Early neonatal experience of Long-Evans rats results in long-lasting changes in morphine tolerance and dependence

Rationale: Daily, 3-h separations from the dam on postnatal days 2-14 produce long-lasting changes in behavioral and neuroendocrine responses to stressors and sensitivity to acute morphine in Long-Evans rats. Objective: We tested whether offspring that were separated from their dam for 3 h daily (MS) on postnatal days 2-14 exhibit altered sensitivity to chronic morphine, compared to animals that experienced only brief (15 min) separations (H) from the dam or that were left undisturbed (NH) during the same period. Methods: Subjects received I week SC infusion of either morphine, or saline via osmotic pumps. Twenty-hours after pump removal, the global opioid withdrawal scores were recorded. Four hours later, animals were tested for antinociception (tail-flick and hot-plate tests) during cumulative morphine administration. Results: MS males and MS females undergoing withdrawal from chronic morphine had higher global withdrawal scores compared to NH controls. MS males (but not MS females) were less sensitive to the antinociceptive effects of morphine compared to H and NH controls, primarily in the hot-plate test, regardless of whether they had received a saline or a morphine infusion. MS males consistently exhibited significant morphine tolerance, whereas control males failed to exhibit tolerance either in the hot-plate test (NH group) or in both antinociception assays (H group). In contrast, tolerance was exhibited by all females in both tests for antinociception. Conclusions: These data indicate that repeated neonatal maternal separation alters sensitivity to chronic morphine administration in a sex-dependent manner.