'Physiological pain' is a first line defense necessary for the preservation of life. The intensity of this pain is correlated with the noxious stimulus intensity and lasts only as long as the stimulus. 'Pathological' or 'chronic pain', on the other hand, is associated with an altered sensitivity to stimuli manifested as allodynia (pain sensations to non-painful stimuli) or hyperalgesia (increased sensitivity to painful stimuli). These pathological pain sensations are not directly correlated to stimulus intensity and commonly outlast the duration of the stimulus. Key to the effective treatment persistent pain is having an understanding of the underlying mechanisms. One molecule that is intimately involved in thermal nociception is VR1. This receptor is almost exclusively expressed in cells involved in nociceptive transmission, and is activated by heat, low pH and capsaicin, the pungent component of hot peppers. Studies of knockout mice show that VR1 is critical for thermal hyperalgesia. Other studies show that inflammation-induced thermal hypersensitivity involves kinase-dependent amplification of capsaicin- or heat-evoked currents, suggesting that VR1 function is upregulated by phosphorylation in response to activation of G protein-coupled receptors for various inflammatory mediators. One such inflammatory mediator is glutamate (Glu), which is released into peripheral tissues during inflammation. We have found that G protein-coupled receptors for Glu (known as metabotropic Glu receptors or mGluRs) are expressed in sensory nerve endings. Peripheral application of mGluR agonists leads to thermal hypersensitivity, whereas antagonists reduce inflammatory hyperalgesia, suggesting that Glu released in the periphery following inflammation is a key mediator of inflammation-evoked hyperalgesia. To gain more understanding of the mechanisms underlying peripheral mGluR modulation of thermal sensitivity, we are studying the phosphorylation and modulation of VR1 by different protein kinases involved in thermal hyperalgesia. These studies will include electrophysiological recordings and Ca2+ imaging to determine the molecular basis of mGluR modulation of VR1, and phosphorylation studies will identify functionally relevant sites of phosphorylation. Finally, we will generate and utilize antibodies that specifically recognize the phosphorylated form of VR1 to determine the conditions under which VR1 is phosphorylated in vivo. These studies will provide valuable insights into the molecular basis for persistent pain states, and may suggest new targets for the development of novel analgesic agents.
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