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Cited by 130Neuropeptides and Animal PhysiologyReceptor Mechanisms and SignalingPain Management and Opioid Use

Stereoselective Interaction of Ketamine with Recombinant [micro sign], [small kappa, Greek], and [small delta, Greek] Opioid Receptors Expressed in Chinese Hamster Ovary Cells

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Hirota, Kazuyoshi, Okawa, Hirobumi, Appadu, Balraj L., Grandy, David K., Devi, Lakshmi A., Lambert, David G.·1999·Anesthesiology
DOI 10.1097/00000542-199901000-00023
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Abstract

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.

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  • The Joseph et al. conclusions depend on computational predictions, and their reported affinities and G protein recruitment values conflict with earlier work.

    “However, this study’s main findings rely on computational analysis and the predicted affinity and G protein recruitment values it reports are not consistent with several prior publications (Bonaventura et al., 2021; Hirota et al., 1999; Nemeth et al., 2010).”

    From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Hirota et al., 1999

    Table 2 (Discussion, p. 5) reports measured ketamine affinities at μ, κ, and δ opioid receptors, providing earlier values against which predictions could be compared. The Discussion (p. 8) reports effects on cAMP signaling, but the paper does not measure G protein recruitment or compare its results with Joseph et al.’s predictions. It therefore cannot establish the claimed inconsistency in recruitment values. (LLM, conf=0.82)

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  • Using recombinant human opioid receptors in CHO cells, (S)-ketamine showed greater affinity than (R)-ketamine at μ, κ, and δ receptors, indicating stereoselectivity.

    “Another study reported similar observations that ketamine interactions are stereoselective for recombinant human opioid receptors expressed in Chinese hamster ovary cells (Hirota et al., 1999).”

    From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Hirota et al., 1999

    The Results (p. 5) report greater binding potency for S(+)- than R(−)-ketamine at μ, κ, and δ receptors in CHO cells. But the Discussion (pp. 6–7) limits the δ finding to a small effect at supraclinical concentrations, rather than the stereoselectivity observed at μ and κ. Our copy identifies the μ, κ, and δ receptors as recombinant, but does not establish that those receptors were human. (LLM, conf=0.86)

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Research works printed but not linked: 12

  1. [1]1. Reisine T: Opiate receptors. Neuropharmacology 1995; 34:463-72
  2. [3]3. Lambert DG: Opioid receptors. Curr Opin Anaesthesiol 1995; 8:317-22
  3. [8]8. White PF, Ham J, Way WL, Trevor AJ: Pharmacology of ketamine isomers in surgical patients. ANESTHEsIOLOGY 1980; 52:231-9
  4. [14]14. Bunzow JR, Zhang G, Bouvier C, Saez C, Ronnekleiv OK, Kelly MJ, Grandy DK: Characterization and distribution of a cloned rat μ-opioid receptor. J Neurochem 1995; 64:14-24
  5. [16]16. Hjorth SA, Thirstrup K, Grandy DK, Schwartz TW: Analysis of selective binding epitopes for the κ-opioid receptor antagonist norbinaltorphimine. Mol Pharmacol 1995; 47:1089-94
  6. [18]18. Okawa H, Hirst RA, Smart D, McKnight AT, Lambert DG: Studies on the coupling of recombinant ORL-1 receptors to adenylyl cyclase (abstract). Br J Pharmacol 1998; 123:218P
  7. [19]19. Rang HP, Dale MM, Ritter JM: How drugs act: General principles, Pharmacology. 3rd edition. New York, Churchill Livingstone, 1995, pp 3-21
  8. [21]21. Cheng YC, Prusoff WM: Relationship between the inhibition constant (Kj) and the concentration of inhibitor which caused 50% inhibition (IC₅o) of an enzymatic reaction. Biochem Pharmacol 1973; 22: 3099-108
  9. [29]29. Glass PSA, Shafer SL, Jacobs JR, Reves JG: Intravenous anesthetic delivery, Anaesthesia. 4th edition. Edited by Miller RD. New York, Churchill-Livingstone, 1994, pp 389– 416
  10. [33]33. Hirota K, Appadu BL, Grandy DK, Devi LA, Lambert DG: Interaction of lignocaine with recombinant opioid receptors expressed in Chinese hamster ovary cells (abstract). Br J Anaesth 1997; 78:474P
  11. [32]32. Rothman RB, Danks JA, Jacobson AE, Burke TR, Rice KC, Tortella FC, Holaday JW: Morphine tolerance increases mu-non-competitive delta binding sites. Eur J Pharmacol 1986; 124:113-9
  12. [34]34. Standifer KM, Pasternak GW: G-proteins and opioid receptormediated signalling. Cell Signal 1997; 9:237–48

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Related

Authors
Hirota, K., Okawa, H., Appadu, B. L., Grandy, D. K., Devi, L. A., & Lambert, D. G.
Affiliations
  • Leicester Royal Infirmary (GB)
  • Oregon Health & Science University (US)
  • NYU Langone Health (US)
ORCID
Venue
Anesthesiology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
1999-01-01
Volume
90
Issue
1
Pages
174-182
ISSN
0003-3022 (ISSN-L)
DOI
10.1097/00000542-199901000-00023
OpenAlex
W2035312998
Cited by
130
References
27
Citations by year
2026: 4 · 2025: 8 · 2024: 15 · 2023: 8 · 2022: 12 · 2021: 7 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 2 · 2015: 2 · 2014: 4 · 2013: 7 · 2012: 2
FWCI
1.21
Type
journal article
Language
en
Open access
Locations
  • Anesthesiology (publishedVersion)
  • PubMed (publishedVersion)
  • Leicester Research Archive (University of Leicester) (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
Keywords
ketamine, opioid receptors, mu-opioid receptor, kappa opioid receptor, delta opioid receptor, nociceptin receptor, stereoselectivity, enantiomers, receptor binding affinity, diprenorphine, nociceptin, naloxone, enkephalin, antipsychotic drugs
MeSH terms
Cyclic AMP, Animals, Binding, Competitive, Diprenorphine, Colforsin, Cricetinae, Ketamine, Naloxone, Narcotic Antagonists, Radioligand Assay, Recombinant Proteins, Stereoisomerism, CHO Cells, Receptors, Opioid, mu, Receptors, Opioid, delta, Receptors, Opioid, kappa, Excitatory Amino Acid Antagonists, Opioid Peptides

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