Decreased opioid analgesia in weanling rats exposed to endothelin-1 during infancy

Endothelin-1 produces spontaneous nociceptive-associated behaviors that are modulated by the peripheral opioid system. The present study tests the hypothesis that single or repeated exposure to endothelin-1 during infancy decreases opioid analgesia in weanling rats. Morphine analgesia was measured in male and female postnatal day 21 rats following intraplantar endothelin-1 on postnatal day 7, or 11 or both days 7 and 11. In males, exposure to endothelin-1 on postnatal day 11 or both days 7 and 11 produced a statistically significant decrease in morphine analgesia (EC50 = 0.902 and 1.326 mg/kg, respectively) compared to control (EC50 = 0.486 mg/kg). Similarly in females, exposure to endothelin-1 on postnatal day 11 or both days 7 and 11 produced a statistically significant decrease in morphine analgesia (EC50 = 1.367 and 1.226 mg/kg, respectively) compared to control (EC50 = 0.468 mg/kg). In addition, females exposed to endothelin-1 on postnatal day 7 exhibited an intermediate decrease in morphine analgesia with an EC50 of 0.752 mg/kg. In males, exposure to endothelin-1 decreased mu opioid receptor expression without changing endothelin-A receptor or endothelin-B receptor expression in the hindpaw skin. In contrast, in females, exposure to endothelin-1 increased expression of both endothelin receptors and the mu opioid receptor in hindpaw skin. These findings suggest a sex-difference in the window of vulnerability and the mechanism by which an acute nociceptive event can induce morphine tolerance.