Interactions of (2S,6S;2R,6R)-Hydroxynorketamine, a Secondary Metabolite of (R,S)-Ketamine, with Morphine
| Autor: | Tuomas Lilius, Eija Kalso, Mikko Niemi, Viljami Jokinen, Pekka Rauhala, Hanna Viisanen |
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| Přispěvatelé: | Medicum, Department of Pharmacology, Department of Clinical Pharmacology, Clinicum, Mikko Olavi Niemi / Principal Investigator, Eija Kalso / Principal Investigator, Anestesiologian yksikkö, Department of Diagnostics and Therapeutics, Pekka Rauhala / Principal Investigator, HUS Perioperative, Intensive Care and Pain Medicine |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Nociception LIVER MICROSOMAL PREPARATIONS Hydroxynorketamine Pharmacology Toxicology Nociceptive Pain Rats Sprague-Dawley 0302 clinical medicine Drug tolerance Opioid receptor Drug Interactions Receptor Behavior Animal Morphine Brain General Medicine Drug Tolerance 3. Good health Analgesics Opioid 317 Pharmacy NMDA receptor Ketamine SPINAL-CORD medicine.drug Pain Threshold medicine.drug_class Motor Activity NMDA RECEPTOR ANTAGONIST OPIOID RECEPTOR 03 medical and health sciences ARRIVE GUIDELINES medicine Animals UDP-GLUCURONOSYLTRANSFERASES SPRAGUE-DAWLEY RATS Anesthetics Dissociative business.industry IN-VITRO CANCER PAIN Disease Models Animal 030104 developmental biology MAMMALIAN TARGET 3111 Biomedicine business 030217 neurology & neurosurgery |
| Zdroj: | Basicclinical pharmacologytoxicology. 122(5) |
| ISSN: | 1742-7843 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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