Interactions of (2S,6S;2R,6R)-Hydroxynorketamine, a Secondary Metabolite of (R,S)-Ketamine, with Morphine

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Lilius , T O , Viisanen , H , Jokinen , V , Niemi , M , Kalso , E A & Rauhala , P V 2018 , ' Interactions of (2S,6S;2R,6R)-Hydroxynorketamine, a Secondary Metabolite of (R,S)-Ketamine, with Morphine ' , Basic & Clinical Pharmacology & Toxicology , vol. 122 , no. 5 , pp. 481-488 . https://doi.org/10.1111/bcpt.12941

Title: Interactions of (2S,6S;2R,6R)-Hydroxynorketamine, a Secondary Metabolite of (R,S)-Ketamine, with Morphine
Author: Lilius, Tuomas O.; Viisanen, Hanna; Jokinen, Viljami; Niemi, Mikko; Kalso, Eija A.; Rauhala, Pekka V.
Contributor: University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Eija Kalso / Principal Investigator
University of Helsinki, Pekka Rauhala / Principal Investigator
Date: 2018-05
Language: eng
Number of pages: 8
Belongs to series: Basic & Clinical Pharmacology & Toxicology
ISSN: 1742-7835
URI: http://hdl.handle.net/10138/234711
Abstract: Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N-methyl-d-aspartate (NMDA) receptors. Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)-hydroxynorketamine (6-hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of 7 nicotinic acetylcholine receptors. We studied whether 6-hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings. Male Sprague Dawley rats received subcutaneous 6-hydroxynorketamine or ketamine alone or in combination with morphine, as a cotreatment during induction of morphine tolerance, and after the development of tolerance induced by subcutaneous minipumps administering 9.6 mg morphine daily. Tail flick, hot plate, paw pressure and rotarod tests were used. Brain and serum drug concentrations were quantified with high-performance liquid chromatography-tandem mass spectrometry. Ketamine (10 mg/kg), but not 6-hydroxynorketamine (10 and 30 mg/kg), enhanced antinociception and decreased rotarod performance following acute administration either alone or combined with morphine. Ketamine efficiently attenuated morphine tolerance. Acutely administered 6-hydroxynorketamine increased the brain concentration of morphine (by 60%), and brain and serum concentrations of 6-hydroxynorketamine were doubled by morphine pre-treatment. This pharmacokinetic interaction did not, however, lead to altered morphine tolerance. Co-administration of 6-hydroxynorketamine 20 mg/kg twice daily did not influence development of morphine tolerance. Even though morphine and 6-hydroxynorketamine brain concentrations were increased after co-administration, the pharmacokinetic interaction had no effect on acute morphine nociception or tolerance. These results indicate that 6-hydroxynorketamine does not have antinociceptive properties or attenuate opioid tolerance in a similar way as ketamine.
Subject: LIVER MICROSOMAL PREPARATIONS
NMDA RECEPTOR ANTAGONIST
SPRAGUE-DAWLEY RATS
IN-VITRO
UDP-GLUCURONOSYLTRANSFERASES
ARRIVE GUIDELINES
MAMMALIAN TARGET
OPIOID RECEPTOR
CANCER PAIN
SPINAL-CORD
3111 Biomedicine
317 Pharmacy
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