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.

Highlights

  • IntroductionOpioid drugs interact with the 3 canonical opioid receptors (mu, kappa, delta [mu opioid receptor (MOR), Kappa Opioid Receptor (KOR), Delta Opioid Receptor (DOR)]) with varying selectivity ratios [1,2,3]

  • Opioid drugs interact with the 3 canonical opioid receptors with varying selectivity ratios [1,2,3]

  • The nociception receptor (NOP)-Chinese Hamster Ovary (CHO) and cannabinoid receptor type 1 (CB1)-CHO lines are commercial, the σ1R and monoamine transporter lines were created during this project, so this analysis validates the successful creation of those lines

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Summary

Introduction

Opioid drugs interact with the 3 canonical opioid receptors (mu, kappa, delta [MOR, KOR, DOR]) with varying selectivity ratios [1,2,3]. Experiments with the MOR knockout (KO) mouse demonstrated that morphine anti-nociception was fully mediated through the MOR, and most clinical opioids are thought to exert their analgesic/anti-nociceptive effects. Comprehensive opioid screening reveals new receptor targets manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

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