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Licensed Unlicensed Requires Authentication Published by De Gruyter February 8, 2018

The roles of special proresolving mediators in pain relief

Lan-yu Zhang, Ming-rui Jia and Tao Sun


The resolution of acute inflammation, once thought to be a passive process, is now recognized as an active one. The productions of endogenous special proresolving mediators (SPMs) are involved in this process. SPMs, including lipoxins, resolvins, protectins, and maresins, are endogenous lipid mediators generated from ω-6 arachidonic acid or ω-3 poly-unsaturated fatty acids during the resolution phase of acute inflammation. They have potent anti-inflammatory and proresolving actions in various inflammatory disorders. Due to the potent proresolving and anti-inflammatory effects, SPMs are also used for pain relief. This review focuses on the mechanisms by which SPMs act on their respective G-protein-coupled receptors in immune cells and nerve cells to normalize pain via regulating inflammatory mediators, transient receptor potential ion channels, and central sensitization. SPMs may offer novel therapeutic approaches for preventing and treating pain conditions associated with inflammation.


This work was supported by grants from the National Natural Science Foundation of China, Funder Id: 10.13039/501100001809 (Grant No. 81772443) and Provincial Natural Science Foundation of Jiangxi Province, China (Grant No. 20171BAB205037).

  1. Conflict of interest statement: The authors declare that they have no competing interests.


Abdelmoaty, S., Wigerblad, G., Bas, D.B., Codeluppi, S., Fernandez-Zafra, T., El-Awady el, S., Moustafa, Y., Abdelhamid Ael, D., Brodin, E., and Svensson, C.I. (2013). Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release. PLoS One 8, e75543.10.1371/journal.pone.0075543Search in Google Scholar PubMed PubMed Central

Abdulnour, R.E., Sham, H.P., Douda, D.N., Colas, R.A., Dalli, J., Bai, Y., Ai, X., Serhan, C.N., and Levy, B.D. (2016). Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation. Mucosal. Immunol. 9, 1278–1287.10.1038/mi.2015.129Search in Google Scholar PubMed PubMed Central

Adlakha, Y.K. and Seth, P. (2017). The expanding horizon of MicroRNAs in cellular reprogramming. Prog. Neurobiol. 148, 21–39.10.1016/j.pneurobio.2016.11.003Search in Google Scholar PubMed

Arita, M., Ohira, T., Sun, Y.P., Elangovan, S., Chiang, N., and Serhan, C.N. (2007). Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J. Immunol. 178, 3912–3917.10.4049/jimmunol.178.6.3912Search in Google Scholar PubMed

Arnardottir, H.H., Dalli, J., Norling, L.V., Colas, R.A., Perretti, M., and Serhan, C.N. (2016). Resolvin D3 is dysregulated in arthritis and reduces arthritic inflammation. J. Immunol. 197, 2362–2368.10.4049/jimmunol.1502268Search in Google Scholar PubMed PubMed Central

Bang, S., Yoo, S., Oh, U., and Hwang, S.W. (2010a). Endogenous lipid-derived ligands for sensory TRP ion channels and their pain modulation. Arch. Pharm. Res. 33, 1509–1520.10.1007/s12272-010-1004-9Search in Google Scholar PubMed

Bang, S., Yoo, S., Yang, T.J., Cho, H., Kim, Y.G., and Hwang, S.W. (2010b). Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception. Br. J. Pharmacol. 161, 707–720.10.1111/j.1476-5381.2010.00909.xSearch in Google Scholar PubMed PubMed Central

Bang, S., Yoo, S., Yang, T.J., Cho, H., and Hwang, S.W. (2012). 17(R)-resolvin D1 specifically inhibits transient receptor potential ion channel vanilloid 3 leading to peripheral antinociception. Br J. Pharmacol. 165, 683–692.10.1111/j.1476-5381.2011.01568.xSearch in Google Scholar PubMed PubMed Central

Bannenberg, G. and Serhan, C.N. (2010). Specialized pro-resolving lipid mediators in the inflammatory response: an update. Biochim. Biophys. Acta 1801, 1260–1273.10.1016/j.bbalip.2010.08.002Search in Google Scholar PubMed PubMed Central

Basbaum, A.I., Bautista, D.M., Scherrer, G., and Julius, D. (2009). Cellular and molecular mechanisms of pain. Cell 139, 267–284.10.1016/j.cell.2009.09.028Search in Google Scholar PubMed PubMed Central

