Oxidized Phospholipid OxPAPC Activates TRPA1 and Contributes to Chronic Inflammatory Pain in Mice.
Oxidation products of the naturally occurring phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine (PAPC), which are known as OxPAPC, accumulate in atherosclerotic lesions and at other sites of inflammation in conditions such as septic inflammation and acute lung injury to exert pro- or anti-inflammatory effects. It is currently unknown whether OxPAPC also contributes to inflammatory pain and peripheral neuronal excitability in these conditions. Here, we observed that OxPAPC dose-dependently and selectively activated human TRPA1 nociceptive ion channels expressed in HEK293 cells in vitro, without any effect on other TRP channels, including TRPV1, TRPV4 and TRPM8. OxPAPC agonist activity was dependent on essential cysteine and lysine residues within the N-terminus of the TRPA1 channel protein. OxPAPC activated calcium influx into a subset of mouse sensory neurons which were also sensitive to the TRPA1 agonist mustard oil. Neuronal OxPAPC responses were largely abolished in neurons isolated from TRPA1-deficient mice. Intraplantar injection of OxPAPC into the mouse hind paw induced acute pain and persistent mechanical hyperalgesia and this effect was attenuated by the TRPA1 inhibitor, HC-030031. More importantly, we found levels of OxPAPC to be significantly increased in inflamed tissue in a mouse model of chronic inflammatory pain, identified by the binding of an OxPAPC-specific antibody. These findings suggest that TRPA1 is a molecular target for OxPAPC and OxPAPC may contribute to chronic inflammatory pain through TRPA1 activation. Targeting against OxPAPC and TRPA1 signaling pathway may be promising in inflammatory pain treatment.
Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, P.R. China.
Boyi
B
Liu
Department of Laboratory and Equipment Administration, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, P.R. China.|Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
Yan
Y
Tai
Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
Ana I
AI
Caceres
Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
Satyanarayana
S
Achanta
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Shrilatha
S
Balakrishna
Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, P.R. China.
Xiaomei
X
Shao
Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, P.R. China.
Junfan
J
Fang
Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
Sven-Eric
http://orcid.org/0000-0001-6171-5622
SE
Jordt
D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D059350:Chronic Pain / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects; D010713:Phosphatidylcholines / Q000378:metabolism / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D010713:Phosphatidylcholines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine