Project 4: Serotonergic cell subtypes ameliorate sleep-disordered breathing in the setting of opioids

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY/ABSTRACT Opioids are widely used to manage acute and chronic pain in post-surgical and other settings, but even at low doses, they carry debilitating, even life-threatening side effects that are exacerbated during sleep. These include worsening or developing a form of sleep-disordered breathing (SDB) that is treatment-resistant and characterized by respiratory suppression and insufficient upper airway dilator tone. Ensuing conditions range from the extreme of respiratory failure to obstructive sleep apnea with sleep fragmentation and metabolic and cardiovascular comorbidities. This project seeks to identify mechanisms by which brain serotonergic cell subtypes can differentially offset these adverse effects of opioids without compromising analgesia. Here, the focus is on medullary serotonergic neurons of the Tac1-Pet1 population: (1) Tac1-Pet1 neurons innervate motor centers relevant to airway tone and breathing. (2) Tac1-Pet1 neurons largely lack opioid receptor expression and thus are not cell-autonomously affected by opioids; moreover, these neurons act downstream from and thus bypass other neuronal populations that are sensitive to opioids. (3) Pilot data show that Tac1-Pet1 neuron activation en masse lessens or rescues aspects of the opioid-mediated depression of breathing and upper airway tone and the associated irregular breathing. (4) Preliminary data further suggest that neuron subtypes within the Tac1-Pet1 population may separately modulate respiration versus upper airway muscle tone, as the effects of Tac1-Pet1 neuron stimulation on respiratory parameters but not muscle tone are state- or activity-dependent. This difference suggests that distinct mechanisms underlie the respiratory versus muscle tone responses, including differential innervation of target neurons and/or differences within the Tac1-Pet1 neuron population. (5) Indeed, single-cell RNA-sequencing pilot data show at least two subtypes of Tac1-Pet1 neurons (referred to as Group 3 and Group 5), with differential expression of receptors and neurotransmitters, suggesting Group-specific input and output properties. The central hypothesis of this project is that Group 3- versus Group-5-Tac1-Pet1 neurons separately modulate ventilation versus upper airway muscle tone and that group-specific activation during sleep will counter specific adverse effects of opioids. In Aim 1, the molecular and circuit organization of Group 3- versus 5-Tac1-Pet1 neurons will be determined. Aim 2 will uncover which Tac1-Pet1 neuron subtype(s) contribute to lessening respiratory depression and the augmentation of upper airway tone as relevant for mitigating opioid- induced respiratory depression (OIRD) and SDB. In Aim 3, Group 3 versus Group 5 neurons will be separately activated pharmacologically, based on differential receptor expression, to mitigate aspects of OIRD/SDB. This work may have substantial translational value, informing the development of selective, innovative therapies for OIRD and SDB.