Cross-tolerance between mu- and kappa-opioid agonists in the guinea pig ileum myenteric plexus.
The present investigation was aimed at elucidating if chronic activation of mu opioid receptor induces development of tolerance to mu (specific tolerance) and kappa agonists (cross-tolerance) in the guinea pig ileum myenteric plexus-longitudinal muscle strip. Morphine (prototype of mu agonist), [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) and sufentanil (selective mu-agonists) and U-50,488H (selective kappa agonist) were selected. Tolerance to morphine was induced by subcutaneous implantation of morphine pellets (75 mg per pellet) for 7 days. Tolerance to sufentanil was induced by subcutaneous implantation of osmotic minipumps for 7 days, which deliver at a rate of 2 micrograms/microliters/hr. Control groups received placebo pellets or minipumps of vehicle. Tolerance to morphine and DAMGO was observed after chronic treatment with morphine or sufentanil and was revealed as a rightward shift of the concentration-response curve. In addition, a decrease in maximal response was observed. Preparations from morphine-pelleted guinea pigs were also tolerant to the kappa-selective agonist trans-(+-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidynyl)- cyclohexyl]benzeneacetamide (U-50,488H); that is, there was cross-tolerance to the kappa agonist. The development of tolerance to U-50,488H was characterized by a parallel rightward shift of the concentration-response curve, but the maximal response was unchanged. Sufentanil-tolerant tissues were also tolerant to the inhibitory effects of U-50,488H (cross-tolerance). These data indicate that alterations occur during chronic mu opioid administration that are not receptor specific and suggest that tolerance would be associated with a functional change in the myenteric neurons that is unrelated to individual receptor system.
Department of Physiology and Pharmacology, University School of Medicine, Murcia, Spain.
J V
JV
Garaulet
M L
ML
Laorden
M V
MV
Milanés
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009197:Myenteric Plexus / Q000187:drug effects*; D009294:Narcotics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D017409:Sufentanil / Q000494:pharmacology
D004745:Enkephalins; D009294:Narcotics; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D017409:Sufentanil