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Novel small molecule α9α10 nicotinic receptor antagonist prevents and reverses chemotherapy-evoked neuropathic pain in rats.

Abstract：

BACKGROUND: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). METHODS:In this study, a lead bis-analog, ZZ1-61c, was characterized in a rat model of vincristine-evoked neuropathy. Male Sprague-Dawley rats were repeatedly dosed with the vinca-alkaloid, vincristine (100 μg/kg/day IP, days 1 to 5 and 8 to 12). ZZ1-61c (100 μg/kg/day IP) was given either along with or after completion of vincristine (commencing by day 15 when neuropathy was maximum). Responsiveness was assessed with von Frey hairs and the paw-pressure test. The effects of ZZ1-61c on motor function (rotarod) and muscle strength (grip test) were characterized in naïve rats. RESULTS:The development of neuropathy was demonstrated with repeated dosing of vincristine (pain hypersensitivity in response to mechanical stimulation). ZZ1-61c showed both preventive and restorative effects on this condition: (1) vincristine-evoked sensitivity to pressure was reduced by coadministration of ZZ1-61c; (2) established neuropathy was diminished by ZZ1-61c after cessation of chemotherapy. ZZ1-61c did not cause motor dysfunction (rotarod) or muscular weakness (the grip test). CONCLUSIONS:This study suggests that ZZ1-61c, a novel compound with a unique mechanism of antagonistic action at the α9α10 nAChR, may be a potential drug candidate for prevention and attenuation of neuropathic pain resulting from chemotherapy. Such a strategy may provide effective treatment that circumvents toxicity of centrally acting agonists at nAChR.

journal_name

Anesth Analg

journal_title

Anesthesia and analgesia

authors

Wala EP,Crooks PA,McIntosh JM,Holtman JR Jr

doi

10.1213/ANE.0b013e31825a3c72

subject

Has Abstract

pub_date

2012-09-01 00:00:00

pages

713-20

issue

eissn

0003-2999

issn

1526-7598

pii

ANE.0b013e31825a3c72

journal_volume

115

pub_type

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Novel small molecule α9α10 nicotinic receptor antagonist prevents and reverses chemotherapy-evoked neuropathic pain in rats.