Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids.

Article Details

Citation

Olson KM, Duron DI, Womer D, Fell R, Streicher JM

Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids.

PLoS One. 2019 Jun 6;14(6):e0217371. doi: 10.1371/journal.pone.0217371. eCollection 2019.

PubMed ID
31170174 [ View in PubMed
]
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 [sigma1R], 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 sigma1R 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.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
HydrocodoneDelta-type opioid receptorProteinHumans
Yes
Agonist
Details
HydrocodoneMu-type opioid receptorProteinHumans
Yes
Agonist
Details
HydrocodoneSigma non-opioid intracellular receptor 1ProteinHumans
Unknown
Ligand
Details