The long-term objective of the proposed studies is an enhanced understanding of the cellular mechanisms of nociception and analgesia. The transmission of noxious stimuli from peripheral nociceptors to the spinal cord is dependent in large part on the interaction of substance P (SP), a peptide released from sensory nerve endings, and substance P receptors (SPR) which are expressed by neurons in the spinal cord and dorsal column nuclei (DCN). Recently, we have shown that SP release from primary afferents drives SPR internalization in spinal cord neurons and provides a specific image of the cells activated by SP in the spinal cord in vivo. Building on this and related observations we will: (1) Determine the somatosensory stimuli that induce SP release in the spinal cord and DCN in the normal rat, determine how different anesthetic agents influence the release of SP and the SP-induced SPR internalization, and determine whether morphologically distinct classes of SPR- immunoreactive neurons and glia in the spinal cord and DCN are activated by different modalities of somatosensory stimulation. (2) Determine the neuronal and glial cell types that show an up- regulation of the SPR after nerve injury or in an inflammatory pain state. (3) Determine whether, after nerve injury or in inflammatory pain, there is an increased release or diffusion of SP in the spinal cord or DCN in response to noxious and non-noxious stimuli or nerve stimulation and whether an additional subset of neurons and glia is now activated by SP released from primary afferents. (4) Determine whether opiates, prostaglandins and other ligands that target receptors expressed on the presynaptic terminals of primary afferent neurons differentially modulate the release of SP from sensory neurons in the normal animals vs. animals with nerve injury or persistent inflammatory pain. (5) Using similar techniques that we have successfully employed to raise antibodies to the SPR, raise antibodies that recognize; a subtype of the SPR that has a truncated C-terminus, the neurokinin-2 and neurokinin-3 receptors and determine what role these tachykinin receptors play in nociception and analgesia. The goal of the proposal is to explore the cellular basis of pain perception and discover targets in the signal transduction pathway that may be the most effective points for interventions in the control of pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS023970-12S1
Application #
6092094
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Kitt, Cheryl A
Project Start
1987-04-01
Project End
2000-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Psychiatry
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Chartier, Stephane R; Mitchell, Stefanie A T; Majuta, Lisa A et al. (2018) The Changing Sensory and Sympathetic Innervation of the Young, Adult and Aging Mouse Femur. Neuroscience 387:178-190
Majuta, Lisa A; Mitchell, Stefanie A T; Kuskowski, Michael A et al. (2018) Anti-nerve growth factor does not change physical activity in normal young or aging mice but does increase activity in mice with skeletal pain. Pain 159:2285-2295
Chartier, Stephane R; Mitchell, Stefanie At; Majuta, Lisa A et al. (2017) Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur. Mol Pain 13:1744806917745465
Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2017) Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery-induced pain. Pain 158:605-617
Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2017) Mice with cancer-induced bone pain show a marked decline in day/night activity. Pain Rep 2:e614
Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2016) Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery induced pain. Pain :
Thompson, Michelle L; Chartier, Stephane R; Mitchell, Stefanie A et al. (2016) Preventing painful age-related bone fractures: Anti-sclerostin therapy builds cortical bone and increases the proliferation of osteogenic cells in the periosteum of the geriatric mouse femur. Mol Pain 12:
Guedon, Jean-Marc G; Longo, Geraldine; Majuta, Lisa A et al. (2016) Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain. Pain 157:1239-47
Thompson, Michelle L; Jimenez-Andrade, Juan Miguel; Mantyh, Patrick W (2016) Sclerostin Immunoreactivity Increases in Cortical Bone Osteocytes and Decreases in Articular Cartilage Chondrocytes in Aging Mice. J Histochem Cytochem 64:179-89
Thompson, Michelle L; Jimenez-Andrade, Juan M; Chartier, Stephane et al. (2015) Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer. Pain 156:1692-702

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