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.

Nitazenes, benzimidazole synthetic potent opioid μ‐receptor agonists, have been implicated in increased risk for opioid toxicity. Subtypes of nitazenes, including protonitazene, have been recently detected in multiple overdose cases in Australia. We describe a case report of protonitazene dependence, inpatient withdrawal management and induction onto opioid dependence treatment.

A 22‐year‐old man with no significant medical history presented to a metropolitan emergency department in opioid withdrawal after regular vaping of a product sold as cannabinoids. He required higher than expected buprenorphine doses and other standard treatment including diazepam and olanzapine to manage opioid withdrawal. Blood and urine samples taken in the emergency department later tested positive for protonitazene. Analysis of the vaping liquid was only positive for protonitazene. He was discharged for outpatient follow‐up to later receive a 300 mg subcutaneous buprenorphine monthly injection.

This case describes the clinical presentation of dependence, withdrawal and buprenorphine induction for opioid dependence due to chronic protonitazene vaping. Future research may help guide optimal doses of buprenorphine to manage nitazene withdrawal. Vaping devices have increased in popularity, especially amongst youth, which poses public health risks to the community if adulterated with other substances. Detection of nitazenes currently requires specialised laboratories. Protonitazene withdrawal management was complex in this case report. Youth are at risk of harms in vaping products adulterated with other substances, including nitazenes. State‐wide toxicosurveillance programs, such as the NSW PRISE program, are essential for coordinating detection, clinical management and community awareness of nitazenes.