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 non-peptide 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 (i.e., 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 1–5 and 8–12). 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 co-administration of ZZ1-61c; 2) established neuropathy was diminished by ZZ1-61c after cessation of chemotherapy. ZZ-1-61c 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 which circumvents toxicity of centrally acting agonists at nAChR.

Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist

“…The 4.6 nM IC 50 of GeXIVA [1,2] places it among the most potent peptides that target α9α10 nAChRs; the IC 50 s (nanomolar) for α-conotoxins Vc1.1, RgIA, and PeIA are 19, 5.2, and 6.9, respectively (43,46). Small-molecule antagonists of α9α10 nAChRs (which have IC 50 s as low as 0.51 nM) are also analgesic in rodent models of neuropathic pain (47)(48)(49), further validating α9α10 nAChR as an important therapeutic target. Each of these tested α9α10 antagonists produces long-lasting analgesia after single injection.…”

Nicotinic acetylcholine receptors in neuropathic and inflammatory pain

“…Compounds that target a9-containing nAChRs, mechanism of action, and therapeutic effects in models of pain and inflammation. [167] potential roles of a7and a9-containing nAChRs in native systems.…”

RgIA4 Potently Blocks Mouse α9α10 nAChRs and Provides Long Lasting Protection against Oxaliplatin-Induced Cold Allodynia

“…Interestingly, rather than CNS targeted agonists, peripherally acting α9α10 antagonists have shown promise (Vincler et al, 2006; Holtman et al, 2011; Zheng et al, 2011; Wala et al, 2012; Luo et al, 2015). …”