Bazan, N.G. (2012). Neuroinflammation and proteostasis are modulated by endogenously biosynthesized neuroprotectin D1. Mol. Neurobiol. 46, 221–226.10.1007/s12035-012-8322-5Search in Google Scholar PubMed

Beggs, S., Trang, T., and Salter, M.W. (2012). P2X4R+ microglia drive neuropathic pain. Nat. Neurosci. 15, 1068–1073.10.1038/nn.3155Search in Google Scholar PubMed

Benabdoune, H., Rondon, E.P., Shi, Q., Fernandes, J., Ranger, P., Fahmi, H., and Benderdour, M. (2016). The role of resolvin D1 in the regulation of inflammatory and catabolic mediators in osteoarthritis. Inflamm. Res. 65, 635–645.10.1007/s00011-016-0946-xSearch in Google Scholar PubMed

Borgeson, E., Johnson, A.M., Lee, Y.S., Till, A., Syed, G.H., Ali-Shah, S.T., Guiry, P.J., Dalli, J., Colas, R.A., Serhan, C.N., et al. (2015). Lipoxin A4 attenuates obesity-induced adipose inflammation and associated liver and kidney disease. Cell. Metab. 22, 125–137.10.1016/j.cmet.2015.05.003Search in Google Scholar PubMed

Borsook, D., Kussman, B.D., George, E., Becerra, L.R., and Burke, D.W. (2013). Surgically induced neuropathic pain: understanding the perioperative process. Ann. Surg. 257, 403–412.10.1097/SLA.0b013e3182701a7bSearch in Google Scholar PubMed

Botz, B., Bolcskei, K., and Helyes, Z. (2017). Challenges to develop novel anti-inflammatory and analgesic drugs. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 9. DOI: 10.1002/wnan.1427.10.1002/wnan.1427Search in Google Scholar PubMed

Calvo, M., Dawes, J.M., and Bennett, D.L. (2012). The role of the immune system in the generation of neuropathic pain. Lancet Neurol. 11, 629–642.10.1016/S1474-4422(12)70134-5Search in Google Scholar PubMed

Cash, J.L., Hart, R., Russ, A., Dixon, J.P., Colledge, W.H., Doran, J., Hendrick, A.G., Carlton, M.B., and Greaves, D.R. (2008). Synthetic chemerin-derived peptides suppress inflammation through ChemR23. J. Exp. Med. 205, 767–775.10.1084/jem.20071601Search in Google Scholar PubMed PubMed Central

Chandrasekharan, J.A. and Sharma-Walia, N. (2015). Lipoxins: nature’s way to resolve inflammation. J. Inflamm. Res. 8, 181–192.10.2147/JIR.S90380Search in Google Scholar PubMed PubMed Central

Cheng, Q., Wang, Z., Ma, R., Chen, Y., Yan, Y., Miao, S., Jiao, J., Cheng, X., Kong, L., and Ye, D. (2016). Lipoxin A4 protects against lipopolysaccharide-induced sepsis by promoting innate response activator B cells generation. Int. Immunopharmacol. 39, 229–235.10.1016/j.intimp.2016.07.026Search in Google Scholar PubMed

Chiang, N. and Serhan, C.N. (2017). Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Mol. Aspects Med. 58, 114–129.10.1016/j.mam.2017.03.005Search in Google Scholar PubMed PubMed Central

Chiang, N., Fredman, G., Backhed, F., Oh, S.F., Vickery, T., Schmidt, B.A., and Serhan, C.N. (2012). Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524–528.10.1038/nature11042Search in Google Scholar PubMed PubMed Central

Chiang, N., Dalli, J., Colas, R.A., and Serhan, C.N. (2015). Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J. Exp. Med. 212, 1203–1217.10.1084/jem.20150225Search in Google Scholar PubMed PubMed Central

Chiang, N., de la Rosa, X., Libreros, S., and Serhan, C.N. (2017). Novel resolvin D2 receptor axis in infectious inflammation. J. Immunol. 198, 842–851.10.4049/jimmunol.1601650Search in Google Scholar PubMed PubMed Central

Choi, G. and Hwang, S.W. (2016). Modulation of the activities of neuronal ion channels by fatty acid-derived pro-resolvents. Front. Physiol. 7, 523.10.3389/fphys.2016.00523Search in Google Scholar PubMed PubMed Central

Cholkar, K., Gilger, B., and Mitra, A. (2016). Topical delivery of aqueous micellar Resolvin E1 analog (RX-10045). Int. J. Pharm. 498; 326–334.10.1016/j.ijpharm.2015.12.037Search in Google Scholar PubMed PubMed Central

