Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation

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.

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice

“…Phosphocholine (PC) containing oxidized phospholipids (OxPL) are a prominent example, and the PC headgroup of OxPL in OxLDL (as a lipid or OxPL-protein adduct) is recognized by macrophage scavenger receptors and TLRs, by innate protein CRP and by the IgM natural antibody (NAb) E06 1 . OxPLs accumulate in OxLDL, apoptotic cells and microparticles released by activated and dying cells 4,6 and are ubiquitous in a wide variety of inflammatory settings, including atherosclerosis 7 , pulmonary 8,9 and neurological diseases 10-12 and NASH 13 among others 1 . In addition, OxPL present on Lp(a) are thought to mediate, in part, the ability of Lp(a) to promote atherogenesis and calcific aortic valve disease (CAVD) 14 .…”

Antinociception by the anti‐oxidized phospholipid antibody E06

“…Recently, we and others have shown that OxPL including oxidized 1‐palmitoyl‐2‐arachidonoyl‐sn‐glycero‐3‐phosphocholine (OxPAPC) activate heterologous and native TRPA1 as well as TRPV1 channels in vitro . Once locally injected, these lipids elicit thermal and mechanical hypersensitivity as well as acute nociception in vivo (Patwardhan et al ., ; Liu et al ., ; Oehler et al ., ). Furthermore, we showed that OxPAPC‐mediated activation of TRPA1 channels in vitro , as well as thermal and mechanical hypersensitivity induced by OxPAPC in vivo are blocked by a function‐blocking autoantibody against oxidized phosphatidylcholine (OxPC), the E06 monoclonal antibody (Oehler et al ., ).…”

“…Once locally injected, these lipids elicit thermal and mechanical hypersensitivity as well as acute nociception in vivo (Patwardhan et al ., ; Liu et al ., ; Oehler et al ., ). Furthermore, we showed that OxPAPC‐mediated activation of TRPA1 channels in vitro , as well as thermal and mechanical hypersensitivity induced by OxPAPC in vivo are blocked by a function‐blocking autoantibody against oxidized phosphatidylcholine (OxPC), the E06 monoclonal antibody (Oehler et al ., ). In addition, mechanical hypersensitivity in hind paw inflammation induced by complete Freund's adjuvant (CFA) and in collagen‐induced arthritis was ameliorated.…”

Diverse TRPV1 responses to cannabinoids

“…Channels of the Transient Receptor Superfamily (TRP), such as TRPV1, TRPM8, and TRPA1, are non-selective cation channels that conduct calcium and sodium into a range of cell types in mammals. They are present on sensory neurons, and were initially identified as having a role in nocioception because of their responsiveness at the molecular level to plant secondary metabolites that are nocimimetic (e.g., Capsaicin) and to compounds that are otherwise pungent and mimic burning or cooling sensations (e.g., allicin, cinnamaldehyde, menthol) [31][32][33][34][35][36]. Several of these channels are targets for cannabinoids including THC, CBD and CBN and some minor Cannabis compounds [37][38][39][40][41][42][43][44].…”