Decreased response to GABA-B agonists in longitudinal smooth muscle-myenteric plexus preparations from morphine-tolerant guinea-pigs

Summaryo1)Responsiveness of guinea-pig ileal longitudinal smooth muscie-myenteric plexus preparations to drugs activating GABA-B receptors was studied in morphine-tolerant animals. For this purpose morphine pellets (75 mg each) were implanted subcutaneously in guinea-pigs and experiments were performed three days later in electrically-stimulated ileal strips.2)Activation of GABA-B receptors with GABA (10^-6-10^-3 M) or (-)-baclofen (10^-6-10^-3 M) caused a dose-related inhibition of twitch response that was about 80% lower in preparations from morphine-tolerant animals than in controls. This was found both in preparations maintained in the presence of morphine (10^-6 M) and in morphine-free Krebs. The effect was evident also in ileal preparations from morphine-tolerant animals in which a withdrawal syndrome was induced by the administration of naloxone before sacrifice.3)The phenomenon was specific since the dose-response curve of the adenosine-inhibitory effect was comparable in preparations from tolerant animals and controls.4)The hyporesponsiveness to GABA-B receptor activation began 12 h after pellet implantation and was maximal on the third day.5)It is concluded that during tolerance to and withdrawal from morphine there is a hyporesponsiveness of GABA-B receptors in "in vitro" guinea-pig ileal longitudinal muscle-myenteric plexus preparations.