The current proposal, for the first time, addresses the role of neuro-immune activation within the central nervous system as a plausible mechanism underlying the visceral pain component of many common functional gastrointestinal disorders (FGID) including irritable bowel syndrome (IBS). Although increasing evidence has emerged for the role of spinal glia in the mechanisms mediating persistent pain, its implication in visceral pain has not been evaluated. We propose the general hypothesis that chronic stress, known as a key factor in the first onset or exacerbation of IBS symptoms, triggers the activation of a spinal network comprising neurons and immune cells (glia), playing a central role in the modulation of visceral nociception. Using a rat model of chronic water avoidance stress, we propose to characterize the role of stress-induced spinal glia activation in the modulation of visceral sensitivity and determine the molecular pathways engaged in the initiation and maintenance of visceral hyperalgesia. Our first specific aim is to assess the temporal profile of spinal glia activation during and after chronic stress and to test the ability of inhibitors specific of glia to reduce stress- induced visceral hyperalgesia. The second specific aim relates to the characterization of molecular mechanisms linking chronic stress and spinal glial activation. The experimental design proposed in this application includes the behavioral assessment of visceral sensitivity in response to different pharmacological treatments (antagonists, agonists, oligonucleotide antisenses), combined with in vitro analysis using Western blotting, multiplex ELISA, immunohistochemistry and quantitative RT-PCR. The long-term goal of the proposed studies is the characterization of signaling pathways underlying the observed endocrine-neural- immune interactions using selective knockout animals and glia/neurons co-cultures. Targeting specific mediators of the glial-neuronal crosstalk may provide an innovative approach for the development of novel therapeutic targets for the treatment of chronic pain conditions associated with enhanced stress responsiveness. The concept of stress-induced modulation of glial-neurons signaling and its implication in long-term alteration of the sensory system may be generalized to many other stress-sensitive pain conditions, including interstitial cystitis, non-cardiac chest pain and fibromyalgia.

Public Health Relevance

In the current proposal, we have developed the concept that chronic stress may induce activation of the immune system in the spinal cord, initiating a cascade of events that will affect the sensory system. This new approach has considerable implication for the development of novel therapeutic targets for the treatment of chronic pain conditions associated with enhanced stress responsiveness, including functional gastrointestinal disorders, for which effective treatment remains a clinical challenge.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
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Purohit, Vishnudutt
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Brentwood Biomedical Research Institute
Los Angeles
United States
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Bradesi, Sylvie; Karagiannides, Iordanes; Bakirtzi, Kyriaki et al. (2015) Identification of Spinal Cord MicroRNA and Gene Signatures in a Model of Chronic Stress-Induced Visceral Hyperalgesia in Rat. PLoS One 10:e0130938
Golovatscka, Viktoriya; Ennes, Helena; Mayer, Emeran A et al. (2012) Chronic stress-induced changes in pro-inflammatory cytokines and spinal glia markers in the rat: a time course study. Neuroimmunomodulation 19:367-76
Holschneider, Daniel P; Bradesi, Sylvie; Mayer, Emeran A (2011) The role of experimental models in developing new treatments for irritable bowel syndrome. Expert Rev Gastroenterol Hepatol 5:43-57
Bradesi, Sylvie; Golovatscka, Viktoriya; Ennes, Helena S et al. (2011) Role of astrocytes and altered regulation of spinal glutamatergic neurotransmission in stress-induced visceral hyperalgesia in rats. Am J Physiol Gastrointest Liver Physiol 301:G580-9
Smith, Ariana L; Leung, Joanne; Kun, Suny et al. (2011) The effects of acute and chronic psychological stress on bladder function in a rodent model. Urology 78:967.e1-7
Bradesi, S (2010) Role of spinal cord glia in the central processing of peripheral pain perception. Neurogastroenterol Motil 22:499-511
Bradesi, Sylvie; Mayer, Emeran A (2009) Experimental models of stress and pain: do they help to develop new therapies? Dig Dis 27 Suppl 1:55-67
Bradesi, S (2009) PAR4: a new role in the modulation of visceral nociception. Neurogastroenterol Motil 21:1129-32