Resolvin D1 and D2 Inhibit Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Ion Channel Activation on Sensory Neurons via Lipid Raft Modification

Abstract

Transient Receptor Potential Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons and regulate nociceptor and inflammatory functions. Resolvins are endogenous lipid mediators. Resolvin D1 (RvD1) is described as a selective inhibitor of TRPA1-related postoperative and inflammatory pain in mice acting on the G protein-coupled receptor DRV1/GPR32. Resolvin D2 (RvD2) is a very potent TRPV1 and TRPA1 inhibitor in DRG neurons, and decreases inflammatory pain in mice acting on the GPR18 receptor, via TRPV1/TRPA1-independent mechanisms. We provided evidence that resolvins inhibited neuropeptide release from the stimulated sensory nerve terminals by TRPV1 and TRPA1 activators capsaicin (CAPS) and allyl-isothiocyanate (AITC), respectively. We showed that RvD1 and RvD2 in nanomolar concentrations significantly decreased TRPV1 and TRPA1 activation on sensory neurons by fluorescent calcium imaging and inhibited the CAPS- and AITC-evoked 45Ca-uptake on TRPV1- and TRPA1-expressing CHO cells. Since CHO cells are unlikely to express resolvin receptors, resolvins are suggested to inhibit channel opening through surrounding lipid raft disruption. Here, we proved the ability of resolvins to alter the membrane polarity related to cholesterol composition by fluorescence spectroscopy. It is concluded that targeting lipid raft integrity can open novel peripheral analgesic opportunities by decreasing the activation of nociceptors.

Inflammation and tumor progression: signaling pathways and targeted intervention

“…181 Meanwhile, RvD1 and RvD3 exert their bioactions through binding to ALX/FPR2 and DRV1/GPR32, respectively, whereas RvD2 and RvD5 activate their DRV2/GPR18 and DRV1/GPR32 receptors, respectively. 178,182,183 Of interest, the activation of the RvE1-ERV1/ ChemR23 axis has been shown to promote the apoptosis and macrophage-mediated phagocytosis of neutrophils, while reducing the production of pro-inflammatory cytokines. [184][185][186] Recently, we also found that RvD P 5 inhibited the infiltration of neutrophils and promoted the phagocytic function of macrophages through the ALX/FPR2 receptor.…”

Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery

“…Numerous agonists of GPR18 have been proposed, including abnormal cannabidiol (Abn-CBD, 74 ), Δ 9 -tetrahydrocannabinol ( 75 ), O-1918 ( 76 ), N -arachidonoyl glycine ( 77 ), resolvin D1 ( 78 ), and resolvin D2 ( 79 ) (Figure ). , These compounds are cannabinoid related, suggesting that it might be appropriate to classify GPR18 as a cannabinoid receptor together with CB1 and CB2. N -Arachidonoyl glycine ( 77 ) is the putative endogenous ligand of GPR18 .…”

“…117 Numerous agonists of GPR18 have been proposed, including abnormal cannabidiol 12). 118,119 These compounds are cannabinoid related, suggesting that it might be appropriate to classify GPR18 as a cannabinoid receptor together with CB1 and CB2. N-Arachidonoyl glycine (77) is the putative endogenous ligand of GPR18.…”

RvD1 disrupts nociceptor neuron and macrophage activation and neuroimmune communication, reducing pain and inflammation in gouty arthritis in mice

“…For instance, MaR1 reduces TRPV1 and Nav1.8 mRNA expression, and capsaicin neuronal activation (Fattori et al, 2019). RvE1 reduces TNF‐α‐induced excitatory postsynaptic current frequency in spinal cord neurons (Xu et al, 2010) while RvD2 reduces TRPV1 sensitization (Payrits et al, 2020; Perna et al, 2020).…”