Chronic pain is a serious health problem that has remained largely refractory to therapeutic intervention. The development of new pain therapeutics would be aided by a better understanding of the molecular and cellular mechanisms mediating nociception. The Mas-related genes (Mrgs) are a recently discovered, large family of G-protein coupled neuropeptide receptors (GPCRs) that are expressed with exquisite specificity in highly restricted subsets of nociceptive sensory neurons. The goal of this Program Project gram is to mount a concerted, interdisciplinary effort to understand the molecular function of differem Mrgs, the function of the neurons that express them, and the nature of the circuits in which these neurons participate. The project integrates the efforts of three laboratories with complementary expertise. The laboratory of David Anderson, which discovered the Mrgs, will utilize state-of-the art methods of mouse molecular genetics to generate and analyze strains of mice in which different Mrg genes have been deleted, and in which Mrg-expressing neurons can be inducibly ablated or silenced, or their second- and higher-order projections traced. These mice can also be used to prospectively identify Mrg-expressing neurons for physiological and molecular genetic analyses. The laboratory of Allan Basbaum is experienced in the behavioral, neuroanatomical, physiological and pharmacological analysis of nociception, and will collaborate with Anderson's group to thoroughly characterize the phenotypes of mice lacking different Mrg genes, or Mrg-expressing neurons, as well as in the analysis of Mrg synaptic connectivity. Because all Mrg-expressing cells are contained within the IB4-positive subset of nociceptive neurons, this project dovetails with the Basbaum laboratory's ongoing interest in understanding the function of this subpopulation in pain. The laboratory of Melvin Simon has expertise in the molecular genetic analysis of signal transduction by GPCRs and G-proteins. They will apply this expertise to characterize the pharmacology and mechanism of action of Mrgs, as well as to identify both endogenous and surrogate ligands for these receptors. In vitro culture of Mrg-expressing neurons will be employed to analyze and mechanistically dissect the influence of different candidate Mrg ligands, and idemify components of the intracellular signaling circuit. These studies may eventually lead to novel Mrg-based therapeutics for the treatment of pain in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS048499-03
Application #
7231992
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Porter, Linda L
Project Start
2005-01-19
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$1,079,933
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Anderson, David J; Adolphs, Ralph (2014) A framework for studying emotions across species. Cell 157:187-200
Vrontou, Sophia; Wong, Allan M; Rau, Kristofer K et al. (2013) Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo. Nature 493:669-73
Kim, Se-Jeong; Park, Goon Ho; Kim, Donghoon et al. (2011) Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons. Proc Natl Acad Sci U S A 108:3371-6
Bráz, João M; Ackerman, Larry; Basbaum, Allan I (2011) Sciatic nerve transection triggers release and intercellular transfer of a genetically expressed macromolecular tracer in dorsal root ganglia. J Comp Neurol 519:2648-57
Bráz, João M; Basbaum, Allan I (2010) Differential ATF3 expression in dorsal root ganglion neurons reveals the profile of primary afferents engaged by diverse noxious chemical stimuli. Pain 150:290-301
Shields, Shannon D; Cavanaugh, Daniel J; Lee, Hyosang et al. (2010) Pain behavior in the formalin test persists after ablation of the great majority of C-fiber nociceptors. Pain 151:422-9
Scherrer, Gregory; Low, Sarah A; Wang, Xidao et al. (2010) VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity. Proc Natl Acad Sci U S A 107:22296-301
Guan, Yun; Liu, Qin; Tang, Zongxiang et al. (2010) Mas-related G-protein-coupled receptors inhibit pathological pain in mice. Proc Natl Acad Sci U S A 107:15933-8
Bates, E A; Nikai, T; Brennan, K C et al. (2010) Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia 30:170-8
Bráz, J M; Basbaum, A I (2009) Triggering genetically-expressed transneuronal tracers by peripheral axotomy reveals convergent and segregated sensory neuron-spinal cord connectivity. Neuroscience 163:1220-32

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