(260) Examining Sex Differences in Analgesic Tolerance to a Peripherally-Restricted Opioid combination

Abstract

The development of analgesic tolerance to opioid pharmacotherapies presents a persistent issue in the treatment of chronic pain, resulting in dose escalation and increased risk for dependence and respiratory depression. Recent studies have demonstrated the involvement of peripheral opioid receptors in the development of opioid tolerance to classical opioids like morphine and oxycodone. There have also been reports of differences in opioid analgesia, tolerance and addiction between males and females. Therefore, we studied whether peripherally-restricted opioid combinations would differentially induce tolerance in a rodent model of neuropathic pain. For these studies, we used loperamide (Lo), a peripherally-restricted mu-opioid agonist, in combination with oxymorphindole or N-benzyl-oxymorphindole (OMI, BOMI), which are partial and full agonists at the delta-opioid receptor, respectively. The Lo-OMI and Lo-BOMI combinations have been shown to synergistically reverse neuropathic pain states in mice and rats. After the induction of a neuropathic pain phenotype with spared nerve injury, male or female mice and rats were given once daily injections of Lo-OMI, Lo-BOMI or morphine for 10 days, and daily mechanical sensitivity was monitored by an electronic von Frey apparatus. Initial experiments indicate that male mice do not develop tolerance to either peripherally-restricted combination, but that female mice rapidly become tolerant to the analgesic effects of Lo-BOMI. Based on these results, we sought to determine whether the same difference persists in rats. We conclude that in female mice—but not males—the delta-opioid receptor component of the mu-delta synergistic combination is involved in the development of analgesic tolerance.