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.
In this paper, estimates of the selectivities of a series of twelve sympathomimetic agents acting at postjunctional alpha 1- and prejunctional alpha 2-adrenoreceptors were investigated, using epididymal and prostatic segments of the rat vas deferens. The relative order of potency for the twelve agonists at prejunctional alpha 2-adrenoreceptors mediating inhibition of field-stimulation-induced contractions in the prostatic segment of the vas deferens was: clonidine greater than (-)-adrenaline greater than xylazine greater than or equal to (-)-noradrenaline greater than (+)-adrenaline greater than dopamine greater than or equal to phenylephrine greater than or equal to metaraminol greater than or equal to (+)-noradrenaline greater than (-)-isoprenaline greater than methoxamine greater than (+)-isoprenaline. The relative order of potency for the agonists at postjunctional alpha 1-adrenoreceptors mediating contraction of smooth muscle in epididymal segments of the vas deferens was: (-)-adrenaline greater than or equal to (-)-noradrenaline greater than phenylephrine greater than clonidine greater than or equal to (+)-adrenaline greater than or equal to methoxamine greater than or equal to (+)-noradrenaline greater than or equal to metaraminol greater than or equal to dopamine greater than or equal to (-)-isoprenaline greater than or equal to xylazine; (+)-isoprenaline was inactive. (+)-Noradrenaline, the stereoisomers of adrenaline and isoprenaline, dopamine, clonidine, xylazine and metaraminol displayed alpha 2-selectivity whereas phenylephrine and methoxamine displayed alpha 1-adrenoreceptor selectivity. (-)-Noradrenaline possessed a similar potency at both alpha 1- and alpha 2-adrenoreceptors thus making it non-selective by the criteria used in this study.(ABSTRACT TRUNCATED AT 250 WORDS)
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