Acute noxious stimulus differentially alters morphine‐induced operant behavior in male and female mice

Abstract

Fewer studies measure pain‐depressed relative to stimulus‐evoked behaviors in preclinical rodent pain models and even fewer studies use both male and female mice. The purpose of the present study is to test the hypothesis that the presence of an acute noxious stimulus will decrease food‐maintained operant behavior and reduce the potency of morphine to produce discriminative stimulus effects. Firstly, mice were trained to respond on a fixed ratio schedule to 50% ensure solution. In this assay, acetic acid (0.2–0.4%) produced concentration‐dependent suppression of responding in mice that was dose‐dependently prevented by morphine (0.32–3.2 mg/kg). Subsequently, male and female C67Bl/6 mice were trained in a two choice operant procedure to discriminate 3.2 mg/kg morphine or saline following which the dose response curves were generated in the absence and presence of 0.4% acetic acid. Morphine produced dose‐dependent drug‐appropriate responding in both male and female mice with no observed potency differences. However, male mice were significantly less sensitive to morphine and acetic acid‐induced effects on operant response rates. Importantly, the presence of acute noxious stimulus failed to alter the discriminative effects of morphine in female mice but significantly attenuated in male mice. In summary, pain‐depressed operant behavior and morphine‐induced discriminative effects may be differentially modulated in male and female mice suggesting the importance of sex differences in the clinical effectiveness of opioids and the abuse liability of morphine in the presence of pain. (Supported by CA129092)