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.
Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, 6439 Garner's Ferry Road, Columbia, SC 29208, USA. amckelvy@uscmed.sc.edu
Alvin D
AD
McKelvy
Sarah M
SM
Sweitzer
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D019332:Endothelin-1 / Q000494:pharmacology* / Q000502:physiology; D005260:Female; D006614:Hindlimb; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000096:biosynthesis; D044023:Receptor, Endothelin B / Q000096:biosynthesis; D017450:Receptors, Opioid, mu / Q000096:biosynthesis; D012737:Sex Factors; D012867:Skin / Q000378:metabolism; D013997:Time Factors
D000701:Analgesics, Opioid; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017450:Receptors, Opioid, mu; D009020:Morphine