Chronic naloxone-induced supersensitivity affects neither tolerance to nor physical dependence on morphine at hypothalamus-pituitary-adrenocortical axis.
This study reports the endocrine effects of chronic mu-blockade induced by naloxone on morphine tolerance and withdrawal at hypothalamus-pituitary-adrenocortical (HPA) axis level. Naloxone (0.5 mg/kg/h) or vehicle (1 microliter/h) were infused s.c. to Sprague-Dawley rats via osmotic minipumps for 7 days, concomitantly with morphine or placebo pellets for 7-8 days. In opiate-naive rats, the mu-preferring opioid agonist morphine (30 mg/kg) increased plasma corticosterone in a partial but significant naloxone-reversible manner. In vehicle-perfused rats, chronic morphine treatment produced tolerance to its neuroendocrine effect, while the development of morphine tolerance was antagonized in the naloxone-treated group. An enhancement of plasma corticosterone levels after acute morphine (30 mg/kg) occurred 24 h after removal of chronic naloxone treatment in vehicle-perfused rats, as a functional index of supersensitivity to the neuroendocrine effects of the mu agonist. By contrast, 24 h after naloxone removal, rats implanted with morphine pellets were significantly less sensitive to acute morphine (tolerance) than its control-placebo group. Substantial elevation of plasma corticosterone, accompanied by motor and behavioural signs, was observed after acute naloxone injection (1 mg/kg) to tolerant rats 24 h after naloxone-pumps removal, which indicates withdrawal. No endocrine, motor or behavioural signs appeared in the naloxone group with pumps in place. These results indicated that morphine desensitizes mu-opioid receptors that were probably upregulated by chronic naloxone in presence of chronic agonist administration, and suggest that opioid tolerance/dependence as well as opioid supersensitivity simultaneously and independently can occur at mu-opioid receptors mediating HPA function.
Alcaraz
C
C
Department of Physiology & Pharmacology, University School of Medicine, Murcia, Spain.
Vargas
M L
ML
Milanés
M V
MV
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004361:Drug Tolerance; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000503:physiopathology*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000517:prevention & control; D015854:Up-Regulation / Q000187:drug effects
D009292:Narcotic Antagonists; D009294:Narcotics; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; D003345:Corticosterone