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 (EC(50)=0.902 and 1.326mg/kg, respectively) compared to control (EC(50)=0.486mg/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 (EC(50)=1.367 and 1.226mg/kg, respectively) compared to control (EC(50)=0.468mg/kg). In addition, females exposed to endothelin-1 on postnatal day 7 exhibited an intermediate decrease in morphine analgesia with an EC(50) of 0.752mg/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.