SEX-DEPENDENT BEHAVIORAL EFFECTS OF CHRONIC MORPHINE IN A MOUSE MODEL OF NEUROPATHIC PAIN

Neuropathic pain is a disabling condition for which opioid treatment remains clinically common despite concerns regarding tolerance, cognitive impairment, and sex-dependent variability in efficacy. This study aimed to characterize the behavioral effects of prolonged morphine administration in male and female mice subjected to partial sciatic nerve ligation (PSNL). Animals of both sexes received daily intraperitoneal injections of morphine (0.5, 1, or 2 mg/kg) or vehicle for 15 days, and nociceptive, cognitive, and motor outcomes were evaluated.
PSNL induced robust mechanical and thermal hypersensitivity in both sexes, together with impaired recognition memory, confirming a consistent neuropathic phenotype. Chronic morphine treatment produced sustained analgesia across all doses without signs of opioid-induced hyperalgesia, and without sedative-related alterations in locomotor activity or motor coordination. Analgesic efficacy was sex-dependent: females were more sensitive to the 1 mg/kg dose than males, indicating enhanced low-dose opioid responsiveness.
Cognitive performance revealed divergent, dose-dependent outcomes. In males, PSNL-induced deficits in recognition memory were partially reversed by 2 mg/kg morphine, whereas in females, the highest dose abolished the cognitive improvement observed at lower doses, rendering performance comparable to that of untreated PSNL animals. Morphine did not impair locomotion, exploratory behaviour, or motor coordination.
Overall, these findings demonstrate that chronic low-dose morphine maintains analgesic efficacy without motor side effects while producing clear sex-dependent effects on both nociception and cognition. This highlights the need to integrate sex as a key biological variable when evaluating opioid responsiveness and when designing analgesic strategies for neuropathic pain.