Enhancement of Opioid Analgesia by Positive Allosteric Modulation of the μ-Opioid Receptor in a Rat Model of Chronic Neuropathic Pain

Abstract ID 99807 Poster Board 132 Chronic pain severely impacts the lives of Americans, affecting more that 40% of the U.S. population. Of this group, certain pain conditions like neuropathic pain are inadequately treated by current pharmacotherapies. Opioids are a powerful tool for pain treatment, but adverse effects limit their use. In addition, these drugs show limited efficacy in neuropathic pain. Therefore, development of adjuvants to enhance pain relieving effects of opioids while reducing negative side effects could greatly improve outcomes for these patients. Positive allosteric modulators (PAMs) interact with receptors at a distinct location from the orthosteric binding site to increase the activity and/or affinity of an agonist. Use of PAMs at opioid receptors could increase opioid-mediated analgesia in chronic pain patients and limit unwanted effects. Administration of an opioid PAM (BMS-986122) in the mouse enhances the analgesia of clinically used opioids in acute models of pain. In addition, BMS-986122 administration at doses effective for pain did not enhance opioid-induced constipation, conditioned place preference, nor respiratory depression. These studies, however, were performed in uninjured animals. The opioid PAM has shown efficacy in carrageenan-induced inflammatory pain, as demonstrated by a reversal of tactile hypersensitivity. The utility of BMS-986122 in neuropathic pain, or its efficacy in the rat, is unknown. Our objective is to assess the activity of this PAM alone or in combination with a clinically used opioid on preclinical pain behaviors acutely in mouse and rat, and in a rat model of mononeuropathy. To determine the activity of BMS-986122 in chronic neuropathic pain, male and female Sprague-Dawley rats underwent spared nerve injury (SNI) to induce a nerve-injury induced pain state. After establishment of the chronic neuropathic pain, animals received a pre-treatment of BMS-986122 (10 mg/kg, i.p.) or vehicle, followed by a low dose of methadone (1 mg/kg, i.p.) or saline. Tactile hypersensitivity was determined using von Frey measurements 30 minutes after PAM pre-treatment and 15 minutes after opioid administration. BMS-986122 alone did not reverse SNI-induced tactile hypersensitivity alone, but 10 mg/kg BMS-986122 was able to enhance the reversal of tactile hypersensitivity by 1 mg/kg methadone. Our data suggests opioid PAMs may be effective as opioid adjuvants in chronic neuropathic pain, but future studies remain to be done to fully characterize their activity in this state. Supported by R37 DA039997. Supported by R37 DA039997.