Chronic pain represents a major unmet clinical need. Studies in our lab are designed to identify molecular mechanisms of sensitization in pain pathways with the goal of identifying novel targets for analgesic intervention. Studies performed under the two previous terms of this grant identified a critical signaling cascade in spinal cord dorsal horn neurons that underlies central pain sensitization. This pathway is initiated by mGlu5 activation of extracellular signal-regulated kinase (ERK1/2) signaling, leading to phosphorylation of a Kv4.2- containing K+ channels, resulting in enhanced excitability of dorsal horn neurons. This increase in excitability likely contributes to central sensitization associated with persistent pain. The studies proposed here will test whether modulation of neuronal excitability and nociceptive behaviors by mGlu5 requires ERK2 (and not ERK1), and whether this is a direct result of phosphorylation of Kv4.2 at a functionally identified phosphorylation site. We will also test the potential clinical utility of fenobam, a clinically validated selective mGlu5 antagonist. We will initially test whether tolerance to the analgesic actions of this drug develops with repeated dosing. Finally, we will take our findings of a key role for mGlu5 in central pain sensitization from the laboratory to the clinic by initiating human trials and asking whether an mGlu5 antagonist can reverse central sensitization in healthy volunteers.

Public Health Relevance

Central sensitization is a term that describes changes in the central nervous system that lead to enhanced pain in the context of injury. Central sensitization is believed to important in the development of chronic pain, and this grant seeks to understand the molecular mechanisms that mediate central sensitization. Also proposed is a study testing whether a drug that reverses central sensitization in animal models can also reverse central sensitization, and thus pain hypersensitivity, in an experimental pain model in healthy human subjects.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Babcock, Debra J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
O'Brien, Daniel E; Alter, Benedict J; Satomoto, Maiko et al. (2015) ERK2 Alone Drives Inflammatory Pain But Cooperates with ERK1 in Sensory Neuron Survival. J Neurosci 35:9491-507
Valtcheva, Manouela V; Davidson, Steve; Zhao, Chengshui et al. (2015) Protein kinase Cδ mediates histamine-evoked itch and responses in pruriceptors. Mol Pain 11:1
Sheahan, Tayler D; Copits, Bryan A; Golden, Judith P et al. (2015) Voluntary Exercise Training: Analysis of Mice in Uninjured, Inflammatory, and Nerve-Injured Pain States. PLoS One 10:e0133191
Chen, Yong; Kanju, Patrick; Fang, Quan et al. (2014) TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor. Pain 155:2662-72
Golden, Judith P; Demaro 3rd, Joseph A; Knoten, Amanda et al. (2013) Dopamine-dependent compensation maintains motor behavior in mice with developmental ablation of dopaminergic neurons. J Neurosci 33:17095-107
O'Brien, Daniel E; Brenner, Daniel S; Gutmann, David H et al. (2013) Assessment of pain and itch behavior in a mouse model of neurofibromatosis type 1. J Pain 14:628-37
Chen, Yong; Williams, Susan H; McNulty, Amy L et al. (2013) Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion. Pain 154:1295-304
Stemler, Kristina M; Crock, Lara W; Lai, H Henry et al. (2013) Protamine sulfate induced bladder injury protects from distention induced bladder pain. J Urol 189:343-51
Cavallone, Laura F; Frey, Karen; Montana, Michael C et al. (2013) Reproducibility of the heat/capsaicin skin sensitization model in healthy volunteers. J Pain Res 6:771-84
Crock, Lara W; Stemler, Kristina M; Song, David G et al. (2012) Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception. Mol Pain 8:20

Showing the most recent 10 out of 28 publications