Signaling Pathways Contributing to Central Kappa Opioid Diuresis

Abstract

Central activation of alpha‐2 receptors and nociceptin opioid peptide receptors (NOP) produce marked diuresis in rats, which is mediated in part by a downstream G‐alpha z protein signaling pathway that inhibits antidiuretic hormone (ADH) secretion. These studies investigated whether central G‐alpha protein signaling pathways also contribute in producing the diuretic and/or antinatriuretic response to central administration of the kappa opioid agonist, U‐50488H. Sprague Dawley rats were implanted with an intracerebroventricular (i.c.v.) cannula and pretreated with vehicle or pertussis toxin (PTX), which inhibits the Gi/o family of proteins except for Gz. After 48‐hrs pretreatment, rats were instrumented with cannula in the femoral artery, vein, and bladder and infused i.v. with isotonic saline (55 μl/min). After recovery, blood pressure (BP), heart rate (HR), and urine output (V) were collected in conscious rats before (control) and for 90‐min after (10‐min collections) i.c.v. U‐50488H (n=6). In vehicle pretreated rats, i.c.v. U‐50488H produced a marked increase in V (max Δ, 101±8 μl/min) and decrease in urinary sodium excretion (UNaV; max Δ, 5±0.5 μeq/min). The diuretic response produced by U‐50488H was significantly (p<0.05) blunted by pretreatment with PTX (max Δ, 57±3 ul/min). In contrast, PTX did not alter the decrease in UNaV. U‐50488H did not alter BP or HR in either group. To explore which G‐alpha proteins may participate in the kappa opioid mediated diuresis, separate rats were pretreated i.c.v. (24‐hrs) with an oligodeoxynucleotide (ODN), which selectively targeted a specific G‐alpha protein. In these studies, pretreatment of groups of rats (n=6/group) with a single ODN for either Gi1, Gi2, Gi3, Go, or Gz, failed to blunt the maximal diuresis as compared to the increase in V produced by i.c.v. U‐50488H in scrambled ODN treated rats. These results demonstrate that central kappa opioids produce a pertussis toxin sensitive diuresis, but not antinatriuresis. This suggests that a combination of Gi/o proteins may be required to produce the aquaretic effects of kappa opioid agonists.Support or Funding InformationSupported by NIH P30GM106392 to DRKThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.