Resolvin E1 Inhibits Substance P-Induced Potentiation of TRPV1 in Primary Sensory Neurons

Abstract

The neuropeptide substance P (SP) is expressed in primary sensory neurons and is commonly regarded as a “pain” neurotransmitter. Upon peripheral inflammation, SP activates the neurokinin-1 (NK-1) receptor and potentiates activity of transient receptor potential vanilloid subtype 1 (TRPV1), which is coexpressed by nociceptive neurons. Therefore, SP functions as an important neurotransmitter involved in the hypersensitization of inflammatory pain. Resolvin E1 (RvE1), derived from omega-3 polyunsaturated fatty acids, inhibits TRPV1 activity via activation of the chemerin 23 receptor (ChemR23)—an RvE1 receptor located in dorsal root ganglion neurons—and therefore exerts an inhibitory effect on inflammatory pain. We demonstrate here that RvE1 regulates the SP-induced potentiation of TRPV1 via G-protein coupled receptor (GPCR) on peripheral nociceptive neurons. SP-induced potentiation of TRPV1 inhibited by RvE1 was blocked by the Gαi-coupled GPCR inhibitor pertussis toxin and the G-protein inhibitor GDPβ-S. These results indicate that a low concentration of RvE1 strongly inhibits the potentiation of TRPV1, induced by the SP-mediated activation of NK-1, via a GPCR signaling pathway activated by ChemR23 in nociceptive neurons. RvE1 might represent a new therapeutic target for the treatment of inflammatory pain as a prospective endogenous inhibitor that strongly inhibits TRPV1 activity associated with peripheral inflammation.

Curcumin alleviates lumbar radiculopathy by reducing neuroinflammation, oxidative stress and nociceptive factors

“…The neuropeptide substance P is commonly expressed in primary sensory neurons and is commonly regarded as a pain neurotransmitter (Jo et al ., 2016). Calcitonin gene related peptide (CGRP), a pro-nociceptive neuropeptide, has been shown to have increased synthesis and release in several types of neuropathic pain.…”

“…Also, anti-nociceptive mediators derived from docosahexaenoic acid (DHA), including D-series resolvins, neuroprotectins, maresins and DHA-epoxides, and anti-nociceptive mediators derived from eicosapentaenoic acid (EPA), including E-series resolvins and EPA-epoxides, have been shown to have therapeutics effects. Resolvin E1 (RvE1) inhibits transient receptor potential cation channel subfamily V member 1 (TRPV1) activity by activation of the chemerin 23 receptor (ChemR23), an RvE1 receptor located in dorsal root ganglion (DRG) neurons, and therefore exerts an inhibitory effect on inflammatory pain (Jo et al ., 2016). Neuroprotectin-1 (NPD1), an anti-inflammatory lipid mediator, has been shown to regulate TRPV1/TNF-α-mediated spinal synaptic plasticity, identifying NPD1 as a novel analgesic for treating inflammatory pain (Park et al ., 2011).…”

Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators

“…RvE1 selectively blocks TRPV1 (IC 50 = 1 nM), RvD1 acts via TRPA1 (IC 50 = 9 nM), and RvD2 acts via TRPV1 (IC 50 = 0.1 nM) and TRPA1 (IC 50 = 2 nM) (136). RvE1 inhibits substance P actions on peripheral nociceptive neurons (137). AT-RvD1 also mitigates motor and cognitive deficits in diffuse brain injury, and RvE1 increases posttraumatic sleep (138).…”

Identification and structure elucidation of the pro‐resolving mediators provides novel leads for resolution pharmacology

“…RvE1 was also found to carry potent antinociceptive actions reducing inflammatory pain by regulating both central and peripheral responses with activities of 10 ng per mouse when administered intrathecally and 285–570 pmol when administered peripherally in vivo . These actions were also displayed in vitro at concentrations as low as 3 nM (Xu et al ., ; Jo et al ., ; Fonseca et al ., ). Of note, the antinociceptive properties of RvE1 are more potent than those exerted by the COX‐2 inhibitor NS398 and morphine (Xu et al ., ).…”