Claria, J., Dalli, J., Yacoubian, S., Gao, F., and Serhan, C.N. (2012). Resolvin D1 and resolvin D2 govern local inflammatory tone in obese fat. J. Immunol. 189, 2597–2605.10.4049/jimmunol.1201272Search in Google Scholar PubMed PubMed Central

Corminboeuf, O. and Leroy, X. (2015). FPR2/ALXR agonists and the resolution of inflammation. J. Med. Chem. 58, 537–559.10.1021/jm501051xSearch in Google Scholar PubMed

Dalli, J., Winkler, J.W., Colas, R.A., Arnardottir, H., Cheng, C.Y., Chiang, N., Petasis, N.A., and Serhan, C.N. (2013). Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. Chem. Biol. 20, 188–201.10.1016/j.chembiol.2012.11.010Search in Google Scholar PubMed PubMed Central

Deng, B., Wang, C.W., Arnardottir, H.H., Li, Y., Cheng, C.Y., Dalli, J., and Serhan, C.N. (2014). Maresin biosynthesis and identification of maresin 2, a new anti-inflammatory and pro-resolving mediator from human macrophages. PLoS One 9, e102362.10.1371/journal.pone.0102362Search in Google Scholar PubMed PubMed Central

Dickie, A.C. and Torsney, C. (2014). The chemerin receptor 23 agonist, chemerin, attenuates monosynaptic C-fibre input to lamina I neurokinin 1 receptor expressing rat spinal cord neurons in inflammatory pain. Mol. Pain 10, 24.10.1186/1744-8069-10-24Search in Google Scholar PubMed PubMed Central

Duffield, J.S., Hong, S., Vaidya, V.S., Lu, Y., Fredman, G., Serhan, C.N., and Bonventre, J.V. (2006). Resolvin D series and protectin D1 mitigate acute kidney injury. J. Immunol. 177, 5902–5911.10.4049/jimmunol.177.9.5902Search in Google Scholar PubMed

El Kebir, D., Gjorstrup, P., and Filep, J.G. (2012). Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation. Proc. Natl. Acad. Sci. USA 109, 14983–14988.10.1073/pnas.1206641109Search in Google Scholar PubMed PubMed Central

Fischer, B.D., Adeyemo, A., O’Leary, M.E., and Bottaro, A. (2017). Animal models of rheumatoid pain: experimental systems and insights. Arthritis Res. Ther. 19, 146.10.1186/s13075-017-1361-6Search in Google Scholar PubMed PubMed Central

Flesher, R.P., Herbert, C., and Kumar, R.K. (2014). Resolvin E1 promotes resolution of inflammation in a mouse model of an acute exacerbation of allergic asthma. Clin. Sci. (Lond.) 126, 805–814.10.1042/CS20130623Search in Google Scholar PubMed

Freire, M.O. and Van Dyke, T.E. (2013). Natural resolution of inflammation. Periodontol 2000 63, 149–164.10.1111/prd.12034Search in Google Scholar PubMed PubMed Central

Gangadharan, V. and Kuner, R. (2013). Pain hypersensitivity mechanisms at a glance. Dis. Model. Mech. 6, 889–895.10.1242/dmm.011502Search in Google Scholar PubMed PubMed Central

Gong, J., Wu, Z.Y., Qi, H., Chen, L., Li, H.B., Li, B., Yao, C.Y., Wang, Y.X., Wu, J., Yuan, S.Y., et al. (2014). Maresin 1 mitigates LPS-induced acute lung injury in mice. Br. J. Pharmacol. 171, 3539–3550.10.1111/bph.12714Search in Google Scholar PubMed PubMed Central

Headland, S.E. and Norling, L.V. (2015). The resolution of inflammation: principles and challenges. Semin. Immunol. 27, 149–160.10.1016/j.smim.2015.03.014Search in Google Scholar PubMed

Hsiao, H.M., Thatcher, T.H., Colas, R.A., Serhan, C.N., Phipps, R.P., and Sime, P.J. (2015). Resolvin D1 reduces emphysema and chronic inflammation. Am. J. Pathol. 185, 3189–3201.10.1016/j.ajpath.2015.08.008Search in Google Scholar PubMed PubMed Central

Hu, S., Mao-Ying, Q.L., Wang, J., Wang, Z.F., Mi, W.L., Wang, X.W., Jiang, J.W., Huang, Y.L., Wu, G.C., and Wang, Y.Q. (2012). Lipoxins and aspirin-triggered lipoxin alleviate bone cancer pain in association with suppressing expression of spinal pro-inflammatory cytokines. J. Neuroinflamm. 9, 278.10.1186/1742-2094-9-278Search in Google Scholar PubMed PubMed Central

