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

Abstract

In mice pretreated intracerebroventricularly (i.c.v.) with either saline (1 μl/mouse), pertussis (1 μg/mouse) or cholera (2.5 μg/mouse) toxins, effect of κ-opioid receptor agonists on the colonic temperature and charcoal meal transit time were assessed. The κ-opioid receptor agonist, trans-(+)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide methane sulfonate hydrate (U-50488H, 50, 100 and 200 μg/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 μg/mouse) and (±)-trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl[benz[b]-thio-phene-4-acetamide (PD 117302, 30 μg/mouse). In contrast, cholera toxin pretreatment (48 and/or 96 h before) did not antagonize the hypothermic effect of the κ-opioid receptor agonists. Moreover, both i.c.v. and intrathecal (i.t.) administration of κ-opioid receptor agonists, U-50488H, {[5R-(5α,7α,8β)]-(±)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspirol[4,5]dec-8-yl]-benzeneacetamide} (U-65593) 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 μg/mouse), U-69593 (100 μg/mouse) and PD 117302 (50 μg/mouse). However, pertussis toxin previous pretreatment did not affect the gastrointestinal inhibitory effect of the κ-opioid receptors agonists. The present results extend our previous results on the affect of κ-selective agonists on gastrointestinal motility and indicate, like the prototype opiate agonist morphine, κ-opioid receptor agonists are effective in inhibiting the gastrointestinal motility when administered either by intrathecal or intracerebroventricular routes. Thus, for the antitransit effect of κ-opioid receptor agonists, both spinal and supra spinal site could be implicated. Furthermore, these results also suggest that pertussis and cholera toxin-sensitive transducer G-proteins may be involved in the central κ-opioid receptor mediated hypothermia and gastrointestinal transit inhibition respectively.