 opioid receptor activation of the carotid body mitigates OIRD by fentanyl

ABSTRACT Fentanyl is a widely used opioid in the clinic for relieving chronic pain. Fentanyl abuse leads to mortality due to opioid-induced respiratory depression (OIRD). OIRD is a major health concern in the USA and there is an unmet need for developing therapeutic strategies for mitigating OIRD. Breathing is regulated by brainstem neurons generating respiratory rhythm. Sensory feedback from carotid body (CB) chemoreceptors, which stimulate breathing, is an important regulator of breathing. Current evidence suggests that OIRD is in part due to fentanyl-induced inhibition of brainstem neurons by µ-opioid receptors (MORs). the effects of fentanyl on CB are not known. Preliminary data showed fentanyl stimulates CB sensory nerve (CSN) activity acting on κ- opioid receptors (κ-ORs) and co-administration of fentanyl and a κ-OR agonist prevent OIRD. Based on these observations, we will test the hypotheses: a) fentanyl stimulates CB acting as a partial κ-OR agonist by elevating [Ca2+]I in glomus cells through κ-OR-Gαq signaling and b) full activation of CB with co-application of fentanyl and a κ agonist mitigate OIRD without compromising analgesic effects of fentanyl. These hypotheses are tested in rats and mice using repertoire of approaches. Studies in AIM 1 determine relative abundance of κ-ORs in the rat and murine CBs and assess their role in CB activation by fentanyl. AIM 2 delineate the role of κ-OR-Gαq signaling in [Ca2+]I elevation by fentanyl in glomus cells and assess its significance in CB activation. AIM 3 tests the hypothesis that co-application of fentanyl and κ-OR agonist mitigate OIRD without compromising analgesic efficacy of fentanyl and assess whether CB is the site of action. Major conceptual and technical innovations include that a) Fentanyl activates CB through κ-ORs as opposed to inhibition of brainstem neurons by µOR; b) Mitigating OIRD with κ-OR agonist is a hitherto unexplored concept that may have important therapeutic implications and c) Integrating various standard and state-of-the-art approaches provide information at the systems level and cellular insights. The proposed studies provide much-needed framework for developing novel therapeutic strategies for mitigating OIRD.