Nonspecific tolerance in ileal circular muscle-myenteric plexus preparations from morphine-pretreated guinea pigs

Guinea pigs were treated for 6 to 8 days by s.c. implantation of pellets, each containing a mixture of morphine base (120 mg) and morphine hydrochloride (35 mg). Each guinea pig received one pellet. Circular muscle-myenteric plexus preparations from the pretreated animals exhibited 6.1-fold tolerance to the inhibitory effects of morphine on nerve-mediated contractions of the circular muscle. Morphine-tolerant tissues were also tolerant to the inhibitory effects of another mu agonist, (D-Ala2-N-Me-Phe4,Gly5- ol)enkephalin (2.7-fold), the selective kappa agonist, dynorphin (4.0-fold), the adrenoceptor agonist, clonidine (22-fold) and the adenosine receptor agonist, 2-chloroadenosine (43-fold). That is, tissues were tolerant to four inhibitory agents that acted via four distinct receptors. Tolerance therefore cannot be explained by a change in the opioid receptor that was occupied chronically by morphine. Nonspecific tolerance would result if an intracellular effector mechanism that was shared by each agonist was altered by morphine pellet implantation. Alternatively, tolerance could be a consequence of the neuronal hyperexcitability that is induced by chronic exposure to morphine. As such, inhibitory agents, irrespective of the receptors or intracellular mechanisms that they activate, may be less effective in reducing the excitability of myenteric neurons and hence less effective in decreasing transmitter release.