Chronic visceral pain, especially pain from irritable bowel syndrome or visceral cancer pain, results in major social and health problems and represents one of the most common causes of work absenteeism, long term suffering and disability. Recently, midline myelotomy, a neurosurgical intervention which severs midline axons in the spinal dorsal column, has proved to be successful in alleviating otherwise visceral cancer pain. This approach is based on the interruption of a newly discovered pathway, the postsynaptic dorsal column (PSDC) pathway that transmits visceral painful information. However, the neurobiology of this pathway for visceral nociceptive transmission is inadequately understood. The major objective of this grant application is to examine the role of the immediate early gene, c-Jun, and its regulatory N-terminal protein kinase (JNK) and JNK subunits, in spinal PSDC neurons that process visceral nociceptive information. We hypothesize that the response of spinal viscero-sensitive neurons, especially PSDC neurons, involves the enhancement of c-Jun and phospho-c-Jun and that their activation is regulated by JNK phosphorylation. We will use multidisciplinary approaches, including morphological, molecular, electrophysiological and pharmacological approaches as well as behavioral tests to examine whether the JNK/c-Jun cascade is involved in central visceral nociception, especially in the PSDC pathway, in a rat model of experimentally induced visceral pain. To test our hypothesis, the specific aims of our studies are to measure during visceral pain stimulation: I) the activation of the transcription factor c-Jun and its phosphorylation in the rat spinal cord and specifically in the PSDC pathway; II) the changes in expression of p-c-Jun by inhibition of JNK/c-Jun cascade following visceral pain and determine if changes occur in cellular response of PSDC neurons, as well as in exploratory behavior; III) the expression of neurokinin NK1 receptors in spinal cord and PSDC neurons following inhibition of JNK activity. These studies are important because they should elucidate the signal-transduction mechanisms involved in the processing of visceral nociception that may, in turn, lead to development of drugs selective for management of visceral pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Small Research Grants (R03)
Project #
5R03DE015814-02
Application #
7010000
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
2005-02-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2008-01-31
Support Year
2
Fiscal Year
2006
Total Cost
$73,726
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Surgery
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Wang, Yun; Wu, Jing; Wu, Zhiguo et al. (2010) Regulation of AMPA receptors in spinal nociception. Mol Pain 6:5
Mu, Xiaobo; Wu, Anshi; Wu, Jing et al. (2010) Effects of anesthetic propofol on release of amino acids from the spinal cord during visceral pain. Neurosci Lett 484:206-9
Xu, Xijin; Wang, Peng; Zou, Xiaoju et al. (2009) Increases in transient receptor potential vanilloid-1 mRNA and protein in primary afferent neurons stimulated by protein kinase C and their possible role in neurogenic inflammation. J Neurosci Res 87:482-94
Wu, Jing; Zhang, Xuan; Nauta, Haring J et al. (2008) JNK1 regulates histone acetylation in trigeminal neurons following chemical stimulation. Biochem Biophys Res Commun 376:781-6
Wang, Yun; Wu, Jing; Lin, Qing et al. (2008) Effects of general anesthetics on visceral pain transmission in the spinal cord. Mol Pain 4:50
Li, Dingge; Ren, Yong; Xu, Xijin et al. (2008) Sensitization of primary afferent nociceptors induced by intradermal capsaicin involves the peripheral release of calcitonin gene-related Peptide driven by dorsal root reflexes. J Pain 9:1155-68
Huang, Ping; Qi, Zhifeng; Bu, Xiangning et al. (2007) Neuron-specific phosphorylation of mitogen- and stress-activated protein kinase-1 involved in cerebral hypoxic preconditioning of mice. J Neurosci Res 85:1279-87
Wu, Jing; Su, Guangxiao; Ma, Long et al. (2007) The role of c-AMP-dependent protein kinase in spinal cord and post synaptic dorsal column neurons in a rat model of visceral pain. Neurochem Int 50:710-8
Bu, Xiangning; Huang, Ping; Qi, Zhifeng et al. (2007) Cell type-specific activation of p38 MAPK in the brain regions of hypoxic preconditioned mice. Neurochem Int 51:459-66
Qi, Zhifeng; Bu, Xiangning; Huang, Ping et al. (2007) Increased membrane/nuclear translocation and phosphorylation of p90 KD ribosomal S6 kinase in the brain of hypoxic preconditioned mice. Neurochem Res 32:1450-9

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