Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia

Abstract

Transient receptor potential vanilloid 1 (TRPV1) plays a major role in hyperalgesia and allodynia and is expressed both in the peripheral and central nervous systems (CNS). However, few studies have evaluated mechanisms by which CNS TRPV1 mediates hyperalgesia and allodynia after injury. We hypothesized that activation of spinal cord systems releases endogenous TRPV1 agonists that evoke the development of mechanical allodynia by this receptor. Using in vitro superfusion, the depolarization of spinal cord triggered the release of oxidized linoleic acid metabolites, such as 9-hydroxyoctadecadienoic acid (9-HODE) that potently activated spinal TRPV1, leading to the development of mechanical allodynia. Subsequent calcium imaging and electrophysiology studies demonstrated that synthetic oxidized linoleic acid metabolites, including 9-HODE, 13-HODE, and 9 and 13-oxoODE, comprise a family of endogenous TRPV1 agonists. In vivo studies demonstrated that intrathecal application of these oxidized linoleic acid metabolites rapidly evokes mechanical allodynia. Finally, intrathecal neutralization of 9-and 13-HODE by antibodies blocks CFA-evoked mechanical allodynia. These data collectively reveal a mechanism by which an endogenous family of lipids activates TRPV1 in the spinal cord, leading to the development of inflammatory hyperalgesia. These findings may integrate many pain disorders and provide an approach for developing analgesic drugs.inflammation ͉ pain T ransient receptor potential vanilloid 1 (TRPV1) plays a pivotal role in many pain models, leading to the development of hyperalgesia and/or allodynia (1-2). TRPV1 is expressed in the peripheral as well as central nervous systems (CNS) including several areas involved in nociceptive transmission (3). Numerous studies have demonstrated that peripheral TRPV1 is activated by noxious heat and protons and is regulated by endogenous ligands (2), contributing to peripheral mechanisms of heat hyperalgesia (4). However, TRPV1 is also expressed in the CNS, where comparatively little is known about the role of this receptor in mediating central pain mechanisms.Recent studies have used TRPV1 antagonists to evaluate the role of CNS TRPV1 in inflammatory hyperalgesia. Interestingly, the systemic/spinal administration of TRPV1 antagonists blocks inflammation-induced heat hyperalgesia, as well as mechanical allodynia (5-6). These findings were unexpected since TRPV1 is not activated by mechanical stimuli, suggesting that spinal TRPV1 activation leads to central sensitization to both thermal and mechanical stimuli (7-8). Based upon these observations, we hypothesized that the afferent barrage resulting from peripheral tissue injury leads to generation of endogenous TRPV1 ligands in the spinal cord that activate TRPV1 in the CNS resulting in central sensitization. Results Depolarization of Spinal Cord Results in the Release of EndogenousTRPV1 Ligands. To evaluate the hypothesis that endogenous TRPV1 agonists are released from spinal cord neurons, freshly isolated male rat spinal cords w...

Fat location defines sensation

“…They make a strong case that these mediators contribute substantially to heat-activated TRPV1 currents in sensory neurons. In this issue of PNAS, Patwardhan et al (2) extend the group's findings to show that depolarized spinal cord neurons also release the same oxidized linoleic acid metabolites that act on TRPV1. This release causes not only thermal hyperalgesia but also mechanical allodynia (pain associated with a normally nonnoxious mechanical stimulus).…”

“…This association makes unraveling the physiological actions of lipid metabolites in pain pathways problematic. Interestingly, there is an association between linoleic acid release and inflammation, raising the possibility that the neutralizing antibodies described by Patwardhan et al (2) could have some therapeutic utility. Linoleic acid metabolites have been associated with GPCR-mediated signaling, as well as human pathologies ranging from type II diabetes to Alzheimer's disease (12,13).…”

Unsaturated Fatty Acids and Pain

“…For example, analysis of serum n-3 and n-6 PUFA composition in patients with the complex regional pain syndrome (a neuropathic pain syndrome associated with autonomic nervous and immune abnormalities) revealed that these patients had significantly increased levels of dihomo-glinolenic acid (C20:3) and docosatetraenoic acid (C22:4). 53) Patwardhan et al 54) also reported that the 9-hydroxyoctadecadienoic acid (9-HODE) and 13-HODE, oxidized linoleic acid metabolites, induced pain. Furthermore, these metabolites, formed upon the exposure of cell membranes to noxious heat, are suggested to activate TRPV1 and contribute to the thermal responsiveness of this channel.…”

Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents

“…TRPV1 can be activated by a variety of endogenous lipids (including lipoxygenase and phospholipase D metabolites of arachidonic acid) and by exogenous substances such as capsaicin (the pungent compound in hot chili peppers) (6). We recently discovered that linoleic acid metabolites are synthesized in the spinal dorsal horn following the afferent barrage due to stimuli such as peripheral inflammation and constitute what we believe to be a novel, physiologically active family of endogenous TRPV1 ligands that mediates central sensitization to mechanical stimuli (7).…”