Development of new pharmacological strategies to treat wound pain will require a better understanding of the network of molecular events within nociceptive primary afferents that sensitize these nerve fibers. We have recently obtained compelling evidence that the integrins, a family of cell-surface receptor proteins not previously implicated in pain pathophysiology, plays a pivotal role in nociceptor sensitization. Specifically, integrins are essential in hyperalgesia mediated by both the PKA and PKC pathways activated by inflammatory mediators that are present in wounds. Furthermore, we have determined that integrins are a key element in the molecular events underlying the transition from acute inflammatory hyperalgesia to a state of chronic nociceptive hypersensitivity. Integrin molecules are heterodimers of alpha and beta subunits; the relatively large family of integrin proteins (containing at least two dozen members) and their specific interactions with hyperalgesic pathways present a rich prospect for the discovery of new pharmacological targets for analgesic therapy. The possibility of developing anti-integrin analgesics for use in humans seems very feasible, since such drugs are already being tested in clinical trials for treatment of a wide variety of other pathologies. Toward the ultimate goal of facilitating the rational design of highly specific analgesics to disrupt integrin-dependent mechanisms of wound pain, we propose a detailed analysis of the contributions of integrin subunits to acute and chronic hyperalgesia in the rat. This study will employ ah interdisciplinary approach utilizing behavioral and electrophysiological methods in concert to pharmacologically dissect apart the differential roles of individual integrin subunits in the acute and chronic wound-related pain, with emphasis on pain associated with partial thickness burn injury. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS053880-01A1
Application #
7142165
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Porter, Linda L
Project Start
2006-05-17
Project End
2010-02-28
Budget Start
2006-05-17
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$344,626
Indirect Cost
Name
University of California San Francisco
Department
Dentistry
Type
Schools of Dentistry
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Joseph, E K; Levine, J D (2010) Hyperalgesic priming is restricted to isolectin B4-positive nociceptors. Neuroscience 169:431-5
Dina, Olayinka A; Joseph, Elizabeth K; Levine, Jon D et al. (2010) Mechanisms mediating vibration-induced chronic musculoskeletal pain analyzed in the rat. J Pain 11:369-77
Joseph, Elizabeth K; Reichling, David B; Levine, Jon D (2010) Shared mechanisms for opioid tolerance and a transition to chronic pain. J Neurosci 30:4660-6
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Alessandri-Haber, Nicole; Dina, Olayinka A; Chen, Xiaoje et al. (2009) TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. J Neurosci 29:6217-28
Reichling, David B; Levine, Jon D (2009) Critical role of nociceptor plasticity in chronic pain. Trends Neurosci 32:611-8
Bogen, Oliver; Joseph, Elizabeth K; Chen, Xiaojie et al. (2008) GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican. Eur J Neurosci 28:12-9
Alessandri-Haber, Nicole; Dina, Olayinka A; Joseph, Elizabeth K et al. (2008) Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia. J Neurosci 28:1046-57

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