μ opioid receptor agonists(University of Kentucky)

Fentanyl is widely used perioperatively and illicitly as a drug of abuse. As a potent μ‐opioid receptor agonist, fentanyl canonically inhibits excitability through Gα i/o intracellular signalling pathways resulting in analgesia and respiratory depression. However, fentanyl also paradoxically activates respiratory muscles causing a potentially lethal effect termed wooden chest syndrome. Here we show that fentanyl, but not morphine, causes a persistent tonic component of diaphragmatic muscle activity. Voltage‐clamp studies reveal that fentanyl directly blocks a subset of ether‐à‐go‐go ‐class potassium (K + ) channels. These channels are widely expressed in spinal motoneurons, including those innervating the diaphragm. A significant fraction of these motoneurons are excited by fentanyl, concomitant with blockade of K + currents. Taken together we identified a novel off‐target mechanism for fentanyl action, independent of μ‐opioid receptor activation. Our findings may inform the design of safer analgesics and generalize beyond the activation of motoneurons to other neuronal circuits implicated in fentanyl‐related maladaptive behaviours. image

High doses of fentanyl can cause a lethal phenotype termed ‘wooden chest syndrome’ (WCS) resulting from tonic contractions of respiratory‐associated musculature, precluding the ability to mechanically inflate the lungs. In vivo murine diaphragmatic electromyograms reveal a tonic component of muscle activity elicited by fentanyl, but not morphine. Fentanyl reversibly blocks a subset of ether‐à‐go‐go (EAG)‐class potassium channels (EAG/Kv10 and ERG/Kv11 subclasses) expressed in HEK293 cells. Computational docking of fentanyl into cryogenic electron microscopy structures of these potassium channels predicts a binding site beneath the K + selectivity filter. RT‐PCR and RNA‐scope in situ experiments reveal widespread expression of EAG/Kv10 ( Kcnh1 , Kcnh5 ) and ERG/Kv11 ( Kcnh2 , Kcnh6 , Kcnh7 ) transcripts in cervical motoneurons, including phrenic motoneurons retrogradely labelled from the diaphragm. In vitro patch‐clamp recordings from cervical spinal sections identifies a significant fraction of phrenic motoneurons (44%) electrically excited by fentanyl, concomitant with the blockade of a non‐inactivating voltage‐gated potassium current. Direct block of EAG potassium channels by fentanyl may contribute to WCS.