The major hypothesis of this study is that following induction of inflammation, ascending tonic nociceptive inputs induce prolonged functional changes in the neural circuitry at brainstem sites leading ultimately to a net inhibitory modulation of spinal cord activity. This input to the brainstem triggers a cascade of molecular, biochemical and electrophysiological events that result in enhanced excitability and inducible changes in neurotransmitters and receptor populations.
Specific Aim 1 will test the hypothesis that persistent inflammation leads to time-dependent, dynamic changes in the neuronal excitability of medullary brain stem nuclei.
Specific Aim 2 will test the hypothesis that endogenous mechanisms of inflammation-induced changes in the excitability of medullary brain stem neurons involve excitatory and inhibitory amino acids, opioid peptides and their receptors.
Specific Aim 3 will use molecular and immunohistochemical probes to test the hypothesis that alterations in EAA receptor activation play a key role in enkephalinergic transmission and that reduced GABAergic transmission in the RVM is mediated via postsynaptic mu opioid receptors (MORs) after inflammation.
Specific Aim 4 will test the hypothesis that changes in brain stem excitability after inflammation lead to alterations in the response profile of several different classes of neurons in the RVM. These events will be explored in a lightly anesthetized rat preparation in which both behavioral and electrophysiological responses to hindpaw inflammation can be ascertained sequentially over time. Hindpaw inflammation will be induced with complete Freund's adjuvant (CFA) and the studies done over specific, but relatively short, time frames during the development phase of this persistent inflammatory state. Fixed brainstem tissues from other animals with CFA inflamed hindpaws will be compared to control tissues to determine specific inducible neurotransmitter and receptor changes subsequent to inflammation. The screening process will include anatomical studies identifying excitatory amino acid (EAA) and preproenkephalin (PPE) receptor mRNA expression increases, as well as immunocytochemical localization of changes in Fos, GABA, mu opioid receptor, and glutamate receptor subunit NMDA NR1 expression with specific antibodies. The findings of this study will improve understanding of supraspinally initiated descending mechanisms that modulate the pain experience through alteration of the nociceptive information relayed from the spinal cord.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010275-07
Application #
6515557
Study Section
Special Emphasis Panel (ZRG1-IFCN-5 (03))
Program Officer
Thomas, David A
Project Start
1996-06-20
Project End
2005-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
7
Fiscal Year
2002
Total Cost
$334,125
Indirect Cost
Name
University of Maryland Baltimore
Department
Dentistry
Type
Schools of Dentistry
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Ren, Ke; Dubner, Ronald (2007) Pain facilitation and activity-dependent plasticity in pain modulatory circuitry: role of BDNF-TrkB signaling and NMDA receptors. Mol Neurobiol 35:224-35
Guo, Wei; Wang, Hu; Watanabe, Mineo et al. (2007) Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 27:6006-18
Guo, Wei; Robbins, Meredith T; Wei, Feng et al. (2006) Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation. J Neurosci 26:126-37
Dubner, Ronald; Ren, Ke (2004) Brainstem mechanisms of persistent pain following injury. J Orofac Pain 18:299-305
Anseloni, V; Ren, K; Dubner, R et al. (2004) Ontogeny of analgesia elicited by non-nutritive suckling in acute and persistent neonatal rat pain models. Pain 109:507-13
Guan, Yun; Guo, Wei; Robbins, Meredith T et al. (2004) Changes in AMPA receptor phosphorylation in the rostral ventromedial medulla after inflammatory hyperalgesia in rats. Neurosci Lett 366:201-5
Guo, Wei; Wei, Feng; Zou, Shiping et al. (2004) Group I metabotropic glutamate receptor NMDA receptor coupling and signaling cascade mediate spinal dorsal horn NMDA receptor 2B tyrosine phosphorylation associated with inflammatory hyperalgesia. J Neurosci 24:9161-73
Guan, Yun; Guo, Wei; Zou, Shi-Ping et al. (2003) Inflammation-induced upregulation of AMPA receptor subunit expression in brain stem pain modulatory circuitry. Pain 104:401-13
Guo, Wei; Zou, Shiping; Tal, Michael et al. (2002) Activation of spinal kainate receptors after inflammation: behavioral hyperalgesia and subunit gene expression. Eur J Pharmacol 452:309-18
Terayama, R; Dubner, R; Ren, K (2002) The roles of NMDA receptor activation and nucleus reticularis gigantocellularis in the time-dependent changes in descending inhibition after inflammation. Pain 97:171-81

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