Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat.

BACKGROUND AND PURPOSE: The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. EXPERIMENTAL APPROACH: Morphine minipumps (6 mg·day(-1) ) induced tolerance during 5 days in Sprague-Dawley rats, after which s.c. ketamine (10 mg·kg(-1) ) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. KEY RESULTS: In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. CONCLUSIONS AND IMPLICATIONS: The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans.

The mineralocorticoid receptor antagonist spironolactone enhances morphine antinociception.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.