# Sex and Strain Differences in Analgesic and Hyperlocomotor Effects of Morphine and μ‐Opioid Receptor Expression in Mice

## TL;DR

The study finds that different mouse strains and sexes respond differently to morphine, with strain-specific patterns in pain relief and movement effects linked to opioid receptor expression.

## Contribution

The study reveals strain-specific differences in morphine's effects and MOR expression in mice, emphasizing the importance of strain and sex in opioid research.

## Key findings

- C57BL/6 mice showed greater hyperlocomotor activity than CD1 mice after morphine treatment.
- CD1 mice had higher MOR expression in spinal cord and periaqueductal gray, while C57BL/6 mice had elevated MOR in the caudoputamen.
- Morphine increased spinal MOR expression in CD1 mice but not in C57BL/6 mice.

## Abstract

Sex and gender differences in the analgesic efficacy and side effects of opioids have been widely reported, but their underlying neurobiological mechanisms remain poorly understood. Preclinical animal models are essential tools for investigating these differences and providing insights into the neurobiology of opioid effects. Although studies in rats have revealed sex‐specific effects of opioids, the sex‐dependent behavioral profiles of opioids in mice, particularly across strains, remain largely unexplored. In this study, we characterized sex and strain differences in the antinociceptive and hyperlocomotor effects of morphine in the two most widely used mouse strains—CD1 and C57BL/6—and quantified regional expression of the μ‐opioid receptor (MOR) in key brain and spinal cord regions. Both strains exhibited clear, dose‐dependent antinociceptive and hyperlocomotor responses to morphine. While no significant sex or strain differences were observed in antinociceptive effects, C57BL/6 mice displayed significantly greater hyperlocomotor activity than CD1 mice. Western blot analyses revealed strain‐specific MOR expression, with CD1 mice showing higher spinal cord and periaqueductal gray MOR levels, particularly in females, while C57BL/6 mice exhibited elevated MOR expression in the caudoputamen. Morphine treatment increased spinal MOR expression in CD1 mice but not C57BL/6, suggesting strain‐dependent regulation of MOR. These findings highlight strain‐specific behavioral and molecular responses to morphine, emphasizing the importance of strain and sex considerations in preclinical opioid research.

Morphine dose‐dependently increased analgesia in both CD‐1 and C57BL/6 mice, with no observed sex differences. However, C57BL/6 mice of both sexes exhibited greater morphine‐induced locomotor activity compared to CD‐1 mice. These behavioral differences were paralleled by strain‐specific patterns of μ‐opioid receptor (MOR) expression: CD‐1 mice showed elevated MOR levels in the spinal cord and periaqueductal gray, whereas C57BL/6 mice had increased MOR expression in the caudoputamen.