The mineralocorticoid receptor antagonist spironolactone enhances morphine antinociception

Abstract

Spironolactone, a commonly used mineralocorticoid receptor antagonist, has been reported to potentiate the effect of morphine in the rat. The aim of this study was to investigate the effects of spironolactone on morphine antinociception and tissue distribution. The effects of spironolactone on acute morphine-induced antinociception, induction of morphine tolerance and established morphine tolerance were studied with tail-flick and hot plate tests in male Sprague-Dawley rats. Serum, brain, and liver morphine and its metabolite concentrations were quantified using high-pressure liquid chromatography-tandem mass spectrometry. Spironolactone was also administered with the peripherally acting, P-glycoprotein (P-gp) substrate loperamide to test whether spironolactone allows loperamide to pass the blood-brain barrier. Spironolactone (50 mg/kg, i.p.) had no antinociceptive effects of its own, but it enhanced the antinociceptive effect of morphine in both thermal tests. Two doses of spironolactone enhanced the maximum possible effect (MPE) from 19.5% to 100% in the hot plate test 90 min after administration of 4 mg/kg morphine. Morphine concentrations in the brain were increased fourfold at 90 min by spironolactone. Spironolactone did not inhibit the formation of morphine-3-glucuronide. Acute spironolactone restored morphine antinociception in morphine-tolerant rats but did not inhibit the development of tolerance. The peripherally restricted opioid, loperamide (10 mg/kg), had no antinociceptive effects when administered alone, but co-administration with spironolactone produced a 40% MPE in the hot plate test. Spironolactone has no antinociceptive effects in thermal models of pain, but it enhances the antinociceptive effects of morphine mainly by increasing morphine central nervous system concentrations, probably by inhibiting P-gp.