Coronaridine congeners decrease neuropathic pain in mice and inhibit α9α10 nicotinic acetylcholine receptors and Cav2.2 channels

The primary aim of this study was to determine the anti-neuropathic activity of ( +/- )-18-methoxycoronaridine [( +/- )-18-MC] and ( + )-catharanthine in mice by using the oxaliplatin-induced neuropathic pain paradigm and cold plate test. The results showed that both coronaridine congeners induce anti-neuropathic pain activity at a dose of 72 mg/kg (per os), whereas a lower dose (36 mg/kg) of ( + )-catharanthine decreased the progress of oxaliplatin-induced neuropathic pain. To determine the underlying molecular mechanism, electrophysiological recordings were performed on alpha 9 alpha 10, alpha 3 beta 4, and alpha 4 beta 2 nAChRs as well as voltage-gated calcium (Ca(v)2.2) channels modulated by G protein-coupled gamma-aminobutyric acid type B receptors (GABA(B)Rs). The results showed that ( +/- )-18-MC and ( + )-catharanthine competitively inhibit alpha 9 alpha 10 nAChRs with potencies higher than that at alpha 3 beta 4 and alpha 4 beta 2 nAChRs and directly block Ca(v)2.2 channels without activating GABA(B)Rs. Considering the potency of the coronaridine congeners at Ca(v)2.2 channels and alpha 9 alpha 10 nAChRs, and the calculated brain concentration of ( + )-catharanthine, it is plausible that the observed anti-neuropathic pain effects are mediated by peripheral and central mechanisms involving the inhibition of alpha 9 alpha 10 nAChRs and/or Ca(v)2.2 channels.