Monday, May 3, 2010

Some new insights into the molecular mechanisms of pain perception....

UT Health Science Center researchers,  lead by Dr. Kenneth M. Hargreaves,  found a new family of fatty acids  produced by the body itself, that play an important role in the biology of pain.

Researchers evaluated the hypothesis that,  the heat sensitivity of TRPV1 is regulated by the generation of endogenous ligands and they found that heat-generated linoleic acid metabolites comprise a family of physiologically relevant TRPV1 agonists that contribute to the heat responsiveness of this channel. More interestingly the results also suggest, a previously unknown mechanism by which TRPV1 might mediate biological actions of oxidized linoleic acid metabolites in conditions such as inflammation and hypotension.

Encouraged by the facts that,  heat activation of TRPV1 (mechanistically distinct from capsaicin sensitivity) appears to occur in a membrane-delimited fashion (during short periods), its dependence on C terminus or voltage gating and their  own results, researchers proposed that heating leads to the generation of oxidized linoleic acid products in the plasma membrane that are important for TRPV1 responses to noxious thermal stimuli. It should be noted that in inflammatory diseases, relatively high levels of HODEs are observed even in extracellular compartments.

The data indicate that 9-HODE and 13-HODE substantially contribute to the heat responsiveness of TRPV1 in vitro and in vivo (apart from intrinsic heat sensitivity of TRPV1). Researchers claim that, heat directly activates TRPV1 with a subsequent generation of endogenous ligands that further amplifies the heat response and biological actions occur only in WT neurons and not neurons from TRPV1.

Researchers conclude by their in vitro and in vivo results that, blockade of the endogenous linoleic acid metabolites substantially decreased responses to thermal stimuli and the heat sensitivity of another member of the TRP family, TRPV4, is mediated via generation of a soluble ligand.

Previous studies have demonstrated that leukotrienes activate TRPV1, epoxyeicosatrienoic acids activate TRPV4, and 4-hydroxynonenal and 15d-PGJ2 activate TRPA1. These results by UT researchers add HODEs as endogenous ligands for TRPV1. It is noteworthy that all these TRP ligands are lipid oxidation products and therefore encouraged the researchers to speculate that, one of the major roles of certain TRP channels in mammals is to act as sensors of membrane lipid oxidation as a surrogate for cellular damage. ..

Ref :

Turning up the Heat on Pain: TRPV1 Receptors in Pain and Inflammation (Progress in Inflammation Research)Vanilloid Receptor TRPV1 in Drug Discovery: Targeting Pain and Other Pathological Disorders

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