The kappa opioid agonist U-50,488H antagonizes respiratory effects of mu opioid receptor agonists in conscious rats

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 264; no. 2; pp. 631 - 637
• Main Authors: DOSAKA-AKITA, K, TORTELLA, F. C, HOLADAY, J. W, LONG, J. B
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.02.1993
• Subjects: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics - pharmacology; Animals; Biological and medical sciences; Enkephalin, Ala-MePhe-Gly; Enkephalins - antagonists & inhibitors; Male; Medical sciences; Morphine - antagonists & inhibitors; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Pyrrolidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa - drug effects; Receptors, Opioid, mu - drug effects; Respiration - drug effects; Agonist; Rat; Respiratory disease; Rodentia; Morphine; Opiates; Respiratory system; Opioid peptide; Opiate receptor μ; Opiate receptor κ; Vertebrata; Antagonism; Mammalia; Animal; Intracerebral administration; Drug interaction; Respiratory depression; Respiration; Brain (vertebrata)
• ISSN: 0022-3565; 1521-0103

The interactive effects of mu and kappa opioid receptor agonists on respiratory function were investigated following their i.c.v. injection into conscious rats. The highly selective mu receptor agonist [D-Ala2,N-Methyl-Phe4,Gly-ol] enkephalin (DAMGO; 1.2-10 nmol) and the relatively selective mu agonist morphine (20 and 30 nmol) significantly decreased arterial pH and PO2, and increased arterial PCO2 and blood pressure. Morphine and a low dose of DAMGO (1.2 nmol) also significantly elevated respiratory rate. Heart rate was decreased by DAMGO and, depending upon dose, was either decreased (20 nmol) or increased (30 nmol) by morphine. The selective kappa opioid agonist U-50,488H (200 nmol i.c.v.), which by itself had no significant effect on either respiration or cardiovascular function, dose-dependently antagonized the acidotic, hypoxemic and hypercapnic effects of both DAMGO (2.5 nmol) and morphine (30 nmol). Furthermore, these mu antagonistic properties of U-50,488H were blocked completely after pretreatment with 25 nmol of the highly selective kappa opioid antagonist nor-binaltorphimine. These results indicate that the antagonism of mu opioid respiratory depressant effects by U-50,488H is kappa opioid receptor mediated.