Opioid agonist ligands have been widely employed in the pharmacotherapy of pain in spite of side effects such as constipation, tolerance, physical dependence, and respiratory depression. Given the burgeoning evidence for heteromeric opioid receptors, it seems likely that many of these side effects are dependent on the activation of specific heteromers. In view of the pharmacologic diversity that may arise from heteromers that contain a combinations of either opioid receptor subtypes or opioid and nonopioid protomers, it is possible that some of these side effects may be due to the activation of specific heteromers. Here we discuss cell-based and in vivo pharmacological evidence for activation of heteromeric opioid receptors by clinically employed analgesics and by selective ligands synthesized in our laboratory in an effort to address this possibility. Since ligands that selectively activate specific heteromers may lead to the development of analgesics devoid of side effects, we have developed mu pharmacophore-containing ligands that are selective for a variety of heteromers for use as pharmacologic tools. The finding that some of our ligands are devoid of tolerance and/or dependence suggests that selective activation of heteromers offers an approach to developing potent analgesics free of side effects.

Heteromeric G protein-coupled receptors are the principal targets of opioid analgesics

243rd National Meeting (2012)

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