Cross-tolerance and convergent dependence between morphine and cannabimimetic agent WIN 55,212-2 in the guinea-pig ileum myenteric plexus

The cross-tolerance and convergent dependence between morphine and the cann abimimetic agent R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl]pyrrolo[1 ,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate (WIN 55,212 -2) were assessed in vitro on guinea-pig ileum. To induce tolerance and dep endence the myenteric plexus-longitudinal muscle was incubated at 37 degree s C for 5 h with a fixed concentration representing the IC50 for each compo und. Myenteric plexus-longitudinal muscle exposed to WIN 55,212-2 (5 X 10(- 8) M) was less sensitive to its inhibitory effect on electrically evoked co ntractions than naive myenteric plexus-longitudinal muscle. The exposure to cannabinoid induced a parallel rightward shift in the lower part of the co ncentration-response curve of WIN 55,212-2 and a marked reduction in the ma ximal inhibitory effect of the drug. Myenteric plexus-longitudinal muscle t olerant to WIN 55,212-2 was subsensitive to the inhibitory effect of morphi ne on the twitch response. The cross-tolerance between WIN 55,212-2 and mor phine was bidirectional. In fact, after 5 h the morphine (10(-7) M)-incubat ed myenteric plexus-longitudinal muscle was less sensitive to the inhibitor y effect of WIN 55,212-2. The tissue tolerant to morphine or WIN 55,212-2 w as tested for the presence of physical dependence. Naloxone (10(-5) M) prod uced a typical withdrawal contracture in morphine-tolerant myenteric plexus -longitudinal muscle which could be reduced by a 15-min pretreatment with W IN 55,212-2 (5 X 10-8 M). In contrast, SR141716 (10(-6) M) [N-(piperidino)- 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide], a concentration which fully antagonized the inhibitory effect of WIN 55,21 2-2 (10-7 M) in control preparations, did not produce significant contractu re in WIN 55,212-2-tolerant myenteric plexus-longitudinal muscle. The mecha nisms underlying the cross-tolerance and convergent dependence remain to be ascertained. (C) 1999 Elsevier Science B.V. All rights reserved.