Role of endogenous vanilloids and cannabinoids in pain

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DESCRIPTION (provided by applicant): The study of pro- and anti-nociceptive molecules produced by the body may yield important targets for improved treatments of pain. A recent and promising avenue of research has been the elucidation of the biological effects of a family of lipid signalling molecules referred to as fatty acid amides. The proposed experiments focus on the characterization of N-acyldopamines, a novel group of fatty acid amides that may serve as signalling ligands for the vanilloid and/or cannabinoid receptors. Since activation of cannabinoid receptors typically suppresses pain, while activation of vanilloid receptors (e.g. by capsaicin) typically heightens sensitivity to pain, N-acyldopamines may serve endogenously to facilitate or dampen pain. We hypothesize that the actions of these molecules depend on the locations at which they are formed and the state of the cellular environment. Hence, we plan to investigate the occurrence of these compounds at various sites within the nervous system and the effect of various physiological and pathophysiological conditions such as inflammation on their formation and bioactivity. In addition to examining cannabinoid and vanilloid mechanisms, we plan to examine oxygenated metabolites of NADA that we observed in vivo. The proposal aims to elucidate the biology and function of endogenous N-acyldopamines and their oxygenated metabolites in order to enhance our understanding of this emerging class of molecules, which may be important to the perception and modulation of pain. A better understanding of this system may yield novel targets for drug development aimed at treating pain and/or inflammation.