Acute Submaximal Running Potentiates the Straub Tail Response to Meperidine in a Dose- and Sex-Dependent Manner in Mice

Abstract

Physical exercise recruits endogenous opioid mechanisms in the central nervous system, but whether this physiological opioid tone potentiates the effects of exogenous μ-agonists, and whether such interactions differ between sexes, remains unknown. Here, we used the Straub tail response as a behavioral index of central μ₂-opioid receptor activity to investigate whether acute submaximal running modulates the pharmacodynamic effects of meperidine in male and female Swiss mice. In resting animals, meperidine produced a dose- and time-dependent Straub tail response across a 12-fold dose range, and the submaximal doses of 8 and 12 mg/kg were selected for treadmill experiments. Running at approximately 70% of V̇O₂ max potentiated the Straub tail response at 12 mg/kg in both sexes, with the effect substantially larger in females, as indicated by a significant Sex × Exercise interaction. Thermal antinociception was equivalent between sexes at 12 mg/kg, indicating that the dimorphism was specific to the exercise-opioid interaction rather than to baseline drug sensitivity. A separate experiment testing whether running alone elicits a naloxone-sensitive response was inconclusive in both sexes; under opioid receptor blockade, however, females maintained higher running-induced scores than males, indicating that the sex difference persists during naloxone treatment. These findings indicate that acute submaximal running potentiates the Straub tail response to meperidine in a dose- and sex-dependent manner. The sexually dimorphic nature of this interaction suggests that biological sex and exercise intensity may jointly modulate opioid pharmacodynamics during physical activity.