Pharmacodynamic supersensitivity and opioid receptor upregulation in the mouse.
The analgesic potency and toxicity (lethality) of morphine were increased 2.5 times after implantation of 7.5-mg s.c. naltrexone pellets in the mouse for 8 days. Implantation for 8 days also resulted in a 41% [3H][D-Ala2-D-Leu5]enkephalin and 55% [3H] [D-Ala2-MePhe4-Gly(ol)5]enkephalin increase in radiolabeled opioid binding in mouse brain relative to placebo-implanted controls. Treatment for 1 day did not produce any significant increases in binding or morphine's analgesic potency. Brain morphine concentrations did not differ after a dose of morphine (8 mg/kg) that produced analgesia in 86% of 8-day naltrexone-treated mice vs. 39% of placebo-treated mice. The increase in the analgesic potency of morphine by chronic naltrexone treatment in the mouse is particularly striking as it is approximately 3 times greater than that observed for the rat. The decrease in the LD50 of morphine after 8 days of naltrexone treatment raises the possibility that the toxicity of opiates may be increased in patients who discontinue naltrexone maintenance treatment and resume opiate abuse.
D000818:Animals; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000494:pharmacology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009020:Morphine / Q000378:metabolism* / Q000633:toxicity; D009271:Naltrexone / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000378:metabolism*; D013997:Time Factors
D004745:Enkephalins; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine