Differential modulation by [D-Pen², D-Pen⁵]enkephalin and dynorphin A-(1-17) of the inhibitory bladder motility effects of selected Mu agonists in vivo

The possibility that the delta agonist, [D-Pen², D-Pen⁵]enkephalin (DPDPE) and the putative endogenous kappa agonist, dynorphin A-(1-17) could differentially modulate the effects of a group of chemically diverse mu agonists was evaluated using inhibition of volume-induced contractions of the rat urinary bladder as a model of central nervous system opioid receptor function in vivo. Intracerebroventricular administration of equieffective doses of the mu agonists [D-Ala², NMPhe⁴, Gly-ol]enkephalin (DAMGO), [N-MePhe³, D-Pro⁴]enkephalin (PL017), morphine, normorphine, sufentanil, etorphine, phenazocine, meperidine and methadone inhibited spontaneous bladder contractions for approximately 20 to 30 min. Low doses of DPDPE or dynorphin A-(1-17) failed to affect spontaneous bladder contractions; higher doses of DPDPE (greater than 15.5 nmol) and dynorphin A-(1-17) (i.e, greater than 3.7 nmol), inhibited bladder contractions. When coadministered i.c.v. DPDPE displaced the morphine dose-response line to the left and also potentiated the effects of normorphine and etorphine. In contrast, DPDPE failed to alter the actions of equieffective doses of DAGO, PL017, meperidine, methadone, phenazocine or sufentanil. The potentiation of the effects of morphine by DPDPE were prevented by i.c.v. coadministration of the delta antagonist, ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH); at the dose tested, the delta antagonist had no agonist effects alone and did not antagonize the effects of morphine directly. Furthermore, the agonist effects of morphine were potentiated by several different doses of DPDPE. Administration of i.c.v. dynorphin A-(1-17) produced a rightward displacement of the morphine dose-response line and also antagonized the effects of normorphine. Dynorphin A-(1-17) did not alter the actions of equieffective doses of DAMGO, PL017, sufentanil, meperidine, phenazocine or methadone. The antagonism of morphine effects by dynorphin A-(1-17) was prevented by coadministration of the kappa antagonist, nor-binaltorphimine. This antagonist did not directly antagonize the agonist effects of morphine at the dose tested. Furthermore, different doses of dynorphin A-(1-17) were effective in antagonizing morphine effects. Thus, the modulatory profiles of a variety of mu agonists by either DPDPE or dynorphin A-(1-17) were very similar, with the only observed exception being modulation of etorphine. The modulation of some mu agonists by actions at either delta or kappa receptors demonstrate differences between morphine, normorphine and the other mu agonists tested. These results appear to support the concept of mu receptor subtypes in vivo, as well as the hypothesis of functionally coupled opioid receptors.