Activation of the Carotid Body by Kappa Opioid Receptors Mitigates Fentanyl-Induced Respiratory Depression

Abstract Previous studies reported that opioids depress breathing by inhibiting respiratory neural networks in the brainstem. The effects of opioids on sensory inputs regulating breathing are less studied. This study examined the effects of fentanyl and sufentanil on carotid body neural activity, a crucial sensory regulator of breathing. Both opioids stimulated carotid body afferent nerve activity and increased glomus cell [Ca2+]i levels. RNA sequencing and immunohistochemistry revealed a high abundance of κ opioid receptors (KORs) in carotid bodies, but no µ or δ opioid receptors. A KOR agonist, like fentanyl, stimulated carotid body afferents, while a KOR antagonist blocked carotid body activation by fentanyl and KOR agonist. In unanesthetized rats, fentanyl initially stimulated breathing, followed by respiratory depression. A KOR agonist stimulated breathing without respiratory inhibition, and this effect was absent in carotid body-denervated rats. Combining fentanyl with a KOR agonist attenuated respiratory depression in rats with intact carotid body but not in carotid body-denervated rats. These findings highlight previously uncharacterized activation of carotid body afferents by fentanyl via KORs as opposed to depression of brainstem respiratory neurons by µ opioid receptors and suggest that KOR agonists might counteract the central depressive effects of opioids on breathing.