PERTUSSIS AND CHOLERA TOXINS MODULATE KAPPA-OPIOID RECEPTOR AGONISTS-INDUCED HYPOTHERMIA AND GUT INHIBITION

In mice pretreated intracerebroventricularly (i.c.v.) with either sali ne (10 mu l/mouse), pertussis (1 mu g/mouse) or cholera (2.5 mu g/mous e) toxins, effect of K-opioid receptor agonists on the colonic tempera ture and charcoal meal transit time were assessed. The kappa-opioid- r eceptor agonist, yl-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide me thane sulfonate hydrate (U-50488H, 50, 100 and 200 mu g/mouse, i.c.v.) produced dose dependent hypothermia. Pertussis toxin pretreatment (72 and/or 144 h before) antagonized (P < 0.05) the hypothermic effect of U-50488H (100 mu g/mouse) and (+/-)-trans-N- olidinyl)cyclohexyl[benz [b]-thio-phene-4-acetamide (PD 117302, 30 mu g/mouse). In contrast, ch olera toxin pretreatment (48 and/or 96 h before) did not antagonize th e hypothermic effect of the kappa-opioid receptor agonists. Moreover, both i.c.v. and intrathecal (i.t.) administration of kappa-opioid rece ptor agonists, U-50488H, {[5R-(5 alpha,7 alpha,8 idinyl)-1-oxaspiro[4, 5]dec-8-yl]-benzeneacetamide) (U-69593) and PD 117302, produced dose d ependent inhibition of the charcoal meal transit. Cholera toxin pretre atment (48 and 96 h before) augmented (P < 0.05) the antitransit effec t of i.c.v. administered U-50488H (100 mu g/mouse), U-69593 (100 mu g/ mouse) and PD 117302 (50 mu g/mouse). However, pertussis toxin pretrea tment did not affect the gastrointestinal inhibitory effect of the kap pa-opioid receptor agonists. The present results extend our previous r esults on the effect of kappa-selective agonists on gastrointestinal m otility and indicate, like the prototype opiate agonist morphine, kapp a-opioid receptor agonists are effective in inhibiting the gastrointes tinal motility when administered either by intrathecal or intracerebro ventricular routes. Thus, for the antitransit effect of kappa-opioid r ceptor agonists, both spinal and supra spinal site could be implicated . Furthermore, these results also suggest that pertussis and cholera t oxin-sensitive transducer G-proteins may be involved in the central ka ppa-opioid receptor mediated hypothermia and gastrointestinal transit inhibition, respectively.