Putative pain‐like states alter the discriminative stimulus effects of morphine in mice dependent on sex

Abstract

Sex‐differences in pain sensitivity, opioid analgesia, and reinforcing effects of opioids are observed in rodents. The purpose of our study is to test the hypothesis that the presence of an acute noxious stimulus and/or chemotherapy‐induced chronic neuropathy will reduce the potency of morphine to produce discriminative stimulus effects in mice. Saline and morphine (3.2 mg/kg) were established as discriminative stimuli for food‐reinforced responses using a two‐choice operant training procedure in male and female C57Bl6 mice. After obtaining morphine dose‐response curves, mice were tested with acetic acid (0.4% conc.)+ morphine combinations to determine the effects of noxious stimulus on morphine potency. Next, mice were administered with saline or the chemotherapeutic agent paclitaxel (8 mg/kg) on days 1, 3, 5, and 7 while training was suspended for a week. Morphine dose‐curves were re‐established between days 8–14 post‐paclitaxel treatment (period of peak allodynia). The presence of an acute noxious stimulus and chemotherapy‐induced chronic neuropathy significantly decreased the potency of morphine to function as a discriminative cue in male but not in female mice suggesting a differential modulation of the stimulus effects of morphine in the presence of pain between sexes. Overall, these results may have implications for the understanding of potential sex differences in the clinical management of pain and abuse liability of prescription opioids in humans. (Supported by R01 CA129092).