The development and reversal of the tolerance to morphine in the longitudinal smooth muscle-myenteric plexus preparation of the guinea pig.

Chronic treatment with morphine results in a reduction in the potency of morphine in the longitudinal smooth muscle-myenteric plexus of the guinea-pig ileum. Implantation of morphine pellets leads to the development of tolerance to the inhibitory effects of morphine upon neurogenic contractions of this preparation. Tolerance develops within 24 hours, peaks between days 4 and 7 and disappears by day 14. A similar time course for the development of tolerance to the inhibitory effects of 2-chloroadenosine is also seen in these same morphine-tolerant preparations. The rate of reversal of morphine tolerance was assessed after the removal of the morphine pellets four days after implantation. In this situation, tolerance to the effects of morphine were maintained for at least 24 hours, were partially reversed at day 2 and were totally reversed by day 4. The delay in the development and reversal of the effect are consistent with the fact that chronic treatment with morphine evokes an adaptive sensitivity change.

Morphine tolerance and nonspecific subsensitivity of the longitudinal muscle myenteric plexus preparation of the guinea-pig to inhibitory agonists.

1. The sensitivity of the longitudinal smooth muscle/myenteric plexus (LM/MP) to agonists which reduce the amplitude of neurogenic contractions was studied in preparations obtained from animals implanted with either placebo or morphine (75 mg/pellet) pellets 7 days prior. 2. Tolerance or subsensitivity to morphine was observed following chronic treatment with morphine and was revealed as a rightward shift of the concentration-response curve to morphine. The degree of tolerance decayed modestly with time after removal from a morphine containing environment suggesting a time dependence for the loss of subsensitivity to morphine. 3. LM/MP preparations from animals pretreated with morphine also developed subsensitivity to the inhibitory effects of the purine analogue, 2-chloroadenosine. Subsensitivity to 2-chloroadenosine was seen as a parallel rightward shift of the concentration-response curve in morphine-tolerant preparations. The magnitude of the loss in sensitivity was comparable to that observed to morphine. 4. A reduction in sensitivity of the LM/MP following chronic treatment with morphine was also observed to the inhibitory effects of the alpha2 adrenoceptor agonists, clonidine and xylazine. In contrast to the results obtained with morphine and 2-chloroadenosine, the development of subsensitivity to alpha2 adrenoceptor agonists was characterized by a marked reduction in slope and a depression of the maximum response. 5. These data suggest that myenteric neurons possess spare receptors for morphine and 2-chloroadenosine but not for clonidine and xylazine. Furthermore, the studies support the idea that tolerance is associated with a general cellular change or adaptation which impacts on all of these inhibitory substances in such a way as to reduce their efficacy.