The dorsal raphé nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses
List of nonstandard abbreviations: Nicotinic acetylcholine receptor nAChR Serotonin 5-HT Artificial Cerebrospinal Fluid ACSF Area Under the curve AUC Periaqueductal gray PAG Dorsal Raphe DR Recommended section: Neuropharmacology This article has not been copyedited and formatted. The final version may differ from this version. ABSTRACT The mechanisms and sites of action of epibatidine-induced antinociception and side effects are poorly understood. The present study tested the hypothesis that the serotonergic dorsal raphe nucleus is a site of action of epibatidine. Behavioral responses of rats to hindpaw formalin injection were compared after direct administration of epibatidine into the dorsal raphe, and after subcutaneous administration. Different groups of rats were injected with formalin into the rear paw after administration of either epibatidine (0.01-0.015-0.03-0.06 µg) in the dorsal raphe or epibatidine (2.5-5 µg/kg) subcutaneously. Assessment of pain related behavior was done evaluating the incidence of favoring, lifting and licking of the injected paw in the different groups. Abnormal behavior (freezing) was also recorded. Epibatidine was at least 100 times more potent when administered into the dorsal raphe nucleus vs. systemically, implicating this nucleus as a site of action of the analgesic effects of epibatidine. Thus, epibatidine (0.015-0.03-0.06 µg) in the dorsal raphe resulted in a significant lower pain score in the second phase of the formalin test compared to control rats and was as effective as subcutaneous epibatidine. The analgesic effects of epibatidine were regionally selective in that administration of epibatidine within the PAG but outside the dorsal raphe area was not analgesic. The highest doses of intra-raphe epibatidine (i.e., 0.03-0.06 µg) also produced " freezing " behavior immediately after injection, which was relatively short-lived compared to the analgesic effect. Together the results implicate the dorsal raphe nucleus as a target for the analgesic and perhaps anxiogenic effects of epibatidine. This article has not been copyedited and formatted. The final version may differ from this version.