Jv. Garaulet et al., CROSS-TOLERANCE BETWEEN KAPPA-OPIOID AND MU-OPIOID AGONISTS IN THE GUINEA-PIG ILEUM MYENTERIC PLEXUS, The Journal of pharmacology and experimental therapeutics, 272(2), 1995, pp. 658-662
The aim of the present investigation was to determine whether chronic
activation of kappa opioid receptor induces development of tolerance t
o kappa (specific tolerance) and to mu (cross-tolerance) agonists in t
he guinea pig ileum myenteric plexus-longitudinal muscle strip. trans(
+/-)-3,4-dichloro-Nmethyl-N-[2-(1 -pyrrolidynyl)ciclohexyl]-benzeneace
tamde (U-50,488H) a selective kappa agonist, morphine (prototype of a
mu agonist) and DAMGO (a selective mu agonist) were chosen. Tolerance
to the kappa agonist was induced by chronic administration of the kapp
a agonist (15 mg/kg i.p. twice a day for 4 days). The guinea pigs were
killed on day 5. Tolerance to U-50,488H was observed after its chroni
c administration and was revealed as a rightward shift of the concentr
ation-response curve. In addition, we observed a decrease in the maxim
um response and in the slope. Preparations from chronically U-50,488H-
treated guinea pigs were also tolerant to the inhibitory effects of bo
th the mu-selective agonist DAMGO and morphine. That is, there was cro
ss-tolerance to the mu agonists. The development of tolerance to DAMGO
and morphine was characterized by a rightward shift of the concentrat
ion-response curve, a decrease in maximum response and a decrease in t
he slope, although the degree of tolerance appeared to be less than th
at observed to U-50,488H. These data suggest that tolerance at the mye
nteric plexus level may be associated with a functional change in the
myenteric neurons that is unrelated to the individual receptor system.