Nalfurafine, a G-Protein–Biased KOR (Kappa Opioid Receptor) Agonist, Enhances the Diuretic Response and Limits Electrolyte Losses to Standard-of-Care Diuretics

Abstract

Nalfurafine is a G-protein–biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks CNS adverse effects. Here, we examined the cardiovascular and renal responses to intravenous and oral nalfurafine alone and in combination with furosemide, hydrochlorothiazide, or amiloride. We hypothesized that nalfurafine, given its distinct mechanism of vasopressin inhibition, would increase urine output to these diuretics and limit electrolyte loss. Following catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion and were then administered an intravenous bolus of nalfurafine, a diuretic, or a combination. Mean arterial pressure, heart rate, and urine output were recorded for 90 minutes. In another study, rats were placed in metabolic cages and administered drug in an oral volume load. Hourly urine samples were then collected for 5 hours. Intravenous and oral nalfurafine produced a marked diuresis, antinatriuresis, antikaliuresis, and a decrease in mean arterial pressure. Compared with diuretic treatment alone, intravenous coadministration with nalfurafine significantly increased urine output to furosemide and hydrochlorothiazide and decreased sodium and potassium excretion. Notably, mean arterial pressure was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral coadministration of nalfurafine significantly increased urine output to hydrochlorothiazide and decreased sodium and potassium excretion, whereas combination with furosemide only limited the amount of sodium excreted. Further, both intravenous and oral coadministration of nalfurafine enhanced the diuresis to amiloride and decreased sodium excretion. Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, offering a new approach to treat several cardiovascular conditions.

The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

“…KOR agonists have received attention in the past due to being non-addictive anti-nociceptive drugs that do not induce respiratory depression ( Viscusi et al, 2021 ; Wang et al, 2021 ), properties that compare favourably with those of MOR agonists such as morphine. However, they have their own distinctive side effect profiles that include stress and aversion ( Dykstra et al, 1987 ; Land et al, 2008 ; Wee and Koob, 2010 ), depression ( Knoll and Carlezon, 2010 ), sedation ( Dykstra et al, 1987 ), diuresis ( Meariman et al, 2021 ), and neuroendocrine effects (increase in serum prolactin, cortisol, and adrenocorticotropic hormone levels) ( Ko and Husbands, 2020 ). These side effects have hindered clinical development.…”

Effects of sex and hydration status on kappa opioid receptor‐mediated diuresis in rats

“…It may also be that different KOP agonists have differential effects on renal excretion mechanisms. A recent study by Meariman et al 51 showed that administration of nalfurafine, a G‐protein‐biased KOP agonist had diuretic effects but significantly reduced urinary sodium and potassium excretion in water‐loaded male Sprague–Dawley rats 50 . This may be one tool useful to investigate sex differences in sodium and potassium excretion following KOP activation.…”

In Silico Screening of Compounds Similar to Codeine, Tramadol, and Morphine with Better Pharmacodynamic and Pharmacokinetics Profiles

“…Prior work by [14] showed that hyperalgesia effects of morphine are not attributable to the binding of morphine to peripheral receptors but to central mu receptors. Kappa receptors' actions in hypothalamus and in the adrenal glands cause diuresis as a side effect [10]. Delta receptor is associated with convulsions due to actions on the thalamo-cortical areas and the hypothalamus [4].…”