Cancer pain: palliative care: Analgesic effect of the neuronal nicotinic receptor agonist, ABT-594, in a rat chemotherapy-induced neuropathic pain model

Abstract

ABT-594 represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic receptors (NNRs). In addition to its positive effects in rat models of acute and persistent pain, ABT-594 has been shown to be analgesic in the rat spinal nerve ligation model of neuropathic pain. The present study characterized the effects of ABT-594 in a rat model of chemotherapy-induced neuropathic pain in which male Sprague-Dawley rats were surgically implanted with 14-day mini-osmotic pumps set to deliver 30 μg kg-1 day-1 vincristine, i.v. ABT-594 was determined to attenuate mechanical allodynia with an ED50 = 40 nmol/kg, i.p.: therefore, it was approximately one half-log unit more potent in the current model than in the spinal nerve ligation model. The analgesic effect of ABT-594 in the vincristine model was completely blocked by systemic administration of mecamylamine (a non-selective NNR antagonist; 5 μmol/kg, i.p.) and by central administration of chlorisondamine (a non-selective NNR antagonist that does not readily cross the blood brain barrier; 10 μg, i.c.v.), but not at all by systemic administration of chlorisondamine (0.5 μmol/kg, i.p.) nor naloxone (a non-selective opiate receptor antagonist; 25 μmol/kg, i.p.). In summary, the NNR agonist, ABT-594, was demonstrated to attenuate mechanical allodynia in a rat chemotherapy-induced neuropathic pain model via a centrally-mediated, NNR-(and non-opioid-)related mechanism of action. The data are in accordance with previous findings on the effects an NNR agonist (A-85380) on thermal acute pain in rats; however, they are in contrast to A-85380's effects on mechanical allodynia in spinal nerve ligation rats, where it was found to have both centrally- and peripheral-mediated, NNR-related mechanisms of actions. The support of Abbott Laboratories for this project is gratefully acknowledged.