Pertussis and cholera toxins modulate kappa-opioid receptor agonists-induced hypothermia and gut inhibition.

In mice pretreated intracerebroventricularly (i.c.v.) with either saline (10 microliters/mouse), pertussis (1 microgram/mouse) or cholera (2.5 micrograms/mouse) toxins, effect of kappa-opioid receptor agonists on the colonic temperature and charcoal meal transit time were assessed. The kappa-opioid receptor agonist, trans-(+)-3,4-dichloro-N-methyl-[2-(1- pyrrolidinyl)cyclohexyl]-benzeneacetamide methane sulfonate hydrate (U-50488H, 50, 100 and 200 micrograms/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 micrograms/mouse) and (+)-trans-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl[benz[b]-thio-phene-4-acetamide (PD 117302, 30 micrograms/mouse). In contrast, cholera toxin pretreatment (48 and/or 96 h before) did not antagonize the hypothermic effect of the kappa-opioid receptor agonists. Moreover, both i.c.v. and intrathecal (i.t.) administration of kappa-opioid receptor agonists, U-50488H, }[5R-(5 alpha,7 alpha,8 beta)]-(+/-)-N-methyl-N-[7-(1- pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]-benzeneacetamide¿ (U-69593) and PD 117302, produced dose dependent inhibition of the charcoal meal transit. Cholera toxin pretreatment (48 and 96 h before) augmented (P < 0.05) the antitransit effect of i.c.v. administered U-50488H (100 micrograms/mouse), U-69593 (100 micrograms/mouse) and PD 117302 (50 micrograms/mouse). However, pertussis toxin pretreatment did not affect the gastrointestinal inhibitory effect of the kappa-opioid receptor agonists. The present results extend our previous results on the effect of kappa-selective agonists on gastrointestinal motility and indicate, like the prototype opiate agonist morphine, kappa-opioid receptor agonists are effective in inhibiting the gastrointestinal motility when administered either by intrathecal or intracerebroventricular routes.(ABSTRACT TRUNCATED AT 250 WORDS)