Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors.
Molecular pharmacology October 17, 2024 Ivone Gomes, Achla Gupta, Elyssa B Margolis et al. 21 citations
Ketamine, a glutamate receptor antagonist developed as an anesthetic over 50 years ago, also acts as a fast-acting antidepressant and analgesic at subanesthetic doses. This study tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors in cell systems and rodent brain. Submicromolar concentrations of ketamine combined with endogenous opioid peptides produced robust synergistic responses at μ, δ, and κ opioid receptors, with S-ketamine showing higher modulatory effects than R-ketamine or racemic ketamine. The metabolite 6-hydroxynorketamine, which does not bind glutamate receptors, showed strong allosteric activity at μ opioid receptors. These findings suggest some therapeutic effects of ketamine are mediated by engaging the endogenous opioid system.