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GLT-1 over-expression attenuates visceral nociception by pharmacological and gene therapy approaches

Roman, Kenny M.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1332424243

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
The underlying physiopathology of chronic visceral pain conditions remains unclear due to the complexity of visceral nociceptive signaling. Therefore, therapeutic pain management is suboptimal. Afferent neurons utilize glutamate as the principle neurotransmitter to signal nociceptive activity from visceral organs. Previous studies suggest that transgenic or pharmacologic approaches to over-express the predominant glutamate transporter, GLT-1, responsible for removal of glutamate, produce significant reduction in visceromotor response to colon distension. Thus, strategies to decrease glutamate availability in the synaptic cleft may be useful for visceral pain management. This dissertation explored the effect of GLT-1 over-expression on visceral nociception caused by bladder irritation/inflammation, cross-organ sensitization, and neonatal stress. Moreover, this dissertation addresses the site of action of the anti-nociceptive effect of GLT-1 over-expression, the mechanism of action involving glutamate receptor trafficking, and the efficacy of GLT-1 over-expression long-term. Studies began by examining differences in glutamate uptake and GLT-1 expression in mice treated with ceftriaxone (CTX) for seven days and showed a significant increase in GLT-1 expression and activity compared to control. Next, it was demonstrated that GLT-1 over-expression attenuated the visceromotor response (VMR) to urinary bladder distension (UBD). Moreover, irritation or inflammation of the bladder, which enhances the nociceptive response to UBD, was attenuated by 1 week (1-wk) CTX treatment. The next study addressed the site of action of GLT-1 over-expression to mitigate visceral nociception. Intrathecal treatment with dihydrokainate, a selective GLT-1 antagonist, 1 hour before bladder distension and revealed a dose-dependent reversal of the CTX-mitigated visceromotor response to urinary bladder distension. Moreover, the anti-nociceptive effect of CTX induced GLT-1 over-expression was diminished after 30 days in mice. Finally it was shown that adeno-associated virus serotype 9 (AAV9) 1) crossed the blood-brain barrier and transduced the parenchyma following intravascular neonatal gene delivery, 2) AAV9 carrying the EAAT2 (mouse homologue GLT-1) protein gene increased the glutamate uptake activity, and 3) the AAV9-EAAT2 construct attenuated the nociceptive response to colon distension at the highest distension pressure (60 mm Hg) in adult animals. In summary, these exciting findings suggest that GLT-1/EAAT2 over-expression represents a mechanistic-based approach to mitigate visceral pain.
Robert L. Stephens, Jr., PhD (Advisor)
Michele Basso, PhD (Committee Member)
Tony Buffington, PhD (Committee Member)
Joseph Travers, PhD (Committee Member)
170 p.
Biomedical Research
Bladder; Interstitial cystitis; GLT-1; over-expression; EAAT2; Ceftriaxone; AAV9; Colon; Viscera; Chronic visceral pain;

Recommended Citations

Citations

  • Roman, K. M. (2012). GLT-1 over-expression attenuates visceral nociception by pharmacological and gene therapy approaches [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1332424243

    APA Style (7th edition)

  • Roman, Kenny. GLT-1 over-expression attenuates visceral nociception by pharmacological and gene therapy approaches. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1332424243.

    MLA Style (8th edition)

  • Roman, Kenny. "GLT-1 over-expression attenuates visceral nociception by pharmacological and gene therapy approaches." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1332424243

    Chicago Manual of Style (17th edition)

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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.