Coronaridine congeners decrease neuropathic pain in mice and inhibit α9α10 nicotinic acetylcholine receptors and CaV2.2 channels.

Abstract

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 α9α10, α3β4, and α4β2 nAChRs as well as voltage-gated calcium (CaV2.2) channels modulated by G protein-coupled γ-aminobutyric acid type B receptors (GABABRs). The results showed that (±)-18-MC and (+)-catharanthine competitively inhibit α9α10 nAChRs with potencies higher than that at α3β4 and α4β2 nAChRs and directly block CaV2.2 channels without activating GABABRs. Considering the potency of the coronaridine congeners at Cav2.2 channels and α9α10 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 α9α10 nAChRs and/or CaV2.2 channels.

• Authors: Hugo R Arias, Han-Shen Tae, Laura Micheli, Arsalan Yousuf, Carla Ghelardini, David J Adams, Lorenzo Di Cesare Mannelli
• Journal: Neuropharmacology (Neuropharmacology) Vol. 175 Pg. 108194 (09 15 2020) ISSN: 1873-7064 [Electronic] England
• PMID: 32540451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics
• Cav2 protein, mouse
• Caveolin 2
• Receptors, Nicotinic
• Vinca Alkaloids
• Ibogaine
• 18-methoxycoronaridine
• catharanthine

Topics

• Analgesics (administration & dosage)
• Animals
• Caveolin 2 (metabolism)
• HEK293 Cells
• Humans
• Ibogaine (administration & dosage, analogs & derivatives)
• Male
• Membrane Potentials (drug effects)
• Mice
• Neuralgia (metabolism)
• Receptors, Nicotinic (metabolism)
• Vinca Alkaloids (administration & dosage)
• Xenopus laevis