Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells

Anesthesiology. 1999 Jan;90(1):174-82. doi: 10.1097/00000542-199901000-00023.


Background: The authors examined the interaction of ketamine with recombinant mu, kappa, and delta opioid receptors and recombinant orphan opioid receptors expressed in Chinese hamster ovary cells (CHO-mu, CHO-kappa, CHO-delta, and CHO(ORL1), respectively).

Methods: CHO-mu, CHO-kappa, and CHO-delta membranes were incubated with the opioid receptor radioligand [3H]diprenorphine at room temperature. Ketamine (racemic, R(-) and S(+)) was included at concentrations covering the clinical range. CHO(ORL1) membranes were incubated with [125I]Tyr(14)nociceptin and racemic ketamine at room temperature. The effects of racemic ketamine and selective opioid receptor agonists (mu: [D-Ala2, MePhe4, Gly(ol)5] enkephalin (DAMGO); kappa: spiradoline or delta: [D-pen2, D-pen5] enkephalin (DPDPE)) on forskolin-stimulated cyclic adenosine monophosphate formation also were examined. Data are mean +/- SEM.

Results: Racemic ketamine increased the radioligand equilibrium dissociation constant for [3H]diprenorphine from 85+/-5 to 273+/-11, 91+/-6 to 154+/-16, and 372+/-15 to 855+/-42 pM in CHO-mu, CHO-kappa, and CHO-delta, respectively. The concentration of radioligand bound at saturation was unaffected. In CHO-mu and CHO-kappa cells, racemic ketamine did not slow the rate of naloxone-induced [3H]diprenorphine dissociation. Ketamine and its isomers also displaced [3H]diprenorphine binding to mu, kappa, and delta receptors in a dose-dependent manner, with pKi values for racemic ketamine of 4.38+/-0.02, 4.55+/-0.04, and 3.57+/-0.02, respectively. S(+)-ketamine was two to three times more potent than R(-)-ketamine at mu and kappa receptors. Racemic ketamine displaced [125I]Tyr(14)nociceptin with an estimated affinity constant of 0.5 mM. Racemic ketamine inhibited the formation of cyclic adenosine monophosphate (naloxone insensitive) in a dose-dependent manner (concentration producing 50% inhibition approximately 2 mM) in all cell lines, including untransfected CHO cells. Ketamine (100 microM) reversed DAMGO (mu) and spiradoline (kappa) inhibition of formation of cyclic adenosine monophosphate.

Conclusions: Ketamine interacts stereoselectively with recombinant mu and kappa opioid receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive / drug effects
  • CHO Cells
  • Colforsin / pharmacology
  • Cricetinae
  • Cyclic AMP / antagonists & inhibitors
  • Diprenorphine / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Ketamine / pharmacology*
  • Naloxone / pharmacology
  • Narcotic Antagonists / metabolism
  • Opioid Peptides / metabolism
  • Radioligand Assay
  • Receptors, Opioid, delta / drug effects*
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, kappa / drug effects*
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / drug effects*
  • Receptors, Opioid, mu / metabolism
  • Recombinant Proteins / metabolism
  • Stereoisomerism


  • Excitatory Amino Acid Antagonists
  • Narcotic Antagonists
  • Opioid Peptides
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Recombinant Proteins
  • nociceptin, Tyr(1)-
  • Diprenorphine
  • Colforsin
  • Naloxone
  • Ketamine
  • Cyclic AMP