AUTHOR=Luque-Sanchez Kevin , Felix Jasmine , Bilbrey Joshua , Restrepo Luis , Reeves Morgan , McMahon Lance R. , Wilkerson Jenny L. 

TITLE=Evaluation of novel epibatidine analogs in the rat nicotine drug discrimination assay and in the rat chronic constriction injury neuropathic pain model

JOURNAL=Advances in Drug and Alcohol Research

VOLUME=Volume 3 - 2023

YEAR=2023

URL=https://www.frontierspartnerships.org/journals/advances-in-drug-and-alcohol-research/articles/10.3389/adar.2023.11622

DOI=10.3389/adar.2023.11622

ISSN=2674-0001

ABSTRACT=Nicotine is the primary psychoactive component responsible for maintaining tobacco dependence in humans. Chronic pain is often a consequence of tobacco-related pathologies, and the development of a dual therapeutic that could treat chronic pain and tobacco dependence would be advantageous. Epibatidine reliably substitutes for nicotine in the drug discrimination assay, and is a potent analgesic, but has a side-effect profile that limits its therapeutic potential. Thus, considerable efforts are underway to produce derivatives of epibatidine. Here we tested three epibatidine derivatives, 2'fluoro-3'-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102; i.e., RTI-102), 2'fluorodeschloroepibatidine  i.e.,, and 3'-(3″-dimethylaminophenyl)epibatidine (RTI-7527-76; i.e., RTI-76) in both the rat nicotine drug discrimination assay as well as in the rat chronic constriction injury (CCI) of the sciatic nerve neuropathic pain model. Male and female Sprague-Dawley rats were trained on a fixed-ratio 10 schedule to discriminate nicotine (0.32 mg/kg base) from vehicle. All compounds dose-dependently substituted for nicotine, without significant decreases in response rates. The rank-order potency in the discrimination assay was RTI-36 > nicotine > RTI-102 > RTI-76. There is abundant evidence that the α4β2* subtype is of particular importance to the abuse potential of nicotine. Thus, we examined the relative contribution of the β2 subunit with the antagonist dihydro-β-erythroidine (DHβE). DHβE (3.2 mg/kg, s.c.) antagonized the discriminative stimulus effects of nicotine. However, relative to antagonism of nicotine, DHβE produced less antagonism of RTI-102 and RTI-76 and greater antagonism of RTI-36. Thus, it is likely that RTI-102, RTI-36 and RTI-76 possess differing activity at nicotinic receptor subunits. To confirm that the full discriminative stimulus of these compounds was due to nAChR activity beyond the β2 subunit, we examined these compounds in the presence of the non-selective nicotinic receptor antagonist mecamylamine. Mecamylamine (0.56 mg/kg, s.c.) pretreatment abolished nicotine-paired lever responding for all compounds. In a separate cohort, male and female Sprague-Dawley rats underwent CCI surgery and tested for CCI-induced mechanical allodynia via the von Frey assay. Each compound produced CCI-induced mechanical allodynia reversal. RTI-36 displayed higher potency than either RTI-102 or RTI-76. These novel epibatidine analogs may prove to be useful tools in the fight against nicotine dependence as well as novel neuropathic pain analgesics.