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Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids.
PLoS One 2019; 14(6):e0217371Plos

Abstract

Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the efficacy of opioids in activating the MOR in vitro and in inducing analgesia in vivo. In addition, some clinically used opioids do not produce cross-tolerance with each other, and desensitization produced in vitro does not match tolerance produced in vivo. These disparities suggest that some opioids could be acting through other targets in vivo, but this has not been comprehensively tested. We thus screened 9 clinically relevant opioids (buprenorphine, hydrocodone, hydromorphone, morphine, O-desmethyl-tramadol, oxycodone, oxymorphone, tapentadol, tramadol) against 9 pain-related receptor targets (MOR, delta opioid receptor [DOR], kappa opioid receptor [KOR], nociceptin receptor [NOP], cannabinoid receptor type 1 [CB1], sigma-1 receptor [σ1R], and the monoamine transporters [NET/SERT/DAT]) expressed in cells using radioligand binding and functional activity assays. We found several novel interactions, including monoamine transporter activation by buprenorphine and σ1R binding by hydrocodone and tapentadol. Tail flick anti-nociception experiments with CD-1 mice demonstrated that the monoamine transporter inhibitor duloxetine selectively promoted buprenorphine anti-nociception while producing no effects by itself or in combination with the most MOR-selective drug oxymorphone, providing evidence that these novel interactions could be relevant in vivo. Our findings provide a comprehensive picture of the receptor interaction profiles of clinically relevant opioids, which has not previously been performed. Our findings also suggest novel receptor interactions for future investigation that could explain some of the disparities observed between opioid performance in vitro and in vivo.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, United States of America.Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, United States of America.Depomed, Inc., Newark, CA, United States of America.Depomed, Inc., Newark, CA, United States of America.Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, United States of America.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31170174

Citation

Olson, Keith M., et al. "Comprehensive Molecular Pharmacology Screening Reveals Potential New Receptor Interactions for Clinically Relevant Opioids." PloS One, vol. 14, no. 6, 2019, pp. e0217371.
Olson KM, Duron DI, Womer D, et al. Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids. PLoS ONE. 2019;14(6):e0217371.
Olson, K. M., Duron, D. I., Womer, D., Fell, R., & Streicher, J. M. (2019). Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids. PloS One, 14(6), pp. e0217371. doi:10.1371/journal.pone.0217371.
Olson KM, et al. Comprehensive Molecular Pharmacology Screening Reveals Potential New Receptor Interactions for Clinically Relevant Opioids. PLoS ONE. 2019;14(6):e0217371. PubMed PMID: 31170174.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids. AU - Olson,Keith M, AU - Duron,David I, AU - Womer,Daniel, AU - Fell,Ryan, AU - Streicher,John M, Y1 - 2019/06/06/ PY - 2019/03/19/received PY - 2019/05/09/accepted PY - 2019/6/7/entrez PY - 2019/6/7/pubmed PY - 2019/6/7/medline SP - e0217371 EP - e0217371 JF - PloS one JO - PLoS ONE VL - 14 IS - 6 N2 - Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the efficacy of opioids in activating the MOR in vitro and in inducing analgesia in vivo. In addition, some clinically used opioids do not produce cross-tolerance with each other, and desensitization produced in vitro does not match tolerance produced in vivo. These disparities suggest that some opioids could be acting through other targets in vivo, but this has not been comprehensively tested. We thus screened 9 clinically relevant opioids (buprenorphine, hydrocodone, hydromorphone, morphine, O-desmethyl-tramadol, oxycodone, oxymorphone, tapentadol, tramadol) against 9 pain-related receptor targets (MOR, delta opioid receptor [DOR], kappa opioid receptor [KOR], nociceptin receptor [NOP], cannabinoid receptor type 1 [CB1], sigma-1 receptor [σ1R], and the monoamine transporters [NET/SERT/DAT]) expressed in cells using radioligand binding and functional activity assays. We found several novel interactions, including monoamine transporter activation by buprenorphine and σ1R binding by hydrocodone and tapentadol. Tail flick anti-nociception experiments with CD-1 mice demonstrated that the monoamine transporter inhibitor duloxetine selectively promoted buprenorphine anti-nociception while producing no effects by itself or in combination with the most MOR-selective drug oxymorphone, providing evidence that these novel interactions could be relevant in vivo. Our findings provide a comprehensive picture of the receptor interaction profiles of clinically relevant opioids, which has not previously been performed. Our findings also suggest novel receptor interactions for future investigation that could explain some of the disparities observed between opioid performance in vitro and in vivo. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/31170174/Comprehensive_molecular_pharmacology_screening_reveals_potential_new_receptor_interactions_for_clinically_relevant_opioids L2 - http://dx.plos.org/10.1371/journal.pone.0217371 DB - PRIME DP - Unbound Medicine ER -