OPIATE RECEPTORS WITHIN THE BLOOD-BRAIN-BARRIER MEDIATE-KAPPA AGONIST-INDUCED WATER DIURESIS

Data suggest that kappa opioid agonist-induced water diuresis involves inhibition of vasopressin (AVP) secretion; however, it is not clear w hether this action involves kappa receptors in the neurohypophysis or receptors behind the blood-brain barrier (BBB). We have investigated t he site of action using three selective kappa agonists, BRL 52656 1-py rrolidinylme-thyl)-1-(4-trifluoromethylphenyl) acetyl piperidine hydro chloride), BRL 53114 ((-)-1-(4-trifluoromethylphenyl) acetyl-2-(1-pyrr olidi-nylmethyl)3,3-dimethyl piperidine hydrochloride) and BRL 52974 , 4-dichlorophenyl)acetyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine), w ith varying abilities to cross the BBB. Chemical and functional assays indicate that BRL 52974 has limited ability to cross the BBB, whereas BRL 53114 and BRL 52656 can freely penetrate. BRL 52974 was significa ntly less potent than BRL 52656 and BRL 53114 in causing a water diure sis in conscious rats. The ED10s (i.v. doses to cause a positive free water clearance of 10 mul/min . 100 g) for BRL 52974, BRL 52656 and BR L 53114 were 181, 9 and 3.4 mg/kg, respectively. Furthermore, in dogs BRL 52656 and BRL 53114 but not BRL 52974 (30 mug/kg i.v.) were able t o cause a significant water diuresis. The data demonstrate that opiate receptors behind the BBB are primarily involved in kappa agonist-indu ced water diuresis and possibly inhibition of AVP secretion.