Effects of the δ‐Opioid Antagonist Naltrindole on the Antinociceptive and Behaviorally Disruptive Effects of Oxycodone in Squirrel Monkeys

Opioids remain the most commonly prescribed drug class for the management of moderate to severe pain. Often, high doses that are required for effective analgesia have unwanted effects, ranging from tolerance and dependence, to less severe but still debilitating behavioral disruption. Although most opioid analgesics exert both analgesic and adverse effects primarily through μ‐opioid receptors, recent studies also suggest a role for modulatory interactions between μ‐ and δ‐opioid receptors. For example, δ‐agonists have been proposed to enhance the analgesic potency and efficacy of μ‐agonists, and δ‐antagonists to prevent or diminish the development of tolerance induced by μ‐agonists. Based on these observations, the development of new opioid ligands possessing mixed μ/δ–opioid receptor efficacy has emerged as a novel approach to analgesic drug development. Here, we further study the interaction of these two receptor subtypes by determining whether the δ‐opioid antagonist naltrindole modifies the acute effects of oxycodone on tail withdrawal latency and food‐maintained behavior (reinforcement density, response rate) in squirrel monkeys, using an apparatus for concurrently assaying both behavioral measures. Daily sessions comprised four 5‐min response components, each preceded by a long timeout (10‐min) during which cumulative doses of drugs could be administered. During each component, the completion of ten leverpress responses [fixed‐ratio 10 (FR10)] in the presence of stimulus lights initiated food delivery and a 30‐sec short timeout (STO) during which stimulus lights were off and tail withdrawal latency was measured. Results show that naltrindole (1.0 and 3.2 mg/kg) did not significantly alter oxycodone's dose‐effect function for tail withdrawal latency. However, 3.2 mg/kg naltrindole caused a significant rightward shift in the dose‐effect functions for decreases in food‐maintained behavior. ED 50 ratios (i.e., the ratio of ED 50 values for the two measures) were calculated as a preclinical estimate of therapeutic utility. Values >1 suggest antinociceptive effects are present at doses that do not cause significant food‐maintained behavioral disruption. The ED 50 ratios were 1.26 and 3.92 for oxycodone alone and following 3.2 mg/kg naltrindole, respectively. These results support previous findings that δ‐antagonists may reduce the unwanted adverse effects of μ‐opioid agonists at doses that do not heighten the antinociceptive effects of morphine‐like opioids. Additionally, they provide baseline data for studies of repeated exposure to this type of μ/δ–opioid combination on similar or other behavioral endpoints. Support or Funding Information Supported by NIDA Grant DA035857 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .