Abstract
kappa-Opioids produce a centrally mediated diuresis, antinatriuresis, and renal sympathoexcitation in vivo; however, the specific brain sites mediating these responses are unknown. This study examined the role of the hypothalamic paraventricular nucleus (PVN) and the renal sympathetic nerves in mediating the cardiovascular and renal responses to central kappa-opioid receptor activation. In ketamine/xylazine-anesthetized rats, bilateral microinjection of the selective kappa-agonist U-50488H [(trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzene-acetamide) methane sulfonate; 100 ng] into the posterior magnocellular division of the PVN significantly increased urine flow rate (control, 47 +/- 9 microl/min; 40 min, 108 +/- 10 microl/min) without changing urinary sodium excretion or cardiovascular function. In other animals, microinjection of U-50488H into the same site elicited a similar water diuresis without a change in renal sympathetic nerve activity. In contrast, microinjection of U-50488H (100 ng) into the parvocellular PVN produced an immediate pressor response (Delta 16 +/- 3 mm Hg) that occurred with a potential baroreflex evoked bradycardia (Delta -26 +/- 8 beats per minute), renal sympathoinhibition (Delta -18 +/- 4%), natriuresis (Delta 38 +/- 1%), and delayed (30-min) antidiuresis (Delta -22 +/- 9%). These results were prevented by pretreatment with the kappa-receptor antagonist nor-binaltorphimine and were not obtained when U-50488H was injected outside the PVN, or when vehicle was injected into the PVN. Together, these results demonstrate that the posterior magnocellular PVN is a brain site where central kappa-opioids act to produce diuresis, presumably by inhibiting the secretion of arginine vasopressin. Alternatively, central kappa-opioids evoke antinatriuresis via augmenting renal sympathetic nerve activity and/or other neurohumoral sodium retaining pathways at brain sites other than the hypothalamic PVN.
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More From: Journal of Pharmacology and Experimental Therapeutics
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