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

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

Journal of Pharmacology and Experimental Therapeutics 264(2): 631-637

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-Ala-2,N-Methyl-Phe-4,Gly-ol) enkephalin (DAMGO; 1.2-10 nmol) and the relatively selective mu agonist morphine (20 and 30 nmol) significantly decreased arterial pH and PO-2, and increased arterial PCO-2 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 norbinaltorphimine. These results indicate that the antagonism of mu opioid respiratory depressant effects by U-50,488H is kappa opioid receptor mediated.

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Accession: 009534135

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PMID: 8382278

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