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Abstract: SA-PO618

G-Protein Signaling and Kappa Opioid Mediated Aquaresis

Session Information

  • Pharmacology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Ebert, Kevin, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
  • Kapusta, Daniel R., Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States
Background

Kappa opioid agonists act centrally to inhibit antidiuretic hormone (ADH) secretion and increase renal sympathetic nerve activity. Together, these effects lead to a water diuresis. However, the signaling pathway by which kappa opioid receptor (KOR) activation produces these effects remains unknown. In prior studies, we have shown that activation of opioid receptor like one (ORL1) by the ligand nociceptin produces a marked diuresis in rats by a downstream G-alpha z protein pathway that inhibits 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.

Methods

Sprague Dawley rats were implanted with an intracerebroventricular (i.c.v.) cannulae and pretreated with vehicle or pertussis toxin (PT), 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 stabilization, blood pressure (BP), heart rate (HR), and urine output (V) was collected in conscious rats before (control) and for 90-min after (10-min collections) i.c.v. U-50488H (n=6).

Results

In vehicle pretreated rats, i.c.v. U-50488H produced a marked increase in V (max Δ, 101±8 ul/min) and decrease in urinary sodium excretion (UNaV; max Δ, 5±0.5 ueq/min). The diuretic response produced by U-50488H was significantly (p<0.05) blunted by pretreatment with PT (max Δ, 57±3 ul/min). In contrast, PT 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 mediating the kappa 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.

Conclusion

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.

Funding

  • Other NIH Support