Brain stem descending pathways constitute a major mechanism in the modulation of pain transmission by which attentional, motivational and cognitive variables filter ascending information. Recent studies indicate that hyperalgesia in animal models of persistent pain is linked to enhanced activation of descending inhibitory and facilitatory modulatory circuits. Such mechanisms may play an important role in persistent pain conditions such as fibromyalgia, temporomandibular joint disorders, and irritable bowel syndrome by increasing endogenous facilitation leading to an enhancement and spread of the pain. In earlier studies we focused mainly on the activity-dependent plasticity and dynamic temporal changes occurring in the rostral ventromedial medulla (RVM) within the first 24h after complete Freund's adjuvant (CFA)-induced inflammation. The cellular mechanisms mainly responsible for descending inhibition included excitatory amino acid receptors. Less is known about the effects of chemical mediators that contribute to the initiation and maintenance of descending facilitation and behavioral hyperalgesia after inflammation. Therefore, a major objective of our proposal is to determine the chemical signature of RVM circuits involved in the initiation and maintenance of descending facilitation of inflammatory hyperalgesia. Our major hypothesis is that inflammation leads to an increase in the release of multiple chemical mediators whose chemical signature involves activation of a signal transduction cascade in RVM neurons that couples their activity to subunits of the N-methyl-D-aspartate (NMDA) receptor and a descending serotoninergic pathway. We will test these hypotheses utilizing behavioral, molecular, immunohistochemical and pharmacological approaches in the aims presented below.
Aim 1 will test the hypothesis that the balance between descending facilitation and inhibition and their contribution to inflammatory hyperalgesia is dependent, in part, upon the activation of multiple receptors for glutamate, proinflammatory cytokines, brain-derived neurotrophic factor (BDNF) and Substance P.
Aim 2 will test the hypothesis that activation of the receptors for these chemical mediators in the RVM involves changes in receptor expression levels and their activation of signal transduction cascades that lead to phosphorylation of NMDA receptor subunits.
Aim 3 will test the hypothesis that the time course of effect of these chemical mediators is differentially dependent upon primary afferent drive during the initiation and maintenance phases of behavioral hyperalgesia.
Aim 4 will test the hypothesis that descending facilitation produced by BDNF, SP and proinflammatory cytokines is mediated through serotonin-containing descending pathways and spinal 5-HT3 receptors. Finally, Aim 5 will test the hypothesis that these chemical mediators in the RVM contribute to the aversive component of behavioral hyperalgesia via descending circuits originating in the RVM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059028-04
Application #
7778303
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2007-05-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$321,596
Indirect Cost
Name
University of Maryland Baltimore
Department
Dentistry
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Guo, Wei; Miyoshi, Kan; Dubner, Ronald et al. (2014) Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade. Mol Pain 10:35
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
Ren, Ke; Dubner, Ronald (2011) The role of trigeminal interpolaris-caudalis transition zone in persistent orofacial pain. Int Rev Neurobiol 97:207-25
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
Bai, Guang; Wei, Dong; Zou, Shiping et al. (2010) Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia. Mol Pain 6:51
Wei, Feng; Dubner, Ronald; Zou, Shiping et al. (2010) Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain. J Neurosci 30:8624-36
Lagraize, S C; Guo, W; Yang, K et al. (2010) Spinal cord mechanisms mediating behavioral hyperalgesia induced by neurokinin-1 tachykinin receptor activation in the rostral ventromedial medulla. Neuroscience 171:1341-56

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