Jv. Garaulet et al., CROSS-TOLERANCE BETWEEN MU-OPIOID AND KAPPA-OPIOID AGONISTS IN THE GUINEA-PIG ILEUM MYENTERIC PLEXUS, The Journal of pharmacology and experimental therapeutics, 269(3), 1994, pp. 993-999
The present investigation was aimed at elucidating if chronic activati
on of mu opioid receptor induces development of tolerance to mu (speci
fic tolerance) and kappa agonists (cross-tolerance) in the guinea pig
ileum myenteric plexus-longitudinal muscle strip. Morphine (prototype
of mv agonist), [D-Ala(2), N-MePhe(4), Gly-ol(5)]enkephalin (DAMGO) an
d sufentanil (selective mu-agonists) and U-50,488H (selective kappa ag
onist) were selected. Tolerance to morphine was induced by subcutaneou
s implantation of morphine pellets (75 mg per pellet) for 7 days. Tole
rance to sufentanil was induced by subcutaneous implantation of osmoti
c minipumps for 7 days, which deliver at a rate of 2 mu g/mu l/hr. Con
trol groups received placebo pellets or minipumps of vehicle. Toleranc
e to morphine and DAMGO was observed after chronic treatment with morp
hine or sufentanil and was revealed as a rightward shift of the concen
tration-response curve. In addition, a decrease in maximal response wa
s observed. Preparations from morphine-pelleted guinea pigs were also
tolerant to the kappa-selective agonist trans-(+/-)3,4-dichloro-N-meth
yl-N-[2-(1 -pyrrolidynyl)-cyclohexyl]benzeneacetamide (U-50,488H); tha
t is, there was cross-tolerance to the kappa agonist. The development
of tolerance to U-50,488H was characterized by a parallel rightward sh
ift of the concentration-response curve, but the maximal response was
unchanged. Sufentanil-tolerant tissues were also tolerant to the inhib
itory effects of U-50,488H (cross-tolerance). These data indicate that
alterations occur during chronic mu opioid administration that are no
t receptor specific and suggest that tolerance would be associated wit
h a functional change in the myenteric neurons that is unrelated to in
dividual receptor system.