Targeted inhibition of mu-opioid receptors in neuronal subpopulations by membrane-tethered Naloxo-DART antagonists

Opioid receptors are expressed in virtually all neural loci contributing to the experience of pain. Due to this widespread expression, the contribution of specific cell types to the analgesic properties and deleterious side effects of opioids remains incompletely understood. Linking the activity of specific receptors in defined cells to behavioral or physiological processes remains a major challenge of translational pharmacology. In this study, we describe the development of drugs acutely restricted by membrane tethering (DART) antagonists that contain an antagonist naloxone moiety linked to a Halo-tag reactive group. The optimized Naloxo-DART displayed robust blockade of a MOR agonist only when cells co-expressed a Halo-tagged membrane tether. We use the Naloxo-DART delivered in vivo to selectively block MORs in locus coeruleus neurons in brain slide preparations. The Naloxo-DART provides a powerful approach for elucidating the physiological roles of MORs expressed in specific neuronal populations with acute spatiotemporal control.