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J Neurosci. 2014 Nov 12;34(46):15184-91. doi: 10.1523/JNEUROSCI.3475-14.2014.

A lipid gate for the peripheral control of pain.

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Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, California 92697-1275, Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy 16163,
Department of Psychological and Brain Sciences and Program in Neuroscience, and Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana 47405.
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and.
Department of Entomology, University of California, Davies, California 95616-8584.


Cells in injured and inflamed tissues produce a number of proalgesic lipid-derived mediators, which excite nociceptive neurons by activating selective G-protein-coupled receptors or ligand-gated ion channels. Recent work has shown that these proalgesic factors are counteracted by a distinct group of lipid molecules that lower nociceptor excitability and attenuate nociception in peripheral tissues. Analgesic lipid mediators include endogenous agonists of cannabinoid receptors (endocannabinoids), lipid-amide agonists of peroxisome proliferator-activated receptor-α, and products of oxidative metabolism of polyunsaturated fatty acids via cytochrome P450 and other enzyme pathways. Evidence indicates that these lipid messengers are produced and act at different stages of inflammation and the response to tissue injury, and may be part of a peripheral gating mechanism that regulates the access of nociceptive information to the spinal cord and the brain. Growing knowledge about this peripheral control system may be used to discover safer medicines for pain.

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