Biology subjects

Burgraff, N. J.

Publications and source records attributed to Burgraff, N. J..

3 recordsLinked to original sources

bioRxiv2025

Functional Modulation of Retrotrapezoid Neurons Drives Fentanyl-Induced Respiratory Depression

The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), characterized by severe suppression of respiratory rate, destabilized breathing patterns, hypercapnia, and heightened risk of apnea. The retrotrapezoid nucleus (RTN), a critical chemosensitive brainstem region in the rostral ventrolateral medullary reticular formation contains Phox2b+/Neuromedin-B (Nmb) propriobulbar neurons. These neurons, stimulated by CO2/H+, regulate breathing to prevent respiratory acidosis. Since the RTN shows limited expression of opioid-receptors, we expected that opioid-induced hypoventilation should activate these neurons to restore ventilation and stabilize arterial blood gases. However, the ability of the RTN to stimulate ventilation during OIRD has never been tested. We used optogenetic and pharmacogenetic approaches, to activate and inhibit RTN Phox2B+/Nmb+ neurons before and after fentanyl administration. As expected, fentanyl (500 {micro}g/kg, ip) suppressed respiratory rate and destabilized breathing. Before fentanyl, optogenetic stimulation of Phox2b+/Nmb+ or chemogenetic inhibition of Nmb+ cells increased and decreased breathing activity, respectively. Surprisingly, optogenetic stimulation after fentanyl administration caused a significantly greater increase in breathing activity compared to pre-fentanyl levels. By contrast chemogenetic ablation of RTN Nmb neurons caused profound hypoventilation and breathing instability after fentanyl. The results suggest that fentanyl does not inhibit the ability of Phox2b+/Nmb+ cells within the RTN region to stimulate breathing. Thus, this study highlights the potential of stimulating RTN neurons as a therapeutic approach to restore respiratory function in cases of OIRD.

physiology↗

bioRxiv2025

Fentanyl blockade of K+ channels contribute to Wooden Chest Syndrome

Fentanyl is a potent synthetic opioid widely used perioperatively and illicitly as a drug of abuse 1,2. It is well established that fentanyl acts as a -opioid receptor agonist, signaling through Gi/o intracellular pathways to inhibit electrical excitability, resulting in analgesia and respiratory depression 3,4. However, fentanyl uniquely also triggers muscle rigidity, including respiratory muscles, hindering the ability to execute central respiratory commands or to receive external resuscitation. This potentially lethal condition is termed Wooden Chest Syndrome (WCS), the mechanisms of which are poorly understood 5-7. Here we show that fentanyl directly blocks a subset of EAG-class potassium channels 8. Our results also demonstrate that these channels are widely expressed in cervical spinal motoneurons, including those innervating the diaphragm. A significant fraction of these motoneurons is excited by fentanyl, concomitant with blockade of voltage-dependent non-inactivating K+ currents. In vivo electromyography revealed a persistent tonic component of diaphragmatic muscle activity elicited by fentanyl, but not morphine. Taken together our results identify a novel off-target mechanism for fentanyl action, independent of -opioid receptor activation, with a paradoxical excitatory effect that may underlie WCS. We anticipate these findings may inform the design of safer analgesics and generalize to other neuronal circuits implicated in fentanyl-related maladaptive behaviors.

neuroscience↗

bioRxiv2021

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm generating network

The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the -opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBotzinger Complex (preB[o]tC). To unravel the cellular- and network-level consequences of MOR activation in the preBotC, MOR-expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBotC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act together to make the normally robust inspiratory-rhythm-generating network particularly prone to collapse when challenged with exogenous opioids.

neuroscience↗