Research Article: Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids

Date Published: June 6, 2019

Publisher: Public Library of Science

Author(s): Keith M. Olson, David I. Duron, Daniel Womer, Ryan Fell, John M. Streicher, James Porter.


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.

Partial Text

Opioid drugs interact with the 3 canonical opioid receptors (mu, kappa, delta [MOR, KOR, DOR]) with varying selectivity ratios [1–3]. However, 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 through the MOR [4, 5]. Despite this apparent simplicity, different opioids can show different efficacies and side effect profiles in different patients, leading pharmacologists at times to propose MOR subtypes [6, 7]. In addition, not all opioids produce cross-tolerance; for instance, morphine remains anti-nociceptive at equipotent dosages in oxycodone tolerant and naïve animals [8, 9]. This lack of cross-tolerance is the basis behind clinical opioid rotation to retain treatment potency and efficacy [10, 11]. These disparities suggest that something beyond simple activation of the MOR is responsible for the different effects of clinical opioids.

In this study, we comprehensively screened the molecular pharmacology of 9 clinically relevant opioids at 9 pain-related receptor targets (Table 1). Such a comprehensive screen has not been performed for these compounds to our knowledge, and our findings could potentially explain discrepancies between clinical opioids in their in vitro vs. in vivo τ values and lack of cross-tolerance (see Introduction). We found many expected interactions, including expected binding affinities and potencies at the MOR, and NET/SERT interaction for tapentadol and tramadol. These expected findings, rank order affinities/potencies, and the expected behavior of positive control compounds all validate our experimental approach [3].