NOVEL MODULATORS OF THE VANILLOID RECEPTOR

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Linked publications & trials

Abstract

The vanilloid receptor (TRPV1; formerly known as VR1) plays an important role in primary hyperalgesia, a[unreadable] component of chronic pain. TRPV1 is functionally up-regulated in patho-physiologic states such as painful[unreadable] diabetic neuropathy and cystopathy. Activation of TRPV1 occurs through a number of convergent signaling[unreadable] pathways and emerging evidence suggests that TRPV1 function is also negatively regulated by numerous[unreadable] mechanisms. The discovery of novel cellular inhibitors or negative modulators of TRPV1 function and their[unreadable] mode of action should provide additional insights into the role of TRPV1 in peripheral pain signaling and by[unreadable] extension, suggest novel approaches for their application to the control of primary hyperalgesia. We propose[unreadable] to test the hypotheses that (i) novel cellular products play an important role in the inhibition or negative[unreadable] modulation of TRPV1 function and (ii) that vector-based expression of these molecules can control TRPV1[unreadable] signaling in vivo. To test these hypotheses, we have devised a combination of HSV vector-based genetic[unreadable] strategies to identify these potential regulatory molecules and biochemical methods to characterize their role[unreadable] in the negative control of TRPV1 function. Specifically, we will attempt to identify products that (a) inhibit[unreadable] TRPV1 activation by capsaicin (CAP) and resiniferatoxin (RTX) and (b) interfere with TRPV1 potentiation by[unreadable] protein kinase C epsilon (PKCe) activated by Phorbol 12-myristate 13-acetate (PMA). TRPV1 inhibitory[unreadable] genes that either have been engineered or naturally occur, will be studied in some detail to determine the[unreadable] molecular mechanism underlying their ability to impede TRPV1-mediated calcium influx. In four specific aims[unreadable] we intend to (i) create model systems in which HSV TRPV1 expression vectors can be used to examine[unreadable] potential inhibitors of TRPV1 function or calcium overload (ii) create a library of vectors expressing cDNAs[unreadable] derived from rat dorsal root ganglia, (iii) characterize mechanisms by which the selected neuronal gene[unreadable] products inhibit or negatively modulate TRPV1 function and (iv) evaluate the analgesic effects of the[unreadable] engineered and novel TRPV1 inhibitors in vivo using rat models of pain where TRPV1 antagonism has been[unreadable] shown to reduce pain signaling. Both the model inhibitor genes and novel genes obtained by the HSV[unreadable] screening methods will be provided to Projects 1 and 2 for evaluation of their potential analgesic effects in[unreadable] diabetes-related neuropathic pain and models of bladder pain.