Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Jain, P.
Behavioral characterization and signaling mechanisms of visceral pain in a mouse model of psychological stress and experimental colitis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2016. pp. 133
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- Autor*innen der Med Uni Graz:
- JAIN Piyush
- Betreuer*innen:
- Holzer Peter
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- Abstract:
- Introduction: Functional gastrointestinal disorders with abdominal pain are associated with central sensitization and psychological disorders that often are triggered or exacerbated by stress. The transient receptor potential ankyrin 1 (TRPA1) channel is a major transducer of nociceptive signals and is involved in hypersensitivity conditions. The current dissertation project set out to study the multi-dimensional aspects of visceral pain in an animal model involving colitis and stress. Material and methods: Four groups of mice (C57BL/6N) were studied: control mice, mice treated with dextran sulphate sodium (DSS), mice exposed to water avoidance stress (WAS) 1 hour daily, and mice treated with DSS+WAS for the duration of one week. Following these treatments, various dimensions of behavior were assessed, and the pain sensitivity to mechanical stimuli and thermal stimuli evaluated. Neurochemical alterations in the central nervous system (CNS; spinal cord, thalamus, hypothalamus, amygdala and prefrontal cortex) were measured by the expression pp38 and pp42/44 mitogen activated protein kinases (MAPKs). Behavioral changes (freezing, locomotion, rearing) and the expression of c-Fos and MAPKs in the CNS were also determined in response to intracolonic allyl isothiocyanate (AITC) following pre-treatment with an opioid analgesic (morphine). Pharmacological blockade of TRPA1 by the selective antagonist HC-030031 and genetic deletion of TRPA1 were used to investigate the role of TRPA1 in DSS-induced colitis. The expression of mRNA of different TRP channels was quantified in isolated dorsal root ganglion (DRG) neurons of control and DSS-treated mice. I further investigated whether the nociceptive alterations in colitis are reflected by potentiation of TRPA1 channels in DRG neurons and calcitonin gene related peptide release in the spinal cord. Results and discussion: Induction of colitis was confirmed by a decrease in colon length but increased colonic weight, disease activity score and colonic myeloperoxidase levels, these changes remaining unaffected by WAS. Exposure to WAS led to increased locomotion and rearing as well as self-care and motivational behaviour. WAS-exposed and DSS-treated mice were hypersensitive to mechanical and thermal pain stimuli (abdominal and plantar skin), changes that were paralleled by increased c-Fos expression in the spinal cord and brain. DSS treatment caused an increase in pp42/44 MAPK expression in the spinal cord, while WAS exposure caused an increase in pp38 and pp42/44 MAPK expression in all brain regions. Combined treatment with WAS and DSS did not change pain sensitivity (mechanical and thermal) and c-Fos expression in the CNS. Intrarectal AITC administration enhanced freezing behaviour, led to expression of c-Fos, pp38, and pp42/44 in the CNS and diminished locomotion and rearing, which reflects the discriminative, emotional and autonomic processing of a visceral pain stimulus. Morphine reduced specific aspects of the behavioral and neurochemical pain response to intrarectal AITC administration, which affirms that these aspects involved opioid-sensitive pain pathways in the CNS. In addition, DSS treatment increased the mechanical and thermal sensitivity (abdominal, facial and plantar skin). The TRPA1 antagonist and genetic deletion of TRPA1 reduced mechanical sensitivity of both the abdominal and facial region. DSS treatment caused an increase in TRPA1 mRNA expression in the DRG neurons. DSS-induced colitis increased the sensitivity of primary sensory neurons to the TRPA1 agonist, AITC. Taken together, the current findings indicate that the multidimensional aspects of visceral pain can be modeled in mice by the assessment of various behavioral parameters and neurochemical alterations in the CNS. Finally, I conclude that the TRPA1 channel participates in colitis-associated pain hypersensitivity at the somatic level.