Inflammatory bowel disease (IBD) is characterized by chronic visceral hypersensitivity (VH) that is commonly poorly managed. α2-adrenoceptor (AR) agonists, such as clonidine, are effective analgesics for several types of pathological pain. While α2-AR activation has been shown to reduce somatic inflammatory hyperalgesia and to attenuate visceral pain, a role for α2-ARs in attenuating inflammatory VH has not yet been studied. Furthermore, the cellular mechanisms mediating the analgesic effects of α2-ARs remain unknown. The ion channel TRPV4 has been implicated in visceral and pathologic pain. It is sensitized by activated kinases, and its activity is increased by phosphorylation. Both TRPV4 and α 2-ARs are expressed in dorsal root ganglion neurons and α 2-AR activation decreases kinase activity; therefore, activation of α 2-ARs may lead to decreased TRPV4 phosphorylation and sensitivity, thereby attenuating VH. We hypothesized that VH induced by colon inflammation is attenuated following α2-AR activation in part through modulation of TRPV4 channels expressed on visceral afferents. In this study, we used a rat model of VH, in which adult male rats were treated with intracolonic trinitrobenzene sulfonic acid (TNBS) to induce inflammation, and pain was assessed by recording visceromotor reflexes to colorectal distension.
Our results indicate that TRPV4 is an essential mediator of VH in the TNBS model of colon inflammation, and its expression correlates with VH severity. Furthermore, the relative phosphorylation of TRPV4 seems to be increased in rats with TNBS-induced VH, indicating that a correlation exists between TRPV4 phosphorylation and VH. These results suggest that TRPV4 antagonists could potentially be useful for the treatment of visceral pain in IBD patients with limited therapeutic options. Insight into potential treatments for VH is further provided by results showing that α2-AR activation attenuates VH caused by colon inflammation. Additionally, α2-AR activation decreased TRPV4 phosphorylation in rats with TNBS-induced VH. We suggest that α2-AR agonists are potentially effective analgesics for inflammatory VH and that drugs capable of reducing the phosphorylation levels of TRPV4 may be useful in the treatment of VH associated with colon inflammation, such as the pain experienced by patients with IBD.
|Advisor:||Al-Chaer, Elie D., Hayar, Abdallah|
|Commitee:||Davies, David L., Dobretsov, Maxim, Rhee, Sung W.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Neurobiology and Developmental Science|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 75/09(E), Dissertation Abstracts International|
|Keywords:||Adrenoceptors, Inflammatory bowel disease, Vanilloid receptors, Visceral pain|
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