The clinical orofacial pain syndromes are believed to be frequently related to trigeminal nerve damage as a result of trauma or dental surgery and offer a most difficult challenge to therapy. Trigeminal neuropathic pain occurs more frequently than that at spinal levels, but most animal studies on neuropathic pain describe data from animal models of spinal nerve injuries. Thus, in order to clarify the mechanisms underlying trigeminal neuropathic pain, animal models have to be created specifically for the trigeminal system. Evidence has emerged that the maintenance of neuropathic pain depends on descending facilitation from the rostral ventromedial medulla (RVM), a pivotal structure in descending pain modulation. Recent studies suggest that activated glial cells and released proinflammatory cytokines are intimately involved in spinal sensitization after nerve injury. However, a potential contribution of glial-neuronal interactions in the RVM to the development of neuropathic pain has not been studied. We propose to modify a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION) with a new nocifensive measurement and study novel mechanisms underlying descending facilitation of trigeminal neuropathic pain with an emphasis on glial-neuronal interactions in the RVM. Our major hypotheses are that 1) nerve injury induces neuronal plasticity in the RVM through activation of glial and glutamate receptors and related signaling pathways and 2) glial activation and cytokine release affect or facilitate neuronal plasticity through interactions with neuronal glutamate receptors and play a critical role in the development of neuropathic pain.
Aim 1 will set up a reliable method to measure mechanical hyperalgesia and allodynia in the CCI-ION model and to test the hypothesis that glial cells are activated and proinflammatory cytokines are upregulated in the RVM after nerve injury.
Aim 2 will test the hypothesis that the receptors of these cytokines are expressed in RVM neurons and upregulated in the RVM after CCI-ION.
Aim 3 will test the hypothesis that the inhibition of glial function and blockade of cytokine action in the RVM attenuate allodynia associated with CCI-ION.
Aim 4 will test the hypothesis that glial activation and concomitant cytokine release are involved in neural plasticity in the RVM through interactions with neuronal glutamate receptors, and play a critical role in descending facilitation of neuropathic pain. The studies will advance our understanding of the mechanisms of orofacial neuropathic pain and facilitate the design of new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE018573-04
Application #
7821436
Study Section
Special Emphasis Panel (ZDE1-YL (41))
Program Officer
Kusiak, John W
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$367,167
Indirect Cost
Name
University of Maryland Baltimore
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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(2012) Retraction: Gu et al., ""Spinal 5-HT3 receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade"". J Neurosci 32:18270
Guo, Wei; Wang, Hu; Zou, Shiping et al. (2012) Chemokine signaling involving chemokine (C-C motif) ligand 2 plays a role in descending pain facilitation. Neurosci Bull 28:193-207
Guo, Wei; Wang, Hu; Zou, Shiping et al. (2011) Bone marrow stromal cells produce long-term pain relief in rat models of persistent pain. Stem Cells 29:1294-303
Gu, Ming; Miyoshi, Kan; Dubner, Ronald et al. (2011) Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade. J Neurosci 31:12823-36
Yang, Kun; Takeuchi, Keita; Wei, Feng et al. (2011) Activation of group I mGlu receptors contributes to facilitation of NMDA receptor membrane current in spinal dorsal horn neurons after hind paw inflammation in rats. Eur J Pharmacol 670:509-18
Guo, Wei; Wang, Hu; Zou, Shiping et al. (2010) Long lasting pain hypersensitivity following ligation of the tendon of the masseter muscle in rats: a model of myogenic orofacial pain. Mol Pain 6:40

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