E. Tagaya et al., STIMULATION OF OPIOID MU-RECEPTORS POTENTIATES BETA-ADRENOCEPTOR-MEDIATED RELAXATION OF CANINE AIRWAY SMOOTH-MUSCLE, The Journal of pharmacology and experimental therapeutics, 275(3), 1995, pp. 1288-1292
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.