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

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Neuropathic pain is a debilitating condition with limited treatment options.
• Coronaridine congeners, such as (±)-18-methoxycoronaridine [(±)-18-MC] and (+)-catharanthine, are being investigated for their therapeutic potential.

Purpose of the Study:

• To evaluate the anti-neuropathic activity of (±)-18-MC and (+)-catharanthine.
• To elucidate the molecular mechanisms underlying their effects on neuropathic pain.

Main Methods:

• Oxaliplatin-induced neuropathic pain model and cold plate test in mice.
• Electrophysiological recordings of α9α10, α3β4, and α4β2 nicotinic acetylcholine receptors (nAChRs) and Ca_V2.2 channels.
• Assessment of G protein-coupled γ-aminobutyric acid type B receptors (GABA_BRs) modulation.

Main Results:

• Both (±)-18-MC and (+)-catharanthine demonstrated anti-neuropathic pain activity at 72 mg/kg.
• (+)-Catharanthine at 36 mg/kg reduced the progression of neuropathic pain.
• (±)-18-MC and (+)-catharanthine competitively inhibited α9α10 nAChRs and directly blocked Ca_V2.2 channels without activating GABA_BRs.

Conclusions:

• The anti-neuropathic effects of (±)-18-MC and (+)-catharanthine are likely mediated by the inhibition of α9α10 nAChRs and/or Ca_V2.2 channels.
• These findings suggest a potential therapeutic role for these coronaridine congeners in managing neuropathic pain through peripheral and central mechanisms.