The Kappa Opioid Agonist U-50, 488H Antagonizes Respiratory Effects of Mu Opioid Receptor Agonists in Conscious Rats
WALTER REED ARMY INST OF RESEARCH WASHINGTON DC
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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.