Open AccessNovel Small Molecule α9α10 Nicotinic Receptor Antagonist Prevents and Reverses Chemotherapy-Evoked Neuropathic Pain in Rats
Author(s) -
Elzbieta P. Wala,
Peter A. Crooks,
J. Michael McIntosh,
Joseph R. Holtman
Publication year - 2012
Publication title -
anesthesia and analgesia/anesthesia and analgesia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.404
H-Index - 201
eISSN - 1526-7598
pISSN - 0003-2999
DOI - 10.1213/ane.0b013e31825a3c72
Subject(s) - medicine , neuropathic pain , peripheral neuropathy , analgesic , pharmacology , nicotinic agonist , anesthesia , methyllycaconitine , nicotinic acetylcholine receptor , receptor , endocrinology , diabetes mellitus
Peripheral neuropathy is a common dose-limiting side effect of chemotherapy. There are no clinically proven analgesics for the treatment of this condition. Drugs from different classes have been tested with mixed results. Identification of novel molecular targets for analgesic(s) is important. Antagonism of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype (absent in brain) is thought to underlie analgesic efficacy of peptide α-conotoxins. We found novel nonpeptide small molecule analogs from a family of tetrakis-, tris-, and bis-azaaromatic quaternary ammonium salts (high potency with selectivity as antagonists at the α9α10 nAChRs) to produce dose-related analgesia in rat models of nerve injury-evoked neuropathy and persistent inflammatory pain. No tests were done in a model of neuropathy induced by drug administration (ie, chemotherapy).