REWARD-RELATED BEHAVIORAL EFFECTS OF PRESCRIPTION OPIOIDS AS A FUNCTION OF PUTATIVE ACUTE AND CHRONIC PAIN-LIKE STATES IN MALE AND FEMALE C57BL/6 MICE

Abstract

Pain is a leading cause of disability and the most common reason for clinical care. The field of pain research has focused on sex differences in the recent years with an expansive body of literature demonstrating sex-related differences in pain behavior and responsiveness to pharmacological interventions. Prescription opioids are potent analgesics and the mainstay for the clinical management of moderate-to-severe acute and chronic pain conditions. However, the long-term clinical use of prescription opioids for chronic pain remains controversial due to concerns about severe adverse effects, including tolerance, dependence, and addiction associated with opioid use. The non-medical use and abuse of prescription opioids has become a public health crisis, the problem even arising in a subset of chronic pain patients receiving opioid therapy. The vulnerability factors, specifically the role of pain in the propensity to prescription opioid abuse, are poorly understood. The present research project sought to investigate the propensity to opioid reward as a function of pain in male and female mice by incorporating acute (acetic acid-induced) visceral nociceptive and chronic chemotherapy (paclitaxel)-induced peripheral neuropathic pain models. Sexually dimorphic variations in the sensitivities of mice to nociceptive and allodynic behaviors were initially assessed using the two putative pain models. Following that, the two prescription opioids, morphine and oxycodone were examined under both pain contexts and the capacity of the two prescription opioids to produce reward-related behavioral effects were measured using drug discrimination, conditioned place preference, and intravenous drug self-administration procedures. The presence of acute noxious state but not chronic pain selectively attenuated the discriminative stimulus effects of the prescription opioid, morphine in male mice. The magnitude of modulation of the stimulus effects of opioids by the acute noxious state were further observed to be inversely related to the relative intrinsic antinociceptive effectiveness of the two opioids in reversing the acute noxious state and sex-specific sensitivities of mice to opioid-induced antinociception. In contrast, while no change was observed in opioid-reward as a function of the acute noxious state in both sexes, the presence of paclitaxel-induced chronic pain opioid-selectively and dose-selectively enhanced the conditioned rewarding effect of morphine (0.3 mg/kg dose), and the effect was more pronounced in male relative to female mice. These data were further supported by the self-administration results, in that the reinforcing efficacy (breakpoints under progressive ratio (PR) responding) and the incentive-motivational salience of morphine significantly increased in the presence of chronic pain in male mice, while non-selectively increasing regardless of the presence/absence of pain in female mice. Overall, the converging empirical evidence presented here suggest that these models provide preclinical tools to further understand the overlapping neurobiology of pain and opioid abuse, the behavioral effects of prescription opioids, and advance the development of novel sex-specific pain therapeutics with low addiction liability.