P-052 - (Poster #52) Observations from a Rat Model of Fentanyl-Induced Changes Respiratory Function

Background: Opioid-induced respiratory depression (OIRD) persists as a significant global public health concern. To date, OIRD is a leading cause of morbidity and mortality, contributing to overdose deaths worldwide. Despite its clinical significance, there remains a limited understanding of the precise physiological mechanisms underlying OIRD. A key barrier to understanding the mechanisms is the lack of comprehensive assessment in preclinical models. Rats are commonly used to test therapeutics for reversing OIRD due to their known respiratory physiology. However, the translatability of these models is hampered by incomplete mechanistic characterization.
The central nervous system (CNS) effects, i.e., the inhibition of respiratory rhythm generation within the brainstem, including the pre-Bötzinger complex, following activation of μ-opioid receptors has been the prevailing mechanism. Emerging evidence shows that peripheral factors, like opioid-induced muscular rigidity ("wooden chest syndrome"), can impair ventilation mechanics and contribute to respiratory failure, independent of central drive depression. Fentanyl administration in rodents induces profound body wall rigidity that may alter respiratory pump dynamics, further complicating the interpretation of respiratory phenotypes. A comprehensive understanding of the independent and interactive central suppression (CNS response) and peripheral restriction (thoracic response) is essential for the rational design and evaluation of novel OIRD therapies in preclinical models.

Purpose/Objectives: The purpose of this project is to highlight the observations encompassing the contributions of central respiratory depression and peripheral respiratory pump dysfunction to OIRD in the rat model, with a specific focus on fentanyl-induced muscle rigidity. We posit that acute ventilatory compromise in this model is driven as much by opioid-induced thoracoabdominal rigidity as by suppression of brainstem respiratory centers. Through a series of experiments employing both continuous infusion and bolus intravenous administration of fentanyl, we characterize distinct respiratory phenotypes.

Methods: Using a multidisciplinary approach integrating anesthesiology, pain, and pulmonary expertise, we performed a series of studies assessing respiratory parameters in rats receiving either continuous fentanyl infusion or bolus intravenous administration. Real-time measurements of tidal volume, respiratory rate, and body movement were recorded.
·      Assessment of tidal volume
·      Assessment of minute vetilation
·      Assessment of respiratory fatigue
·      Evaluarion of recovery patten

Results: Continuous infusion of high-dose fentanyl resulting in high sustained blood plasma concentrations resulted in progressive respiratory failure in a small proportion of the rats, manifested by decompensation resulting in progressive acidosis leading to moribundity. In subsequent trials of high-dose bolus fentanyl administration (via repetitive bolus at intervals and subsequent plasma concentrations mimicking 2xCED human exposure) rats demonstrated a profound acute interruption of normal breathing patterns. This pattern included a sudden lack of movement (regardless of body position or activity) and a ‘frozen’ posture. This acute stiffing involved all observable musculature, including chest wall. Ventilation (as observed) was dramatically reduced to very small excursion associated with diaphragmatic effort. Over a subsequent short period (typically 3-6 minutes) recruitment of other ventilatory muscle activity progressively improved, with the animal returning to pre-dose ventilatory effort (including chest/abdomen excursion and respiratory rate). These observations suggest that rather than a more centrally-mediated reduction in ventilatory effort/rate, a ‘whole body’ rigidity leading to reduction in minute ventilation. Such whole-body rigidity was significant as it extends beyond simple ‘wooden-chest’ presentation. Key observation include: (1) transient reductions in minute ventilation driven predominantly by decreased tidal volume; (2) progressive respiratory muscle fatigue secondary to sustained rigidity during continuous infusion; and (3) a sequential recovery pattern from whole-body rigidity, beginning with abdominal and followed by thoracic excursions.

Conclusions/Implications for future research and/or clinical care: Continuous fentanyl infusion resulted in transient decreases in minute ventilation, driven primarily by reductions in tidal volume. With sustained infusion, increased body rigidity elevated respiratory effort, contributing to muscular fatigue. Following bolus fentanyl administration, rats exhibited pronounced whole-body rigidity; respiratory activity resumed initially through abdominal excursions, followed by restoration of thoracic motion. These findings suggest that fentanyl-induced respiratory impairment in rats involves substantial mechanical constraints on the respiratory pump, in addition to central depressive effects. This distinction is critical for interpreting therapeutic efficacy in preclinical OIRD studies and for selecting appropriate endpoints in model development.