha antagonist GW6471 blocked the antinociceptive effects of PNU282987, but did not alter the antinociceptive responses evoked by the alpha 7 nAChR PAM PNU120596, ago-PAM GAT107, and silent agonist NS6740. Moreover, GW6471 administered systemically or spinally, but not via the intraplantar surface of the formalin-injected paw blocked PNU282987-induced antinociception. Conversely, exogenous administration of the naturally occurring PPAR-alpha agonist PEA potentiated the antinociceptive effects of PNU282987. In contrast, the cannabinoid 031 antagonist rimonabant and the CB2 antagonist SR144528 failed to reverse the antinociceptive effects of PNU282987. These findings suggest that PPAR-alpha plays a key role in a putative antinociceptive alpha 7 nicotinic signaling pathway. United States Department of Health & Human Services National Institutes of Health (NIH) - USA - GM57481 - R01 CA206028 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) - R01CA206028 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) - R01GM057481 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission - T32DA007027