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.
McKelvy
Alvin D
AD
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
Sweitzer
Sarah M
SM
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