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.
Taylor
D A
DA
Department of Pharmacology and Toxicology, West Virginia University Health Sciences Center, Morgantown 26506.
Leedham
J A
JA
Doak
N
N
Fleming
W W
WW
D015762:2-Chloroadenosine; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects*; D009197:Myenteric Plexus / Q000187:drug effects*; D014991:Xylazine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D015762:2-Chloroadenosine; D014991:Xylazine; D009020:Morphine; D000241:Adenosine; D003000:Clonidine