Fentanyl-induced postural changes across species: behaviors, mechanisms, and translational implications

This narrative review summarizes fentanyl-induced postural effects across species, focusing on a postulated cerulospinal noradrenergic connection linking rodent catalepsy models to human wooden-chest syndrome (WCS). This could have possible translational relevance for fentanyl overdose and its clinical management. A review of English-language literature was conducted using PubMed and EMBASE. Reference lists of retrieved articles and prior reviews on the topic were searched for additional sources. The evidence supports that fentanyl-induced postural effects are centrally mediated to a significant extent through µ-opioid receptor (MOR) activation in the locus cœruleus, with downstream engagement of cerulospinal noradrenergic projections onto spinal α1-adrenoceptors. Further, this integrated pathway is subject to modulation by nitric oxide and glutamatergic signaling, striatal dopaminergic-medium spiny neuron circuitry, and pontine respiratory nuclei. Phenomenology differs substantially across species, dose, and route of administration, but a phylogenetically conserved MOR-cerulospinal-noradrenergic pathway, modulated by nitric oxide and dopaminergic circuitry, appears to underlie fentanyl-induced postural disturbances across species, from cataleptic immobility in rodents to WCS in humans. The conserved mechanism is expressed as species-specific chest-wall mechanics that are a determinant of clinical severity, and helps to understand the potential role of α2-adrenoceptor agonists as being mechanistically rational for overdose management.