| 摘要: | 研究期間：10108~10207;Tissue injury, arthritis and cancer often accompany with inflammation, causing inflammatory pain. Inflammatory pain may have a profound effect on a person’s life and the society, when not effectively treated and relieved. Although a variety of pharmacologic treatments are available, they are limited by unacceptable side effects or short-term efficacy. Development of long-acting pharmacologic therapies requires knowledge of how inflammatory pain signals are initially interpreted and subsequently transmitted and perpetuated. Local tissue acidosis is the major factor to induce inflammatory pain. The degree of associated pain or discomfort is well correlated with the magnitude of acidification. This is attributable to direct excitation of primary sensory neurons that detect noxious stimuli (nociceptors) by proton-sensing receptors. After inflammation, expression and functions of proton-sensing ion channels (such as TRPV1 and ASIC family) are enhanced, they are, therefore, considered as the major factors to respond acid, leading to inflammatory pain. Nevertheless, inflammatory pain cannot be completely inhibited in TRPV1 and ASIC deficient mice. Proton-sensing G-protein-coupled receptors (GPCRs) were recently identified, but their roles in inflammatory pain remain unsolved. We have previously found that proton-sensing GPCRs (OGR1, GPR4, TDAG8, G2A) are expressed in nociceptors and their expression is changed after peripheral inflammation. In chronic inflammatory pain model, only TDAG8 expression is increased and TDAG8 activation can enhance TRPV1 function in DRG neurons. It has recently been reported that inhibition of spinal TDAG8-mediated PKA signaling reduces bond caner pain. Whether TDAG8 is involved in regulating inflammatory pain and in the transition from acute to chronic state remain unclear. The objective of this application is to elucidate the mechanism of TDAG8-mediated modulation in chronic inflammatory pain. The proposed work is innovative, as it is, to my knowledge, the first study to elucidate the mechanism of TDAG8-mediated signalling in chronic inflammatory pain using the non-viral gene silencing and single cell imaging techniques. It is expected to yield the following outcomes: identification of TDAG8 involvement in transition from acute to chronic inflammatory pain and elucidation of the molecular mechanisms of TDAG8-mediated TRPV1 sensitization. These results will be significant because they are expected to facilitate understanding of molecular mechanisms of inflammatory pain and to advance the fields of pain research. In addition, it is expected that the results will present useful information for development of new treatments. |
