Opioid-induced respiratory depression: an underappreciated role of the peripheral nervous system

Opioid overdose often leads to death, largely due to opioid-induced respiratory depression (OIRD). Extensive investigations have focused on the effects of opioids on brainstem breathing circuits. Peripheral sensory pathways also play an important role in shaping breathing behavior. This review highlights the effects of selected opioids and enkephalins on peripheral sensory inputs controlling breathing. Morphine and enkephalins activate vagal pulmonary C-fiber afferents, causing apnea in rodent models, along with increased laryngeal nerve activity and airway constriction; these effects can be reversed with naloxone. It remains unclear whether opioids similarly affect vagal afferents other than C-fiber afferents or whether opioids affect the processing of vagal afferents centrally. Earlier studies suggested opioids inhibit carotid body activity, but recent evidence shows that fentanyl stimulates carotid body activity via κ-opioid receptors (k-ORs), involving calcium signaling in glomus cells. k-OR agonists reduce fentanyl-induced respiratory depression in awake animals. Opioids also cause skeletal muscle rigidity, with increased intercostal activity and reduced diaphragmatic function, possibly through spinal reflexes. Overall, opioids significantly affect peripheral sensory systems related to breathing, contributing to hitherto unexplored roles in OIRD.