A lipid gate for the peripheral control of pain

Abstract

Cells in injured and inflamed tissues produce a number of proalgesic lipid-derived mediators, which excite nociceptive neurons by activating selective G-protein-coupled receptors or ligand-gated ion channels. Recent work has shown that these proalgesic factors are counteracted by a distinct group of lipid molecules that lower nociceptor excitability and attenuate nociception in peripheral tissues. Analgesic lipid mediators include endogenous agonists of cannabinoid receptors (endocannabinoids), lipid-amide agonists of peroxisome proliferator-activated receptor-α, and products of oxidative metabolism of polyunsaturated fatty acids via cytochrome P450 and other enzyme pathways. Evidence indicates that these lipid messengers are produced and act at different stages of inflammation and the response to tissue injury, and may be part of a peripheral gating mechanism that regulates the access of nociceptive information to the spinal cord and the brain. Growing knowledge about this peripheral control system may be used to discover safer medicines for pain.

Figure 1.

Peripheral gating of nociception by lipid-derived mediators. Lipid messengers generated by neural and non-neural cells during injury or inflammation regulate the excitability of peripheral nociceptors. Proalgesic lipids, which heighten nociceptor excitability, include prostanoids, such as prostaglandin E₂ (which binds to G-protein-coupled EP-type receptors), phospholipids, such as lysophosphatidic acid (LPA) (which binds to LPA receptors), and oxidized PUFA derivatives, such as 13-hydroxy-octadecenoic acid (13-HODE), which activates TRPV-1. Persistent TRPV-1 activation can lead to desensitization and consequent reduction in nociceptive signaling. Analgesic lipids, which dampen nociceptor excitability, include endocannabinoids, such as anandamide and 2-AG (which bind to CB₁ and CB₂ cannabinoid receptors), endogenous ligands for PPAR-α, such as PEA, and oxidized PUFA derivatives, such as 14,15-EET. Anandamide can also activate TRPV-1, but at concentrations that are unlikely to be reached under most physiological conditions.

Figure 2.

Targeting analgesic lipid-derived mediators for pain control. Protecting analgesic lipid messengers from enzyme-mediated degradation enhances the intrinsic actions of these agents in animal models and offers multiple opportunities to develop medications that control pain without exerting unwanted centrally mediated side effects. A, Anandamide is hydrolyzed by FAAH, which is inhibited by globally active compounds, such as URB597 and PF'7845, and by peripherally restricted compounds, such as URB937. B, 2-AG is hydrolyzed by MGL and, to a minor extent, by ABHD-6. MGL is inhibited by URB602 and JZL-184, whereas ABHD-6 is inhibited by WWL-70. C, PEA and OEA are hydrolyzed by NAAA. ARN077 inhibits NAAA with high potency and selectivity but is metabolically unstable and cannot be used systemically. D, Epoxides of polyunsaturated fatty acids, such as 14,15-EET, are hydrolyzed by sEH, which is inhibited by compounds such as 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU).