OBJECTIVE Ketamine is known to interact with opioid receptors. However, because this agent does not produce opioid-like respiratory depression, it might not interact with mu(2) opioid receptors. Therefore, we have studied the interaction of ketamine with mu(2) opioid receptors expressed in SH-SY5Y cells. METHODS SH-SY5Y cells (passage 70-80) were used to obtain ketamine dose-response curves for inhibition of 0.4 nM [(3)H][D-Ala(2),MePhe(4),Gly(ol)(5)] enkephalin (DAMGO) binding to mu(2) opioid receptors and of forskolin (1 microM)-stimulated cyclic AMP (cAMP) formation. RESULTS Ketamine displaced [(3)H]DAMGO binding in SH-SY5Y cells with a K(i) of 12.1 microM. However, this concentrations did not inhibit forskolin-stimulated cAMP formation, although at supraclinical concentrations, significant inhibition was observed with an estimated IC(50) of 700 microM. CONCLUSIONS The present study indicates that a clinically relevant concentration of ketamine interacts with mu(2) opioid receptors. However, no agonist activity was observed.