Despite tremendous progress in our understanding of the primary sensory neurons and spinal cord interneuronal circuits that respond to and transmit pain and itch-provoking stimuli, how these stimuli are interpreted by the brain to produce the perceptions of pain and itch are still unclear. To a great extent, this gap in our knowledge reflects the much more limited information that we have about the projection neurons that carry the information from the spinal cord to the brain. That gap is critical as it is the signals carried by the projection neurons that are ?read? by the brain and that ultimately lead to a perception of pain or itch, and to their various submodalities (heat, cold, mechanical, etc.). Our research program is multidisciplinary, using novel viral, genetic and functional (electrophysiological, behavioral and imaging) approaches to characterize the properties of the projection neurons, the circuits that engage them, their supraspinal targets and the functional consequence of their activity. An important focus of the research program is on the question of convergence or segregation of the circuits that respond to painful or itch-provoking stimuli and the extent to which these circuits are altered in the setting of injury. Our program includes several highly innovative experiments that for the first time will not only determine the molecular heterogeneity of the projection neurons, but will also examine the responses of populations of neurons in the brain to activity in the projection neurons. Defining molecular subtypes of projection neurons and the development of Cre-expressing mice based on these molecular features will permit a host of experiments, including viral-based retrograde (rabies) and anterograde (HSV) tracing of circuits that influence subsets of projection neurons, as well as the behavioral consequence of selective ablation, or DREADD-mediated activation/inhibition of these neurons. Finally, using incredibly powerful Ca2+ imaging techniques that signal the activity of populations of neurons in awake, freely moving mice, we will obtain new information on the behavioral correlates of algogen and pruritogen-evoked supraspinal activity. Using novel behavioral paradigms our program will also provide important insights into the processes through which noxious, and even innocuous stimuli (in the setting of injury), are interpreted as painful. These new approaches will provide information about the quality of the pain that the animal experiences and also offer a powerful validation of the mouse models of chronic pain and itch and their translatability to the human condition.

Public Health Relevance

Our program of research uses molecular, genetic, neuroanatomical, cellular imaging and behavioral approaches to provide a comprehensive analysis of the circuits that transmit pain and itch messages to the brain. This program will provide a more complete picture of the extent to which pain and itch circuits remain independent or interact throughout the neuroaxis and we will continue to develop revolutionary cell transplantation approaches to the management of chronic pain and itch.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
5R35NS097306-03
Application #
9616306
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Oshinsky, Michael L
Project Start
2016-12-01
Project End
2024-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Llewellyn-Smith, Ida J; Basbaum, Allan I; Bráz, João M (2018) Long-term, dynamic synaptic reorganization after GABAergic precursor cell transplantation into adult mouse spinal cord. J Comp Neurol 526:480-495
Price, Theodore J; Basbaum, Allan I; Bresnahan, Jacqueline et al. (2018) Transition to chronic pain: opportunities for novel therapeutics. Nat Rev Neurosci :
Dickie, Allen C; Bell, Andrew M; Iwagaki, Noboru et al. (2018) Morphological and functional properties distinguish the substance P and gastrin-releasing peptide subsets of excitatory interneuron in the spinal cord dorsal horn. Pain :
Tran, May; Kuhn, Julia A; Bráz, João M et al. (2017) Neuronal aromatase expression in pain processing regions of the medullary and spinal cord dorsal horn. J Comp Neurol 525:3414-3428
Zhang, Chuchu; Medzihradszky, Katalin F; Sánchez, Elda E et al. (2017) Lys49 myotoxin from the Brazilian lancehead pit viper elicits pain through regulated ATP release. Proc Natl Acad Sci U S A 114:E2524-E2532
Cevikbas, Ferda; Braz, Joao M; Wang, Xidao et al. (2017) Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis. J Allergy Clin Immunol 140:454-464.e2
Basbaum, Allan (2017) Chemogenetic management of neuropathic pain. Brain 140:2522-2525
Braz, Joao M; Etlin, Alex; Juarez-Salinas, Dina et al. (2017) Rebuilding CNS inhibitory circuits to control chronic neuropathic pain and itch. Prog Brain Res 231:87-105