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.
Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, increases dopamine transporter (DAT) activity in cells and rat striatum, which reduces dopamine signaling. This effect is mediated by KOR activation and the ERK1/2 pathway, and involves physical interaction between KOR and DAT proteins. SalA also decreases serotonin transporter activity but does not affect norepinephrine transporter activity. The enhanced dopamine transport, combined with reduced dopamine release, may contribute to the dysphoric and pro-depressant effects of SalA and other KOR agonists.