The metabolism of lipids plays a central role in many higher eukaryotic cellular processes. In addition to their importance in energy production and storage, lipid compounds have been found to be key components in several signaling pathways which regulate pain and inflammation. An early event in the inflammatory response and attendant pain stimuli is the cellular release of lipid-derived mediators which alter the function and biochemistry of surrounding cells and tissues. The ensuing biological responses, as well as much of the pathogenesis which is attributed to inflammation and pain, are thought to be dependent upon the effects of these newly-formed mediators on adjacent cells within the affected region. The synthesis of many lipid mediators is initiated by the cleavage of complex phospholipid precursor molecules to release long-chain fatty acids, such as arachidonate. The availability of free arachidonic acid, a C20 “eicosanoid” fatty acid having four double bonds, represents the rate-limiting step in the formation of a host of bioactive eicosanoid derivatives (e.g., leukotrienes, prostaglandins and thromboxanes) which mediate the inflammatory response and the production of pain and fever (Goodman and Gilman The Pharmacological Basis of Therapeutics (A. Goodman Gilman et al., eds.), Pergamon Press, New York (1990), pp. 600–611; Stryer, Biochemistry (2nd edition), W. H. Freeman and Co., New York (1981), pp. 853–854; Voet and Voet, Biochemistry, John Wiley & Sons, New York (1990) pp. 658–665).
The eicosanoids have a broad spectrum of biological activities related to inflammation and pain, including local vasodialation, activation of neutrophils and platelets, inhibition of platelet aggregation, as well as central nervous system and afferent nerve function. Indeed, one of the earliest analgesics to be identified, aspirin, is known to function by suppressing the synthesis of prostaglandins from arachidonic acid by prostaglandin endoperoxide synthase.
Concomitant with arachidonate release, lysophospholipids are formed. Originally regarded as merely intermediates in lipid biosynthesis (Kent (1995) Anal. Rev. Biochem. 64:315–343), phosphatidic acid (PA), lysophosphatidic acid (LPA), and 1-alkyl-2-acetyl-glycero-3-phosphocholine (Platelet Activating Factor, PAF) have also been identified as phospholipid signaling molecules that affect a wide range of biological responses which include inflammation and pain (McPhail et al., (1995) Proc. Natl. Acad. Sci. USA 92:7931–7935; Williger et al., (1995) J. Biol. Chem. 270:29656–29659, Moolenaar (1995) Curr. Opin. Cell Biol. 7:203–210, and Moolenaar (1995) J. Biol. Chem. 270:12949–12952).
Lipid metabolism is known to also yield components of other pain-related pathways which directly affect nerve termini. The lipid-derived endocannabinoids are endogenous cannabinoid compounds which mediate a number of cellular responses related to pain and inflammation through the cannabinoid (CB) receptors. Closely related to arachidonic compounds, endocannabinoids such as arachidonic acid ethanolamide (anandamide) and 2-arachidoloylglycerol (2-AG) are able to modulate the synthesis, release, and activity of neurotransmitters such as dopamine, GABA, acetylcholine, noradrenaline, and glutamate (Breivogel and Childers (1998) Neurobiol. Dis. 5:417–431, and Martin et al. (1999) Life Sciences 65:573–595, Di Marzo (1999) Life Sciences 65:645–655, Burstein et al. (1994) Biochemical Pharmacology 48:1253–1264, and Pop (1999) Curr. Opinion Chem. Biol. 3:418–425).
It appears that each of the cell types involved in inflammatory and pain response produce and secrete a unique subset of lipid mediators. The quantities and nature of the metabolites depend on which enzymes and precursor phospholipid pools are available to inflammatory cells. Elucidation and molecular characterization of additional molecules that participate in the rich network of biochemical pathways which govern these responses will provide novel therapeutic approaches for pain and inflammatory disorders.
USPTO Backgrounds
USPTO Backgrounds