Michael Bruchas, PhD

Henry Elliot Mallinckrodt Professor of Anesthesiology

Genetic, pharmacological, and behavioral dissection of G-protein coupled receptor signal transduction in pain and neuropsychiatric disorders

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Email: bruchasm@morpheus.wustl.edu
Lab Phone: (314) 747-5754
Website: Bruchas Lab
Lab Location: Clinical Sciences Research Building 5567
Keywords: signal transduction and neural circuits in pain, neuropsychiatric diseases, biochemistry, mouse genetics, behavior, anatomy, optogenetics

Genetic, pharmacological, and behavioral dissection of G-protein coupled receptor signal transduction in pain and neuropsychiatric disorders

Bruchas et al. (2011), Neuron

The Bruchas lab focuses on the genetic, pharmacological, and behavioral dissection of G-protein coupled receptor signal transduction in pain and neuropsychiatric disorders.

Research Projects

Opioid and noradrenergic interactions in stress and drug seeking

It has been well established that the noradrenergic system is important in modulating the rewarding properties of drugs (i.e., morphine, nicotine, and cocaine), anxiety, depression, and in particular the stress-response. In addition, it is now well known that dynorphin/Kappa opioids also modulate these behaviors. This project will use pharmacological, molecular/biochemical, and genetic approaches to characterize and understand the relationship between opioid circuits and noradrenergic circuits in the regulation of stress and motivated behavior. In contrast to the cardiovascular system, the noradrenergic system in the mammalian brain remains poorly understood, and infrequently studied, yet innervates several key brain structures. This opens exciting avenues that could help to uncover this neuromodulaters role in stress-induced behaviors, and potentially identify novel treatment strategies targeting this system.  The results from pilot work have begun to define a putative role of noradrenergic circuits in kappa opioid dependent behavioral effects.  We predict that specific components of the noradrenergic system and its signal transduction pathways are required for dynorphin/KOR-dependent behavioral responses.  Therefore, the primary goal of this project is to understand the neurobiological mechanisms that underlie responses to stress, and how the opioid circuits interact with noradrenergic circuits to ultimately regulate motivated behavior, anxiety, and depression. (Funded by NIH/NIDA through 2014)

Novel receptors and signal transduction pathways in pain, stress, and motivated behaviors

We use multiple biochemical, genetic, and viral approaches to identify new opioid and orphan receptor ligands and biochemical approaches to identify GPCR signaling partners.  One such major interest is the recently “deorphanized” opioid-receptor, Opioid Receptor Like-1 (ORL1).  This receptor and its endogenous ligand  nociceptin are believed to be involved in pain, stress behaviors, and parkinsonism.  Like other opioid receptors, ORL1 is coupled to inhibitory G-proteins, and can interact with the mitogen activated protein kinase (MAPK) cascade, including ERK  1/2 and p38.  We will be developing tools with the ORL1 receptor (Affinity-TAG of ORL1 Receptor for in vitro assays) and in addition we are generating a conditional (floxed) ORL1 receptor mouse, with an affinity-TAG in vivo. This novel “Floxed-TAG ORL1” mouse will allow for the identification of how and where in the CNS ORL1 acts to modulate neurons.  With this technology we will be able to selectively delete ORL1 in specific brain regions, spinal cord cell types, and neuronal populations.  In addition, by introducing an in vivo affinity TAG into this mouse genome, we will be able to visualize the receptor, examine direct neuron and glial cell type effects, and identify novel ORL1-receptor signal transduction networks involved in pain responses and stress-induced motivated behavior.  This project combines in vitro signal transduction with in vivo studies to integrate mechanisms of cellular biology with behavioral output.  Additionally, extension of this project is the identification and characterization of less well studied GPCR systems that may be potentially important in pain and stress related disorders.

Stress, kappa-opioids, and the modulation of nicotine reward

Dynorphin/Kappa opioids have been shown to modulate stress-induced cocaine and alcohol seeking.  This project aims to understand how stress causes potentiation of nicotine reward,  as well as how withdrawal and relapse to drug seeking is mediated by activation of the dynorphin/kappa opioid system.  Preliminary data shows that stress causes potentiation of nicotine reward in a kappa opioid dependent manner, and recent reports have linked the dysphoria associated with nicotine withdrawal to dynorphin/KOR activation.  However, at this time it is unknown which circuits and neuronal cell types mediate these effects.  The goal of this project is to understand the neurobiological mechanism for stress-induced nicotine reward.

Developing novel molecular tools to dissect neurocircuits in pain responses and motivated behavior

The laboratory has a great interest in developing and utilizing new technologies, particularly viral expression techniques, novel reporter systems.  The lab is actively pursuing optogenetic tools (in collaborative efforts) for using light to control (stimulating/inhibiting) selected neuronal cell populations.

In addition, the laboratory’s interest in GPCR signaling requires the development of tools for isolating GPCR signaling partners.  Through the use of affinity TAGs and in vivo proteomic approaches (via collaborative efforts) we hope to detect protein-protein networks important in pain and motivated behavior.