Oral ketamine is antinociceptive in the rat formalin test: Role of the metabolite, norketamine Journal Article
| Authors: | Shimoyama, M.; Shimoyama, N.; Gorman, A. L.; Elliott, K. J.; Inturrisi, C. E. |
| Article Title: | Oral ketamine is antinociceptive in the rat formalin test: Role of the metabolite, norketamine |
| Abstract: | The present study was designed to evaluate the oral efficacy and bioavailability of ketamine. Antinociceptive efficacy was determined with the rat formalin test and oral bioavailability by the measurement of plasma and brain concentrations of ketamine and its major metabolite, norketamine. Oral ketamine in a dose range from 30 to 180 mg/kg or saline was given prior to intraplantar formalin and the flinching behavior was measured. Oral ketamine dose-dependently reduced the flinching during phase 2, while flinching during phase 1 was reduced only with the highest dose given. Following oral ketamine at 100 mg/kg, blood and brain samples were obtained and plasma and brain ketamine and norketamine levels were measured using high-performance liquid chromatography (HPLC). The average concentration ratio of norketamine/ketamine, as expressed by the area under the curve (AUC) value, was 6.4 for plasma and 2.9 for brain. These results demonstrate that a significant amount of norketamine is formed by first pass biotransformation of ketamine and is distributed to the brain. Competition binding assays for the [3H]MK-801-labeled non-competitive site of the N-methyl-D-aspartate receptor (NMDA) receptor revealed that both norketamine and ketamine displaced [3H]MK-801 at low micromolar concentrations with K(i) values of 2.5 and 0.3 mM in the forebrain, and 4.2 and 1.0 mM in the spinal cord, respectively. Spinal norketamine was approximately equipotent to ketamine in producing antinociceptive effects during phase 2 of the formalin test. Thus, norketamine appears to contribute to the antinociceptive effects of oral ketamine through its NMDA receptor antagonist activity. Copyright (C) 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. |
| Keywords: | controlled study; area under the curve; dose response; nonhuman; binding affinity; animals; pain; animal experiment; central nervous system; drug receptor binding; rat; rats; drug bioavailability; drug blood level; rats, sprague-dawley; drug metabolite; administration, oral; formaldehyde; injections, spinal; ketamine; oral drug administration; behavior, animal; nociceptors; n methyl dextro aspartic acid receptor; binding, competitive; antinociception; n-methyl-d-aspartate receptor; drug brain level; dizocilpine; osmolar concentration; n methyl dextro aspartic acid receptor blocking agent; male; priority journal; article; intrathecal drug administration; formalin; norketamine; oral administration |
| Journal Title: | Pain |
| Volume: | 81 |
| Issue: | 1-2 |
| ISSN: | 0304-3959 |
| Publisher: | Elsevier Science BV |
| Date Published: | 1999-01-01 |
| Start Page: | 85 |
| End Page: | 93 |
| Language: | English |
| DOI: | 10.1016/s0304-3959(98)00269-3 |
| PUBMED: | 10353496 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 23 September 2016 -- Source: Scopus |
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