Death from opioid overdose is primarily due to respiratory depression, yet little is known about the cellular mechanisms of opioids on respiratory-controlling neurons. The long-term goal is to become an independent tenure-track investigator studying the mechanisms responsible for the respiratory depressant effects of opioids. This proposal has been designed to supplement the candidate's background in opioid pharmacology and brain slice electrophysiology and provide the additional knowledge and technical skills in respiratory physiology required to accomplish this goal. Opioids have been shown to suppress respiration through multiple areas of the central respiratory network, including the preBotzinger complex in the medulla and the Kolliker-Fuse (KF) nucleus in the pons. Although opioids have been shown to inhibit preBotzinger neurons, the mechanism of opioid actions in the KF has not been studied and is therefore unknown. The immediate goal of this proposal is to determine how opioids modulate KF neurons to alter respiration. The hypothesis is that opioids hyperpolarize KF neurons to disrupt the respiratory network. This hypothesis will be tested by recording (1) from KF neurons in brain slices and (2) from KF neurons and respiratory nerves in an in situ preparation with intact respiratory network and in vivo respiratory cycle.
In Aim 1, extracellular recording from the in situ preparation will identif the respiratory phenotype of KF neurons inhibited by opioids. This new technical skill will be learned through consultation with Drs. Ana Abdala and Julian Paton (University of Bristol) and Mary Heinricher (OHSU) and will be a critical component of the candidate's career development. Given the lack of tolerance to the respiratory depressant effect of opioids, the hypothesis of Aim 2 is that there will be very little tolerance and desensitization of mu opioid receptors on KF neurons. The goal of Aim 3, which will be performed during the independent phase of this award, is to identify the location and function of 5-HT1A receptors that can reverse opioid-induced respiratory depression. A therapeutic strategy such as 5-HT1A agonists that can reverse respiratory depression, but leave analgesia intact would be a significant advance. Mentorship from John Williams, who is a world-renowned electro physiologist and has mentored over 20 scientists to achieve independent careers, will provide continued training in brain slice electrophysiology and development of skills to manage an independent research group. New knowledge in respiratory physiology will be acquired from co-mentor John Bissonnette (OHSU), who has over 30 years of experience in neural control of respiration. The new knowledge, technical skills, continued productivity and practical career guidance will place the candidate in competitive position to become a tenure-track assistant professor studying the respiratory depressant effects of opioids from a cellular and network perspective.
The primary cause of death from opioid overdose is respiratory depression, but the mechanisms responsible are unclear. This proposal will investigate the effect of opioids on brainstem neurons that control respiration. Results will revea information about the relative lack of tolerance to the respiratory depressant effect of opioids, and may lead to alternative strategies to prevent respiratory depression.
| Levitt, Erica S; Williams, John T (2018) Desensitization and Tolerance of Mu Opioid Receptors on Pontine Kölliker-Fuse Neurons. Mol Pharmacol 93:8-13 |
