Receptor Mechanisms in Nicotinic Enhancement of Opioid Antinociception

Abstract

The use of prescription opioids for pain management can be limited by their adverse behavioral effects, which usually are not measured in the initial preclinical assessment of established or novel candidate analgesics. Recently, we have developed a protocol for concurrently assessing the antinociceptive effects of drugs (an indicator of analgesic promise) and their ability to decrease rates of operant behavior (an indicator of unwanted behavioral effects). Under these procedures, nicotine has been shown to augment the antinociceptive, but not the rate‐decreasing, effects of opioid analgesics with an inverse relationship to efficacy at the m‐opioid receptor‐ e.g., nicotine‐induced enhancement of nalbuphine>oxycodone>fentanyl. The present study was designed to further elucidate nicotinic‐opioid interactions by exploring the role of nicotinic receptor efficacy in the nicotinic augmentation of opioid antinociception. Male squirrel monkeys (n=4) lever‐pressed under a fixed ratio (FR) 10 schedule of 20% (v/v) condensed milk reinforcement. A 30‐s timeout (TO) period followed either the completion of the FR 10 or the elapse of 20‐s (limited hold (LH) 20). During the 30‐s TO, the distal portion of the monkey’s tail was immersed in 35, 50, 52, or 55°C water, and the latency to remove the tail was recorded. Dose response functions for tail‐withdrawal latency and decreases in response rate were generated for the high efficacy m‐opioid agonist fentanyl and the low efficacy m‐agonist nalbuphine alone and in the presence of nicotinic agonists reported to have high or intermediate efficacy‐‐epibatidine (0.00056 mg/kg) or varenicline (0.032 mg/kg), respectively. Fentanyl dose‐dependently increased tail‐withdrawal latencies at all water temperatures and, concomitantly, decreased rates of responding. Nalbuphine did not significantly decrease response rate, and increased tail‐withdrawal latencies at 50 and 52°C, but not at 55°C. Neither epibatidine nor varenicline significantly modified the rate decreasing effects of any of the opioids or the antinociceptive effects of fentanyl. However, the antinociceptive potency of nalbuphine was markedly enhanced by epibatidine (up to ~70‐fold) and only slightly increased by varenicline. The present results add to previous findings with nicotine, showing that nicotinic enhancement of opioid antinociception is inversely related to m‐opioid efficacy. They also extend those findings to suggest that such adjuvant effects are more robustly produced by nicotinic full agonists (nicotine, epibatidine) than a partial agonist (varenicline). In conjunction with previous reports, these findings support the idea that nicotinic agonists may be clinically useful as adjuvants for opioid analgesia.Support or Funding InformationDA035857 and Harvard Medical School Livingston Fellowship