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 alpha9alpha10, alpha3beta4, and alpha4beta2 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 alpha9alpha10 nAChRs with potencies higher than that at alpha3beta4 and alpha4beta2 nAChRs and directly block Ca(V)2.2 channels without activating GABA(B)Rs. Considering the potency of the coronaridine congeners at Cav2.2 channels and alpha9alpha10 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 alpha9alpha10 nAChRs and/or Ca(V)2.2 channels. CI - Copyright (c) 2020 Elsevier Ltd. All rights reserved.