4R-Tobacco-Cembranoid is a Positive Allosteric Modulator of the Alpha7 Nicotinic Acetylcholine Receptor that modulates inflammation-induced thermal hypersensitivity in mice

Alpha7 nicotinic acetylcholine receptors (7nAChRs) are activated in response to inflammation and modulate pain in humans and rodent models. The use of 7nAChRs agonists as a therapeutic option for inflammation and pain is challenged by unwanted effects resulting from constant activation and/or desensitization of 7nAChRs. Positive allosteric modulators (PAMs) represent a compelling alternative as they increase endogenous nicotinic transmission but do not result in progressive desensitization or loss of receptor function. In the present study, we evaluated the function of the 4R tobacco cembranoid (4R) as a PAM of 7nAChR that reduces inflammation and pain-related behaviors in mouse models of inflammatory pain. Our electrophysiological experiments show that 4R potentiates choline-evoked currents in SH-SY5Y cells overexpressing 7nAChRs in a dose-dependent manner. At the behavioral level, we show that subcutaneous administration of 4R decreases inflammation-induced thermal but not tactile hypersensitivity or formalin-induced spontaneous nociceptive responses in both male and female mice. We further show reduced inflammation-induced paw edema in 4R-treated males, with no measurable effect observed in female mice. Altogether, the results from the experiments in this study identify 4R as a PAM of 7nAChRs that reduces thermal hypersensitivity in male and female mice and inflammation in a sex-specific manner. These findings highlight the use of 4R as a potential novel treatment strategy for pain and inflammation.