Abstract
Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen-induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology*
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Apolipoprotein A-I / pharmacology*
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Arthritis, Experimental / chemically induced
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / metabolism
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Arthritis, Experimental / pathology
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Calcium / metabolism
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Calcium Signaling / drug effects
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Collagen Type II / administration & dosage
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Female
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Gene Expression
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HEK293 Cells
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Hindlimb
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Humans
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Hyperalgesia / chemically induced
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Hyperalgesia / drug therapy*
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Hyperalgesia / metabolism
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Hyperalgesia / pathology
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Male
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Nociception / drug effects
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Nociception / physiology
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Pain / chemically induced
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Pain / drug therapy*
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Pain / metabolism
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Pain / pathology
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Patch-Clamp Techniques
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Phosphatidylcholines / antagonists & inhibitors*
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Phosphatidylcholines / metabolism
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Phosphatidylcholines / pharmacology
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Rats
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Rats, Inbred Lew
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Rats, Wistar
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TRPA1 Cation Channel / antagonists & inhibitors
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TRPA1 Cation Channel / genetics*
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TRPA1 Cation Channel / metabolism
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TRPV Cation Channels / antagonists & inhibitors
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TRPV Cation Channels / genetics*
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TRPV Cation Channels / metabolism
Substances
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Antibodies, Monoclonal
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Apolipoprotein A-I
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Collagen Type II
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D-4F peptide
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Phosphatidylcholines
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TRPA1 Cation Channel
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TRPV Cation Channels
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Trpa1 protein, rat
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Trpv1 protein, rat
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oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine
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Calcium