Potential mechanisms of opioid depression of the laryngeal adductor reflex: insights from a neuromechanical model of the respiratory control system

Abstract

Opioid use increases the risk of aspiration and pneumonia, presumably through depression of protective reflexes that prevent intrusion of foreign material into the airways. The laryngeal adductor reflex (LAR) is an airway protective behavior that utilizes bilateral thyroarytenoid (TA) muscles and prevents material entering the trachea and lungs. The operational features and specific neural mechanisms which regulate and coordinate the occurrence of the LAR to prevent aspiration during opioid use are not fully understood. In vivo experiments were conducted using unilateral electrical stimulation of the superior laryngeal nerve (SLN) to induce the LAR. Systemic opioid administration preferentially attenuated the contralateral LAR, which is consistent with dysregulation of airway protection. We speculated that computational modeling of a specific LAR circuit would provide testable hypotheses that could account for this effect of opioids on the LAR. We have developed a predictive computational model which incorporates a distributed neural network that excites expiratory laryngeal motoneurons (ELM). The stochastic neural network simulator consists of discrete “integrate and fire” populations. The model circuit was informed by response patterns during the LAR of neurons in the regions of the nucleus tractus solitarius (NTS), the reticular formation (RF), and the ventrolateral respiratory column (VRC). With our network scale model, we simulated modulation of the LAR during administration of opioids by decreasing input currents to neurons in the RF that provide presynaptic input to ELMs of the VRC and then we activated laryngeal receptors. Simulator outputs were compared to collected in vivo data. Computer simulations reproduced the temporal features of the LAR, and the unilateral effects of opioids on the LAR by increasing potassium conductance of presynaptic neurons, depressing presynaptic terminal excitability, and hyperpolarizing ELM populations. Simulations of the LAR and phasic breathing suggest that an important area of focus for modeling efforts will be (i) refining the spatiotemporal characteristics of the behavior, (ii) the potential role of NTS laryngeal interneuronal networks in the effects of opioids, and (iii) synaptic regulation of oscillatory behavior of the LAR.Support or Funding InformationSupported by NIH HL131716, 3OT2OD023854, and NS 110169.