STIMULATION OF OPIOID MU-RECEPTORS POTENTIATES BETA-ADRENOCEPTOR-MEDIATED RELAXATION OF CANINE AIRWAY SMOOTH-MUSCLE

To elucidate the effect of an opioid on airway smooth muscle relaxant responses and its mechanism of action, we studied canine bronchial seg ments under isometric conditions in vitro. Addition of the opioid mu-r eceptor-specific agonist DAMGO (10(-5) M) or Tyr-D-Arg-phe-Lys-NH2 (10 (-6) M) did not alter the resting tension or the contractile responses to Ach but augmented the relaxation induced by isoproterenol: the con centrations of isoproterenol required to produce a half-maximal effect were decreased from 1.9 +/- 0.6 x 10(-8) to 3.1 +/- 1.0 x 10(-7) M (P <.01) by DAMGO and from 2.1 +/- 0.4 x 10(-8) M to 4.3 +/- 0.7 x 10(-7 ) M (P <.01), by Tyr-D-Arg-phe-Lys-NH2. This effect of DAMGO was conce ntration-dependent and was abolished by naloxone or Cys(2),Tyt(3),Om(5 ),Pen(7)-amide, a mu-receptor antagonist. DAMGO likewise caused a left ward displacement of concentration-response curves for forskolin but w as without effect on those for 3-isobutyl-3-methylxanthine and 8-bromo -cAMP. Also, DAMGO did not affect the relaxant responses to verapamil, nitroprusside or 8-bromo-cGMP. Incubation of bronchial smooth muscle with DAMGO (10(-5) M) potentiated the intracellular accumulation of cA MP induced by isoproterenol (10(-6) M) from 258 +/- 22 pmol/g tissue w t. to 420 +/- 27 pmol/g tissue wt. (P <.01), an effect that was abolis hed by naloxone. These results suggest that stimulation of opioid mu-r eceptors specifically augments beta adrenoceptor-mediated bronchodilat ion probably by acting at the site proximal to adenylate cyclase in th e cAMP-dependent pathway.