Huang, L., Wang, C.F., Serhan, C.N., and Strichartz, G. (2011). Enduring prevention and transient reduction of postoperative pain by intrathecal resolvin D1. Pain 152, 557–565.10.1016/j.pain.2010.11.021Search in Google Scholar PubMed PubMed Central

Huang, J., Burston, J.J., Li, L., Ashraf, S., Mapp, P.I., Bennett, A.J., Ravipati, S., Pousinis, P., Barrett, D.A., Scammell, B.E., et al. (2017). Targeting the D series resolvin receptor system for the treatment of osteoarthritis pain. Arthritis Rheumatol. 69, 996–1008.10.1002/art.40001Search in Google Scholar PubMed PubMed Central

Ishida, T., Yoshida, M., Arita, M., Nishitani, Y., Nishiumi, S., Masuda, A., Mizuno, S., Takagawa, T., Morita, Y., Kutsumi, H., et al. (2010). Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodium-induced colitis. Inflamm. Bowel Dis. 16, 87–95.10.1002/ibd.21029Search in Google Scholar PubMed PubMed Central

Ji, R.R., Kohno, T., Moore, K.A., and Woolf, C.J. (2003). Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 26, 696–705.10.1016/j.tins.2003.09.017Search in Google Scholar PubMed

Ji, R.R., Gereau, R.W.t., Malcangio, M., and Strichartz, G.R. (2009). MAP kinase and pain. Brain Res. Rev. 60, 135–148.10.1016/j.brainresrev.2008.12.011Search in Google Scholar PubMed PubMed Central

Ji, R.R., Xu, Z.Z., Strichartz, G., and Serhan, C.N. (2011). Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci. 34, 599–609.10.1016/j.tins.2011.08.005Search in Google Scholar PubMed PubMed Central

Ji, R.R., Berta, T., and Nedergaard, M. (2013). Glia and pain: is chronic pain a gliopathy? Pain 154 (Suppl. 1), S10–S28.10.1016/j.pain.2013.06.022Search in Google Scholar PubMed PubMed Central

Ji, R.R., Xu, Z.Z., and Gao, Y.J. (2014). Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13, 533–548.10.1038/nrd4334Search in Google Scholar PubMed PubMed Central

Ji, R.R., Chamessian, A., and Zhang, Y.Q. (2016). Pain regulation by non-neuronal cells and inflammation. Science 354, 572–577.10.1126/science.aaf8924Search in Google Scholar PubMed PubMed Central

Jin, H., Li, Y.H., Xu, J.S., Guo, G.Q., Chen, D.L., and Bo, Y. (2012). Lipoxin A4 analog attenuates morphine antinociceptive tolerance, withdrawal-induced hyperalgesia, and glial reaction and cytokine expression in the spinal cord of rat. Neuroscience 208, 1–10.10.1016/j.neuroscience.2012.02.009Search in Google Scholar PubMed

Jo, Y.Y., Lee, J.Y., and Park, C.K. (2016). Resolvin E1 inhibits substance P-induced potentiation of TRPV1 in primary sensory neurons. Mediat. Inflamm. 2016, 5259321.10.1155/2016/5259321Search in Google Scholar PubMed PubMed Central

Karra, L., Haworth, O., Priluck, R., Levy, B.D., and Levi-Schaffer, F. (2015). Lipoxin B(4) promotes the resolution of allergic inflammation in the upper and lower airways of mice. Mucosal. Immunol. 8, 852–862.10.1038/mi.2014.116Search in Google Scholar PubMed PubMed Central

Klein, C.P., Sperotto, N.D., Maciel, I.S., Leite, C.E., Souza, A.H., and Campos, M.M. (2014). Effects of D-series resolvins on behavioral and neurochemical changes in a fibromyalgia-like model in mice. Neuropharmacology 86, 57–66.10.1016/j.neuropharm.2014.05.043Search in Google Scholar PubMed

Kohno, M., Hasegawa, H., Inoue, A., Muraoka, M., Miyazaki, T., Oka, K., and Yasukawa, M. (2006). Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem. Biophys. Res. Commun. 347, 827–832.10.1016/j.bbrc.2006.06.175Search in Google Scholar PubMed

Krishnamoorthy, S., Recchiuti, A., Chiang, N., Yacoubian, S., Lee, C.H., Yang, R., Petasis, N.A., and Serhan, C.N. (2010). Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc. Natl. Acad. Sci. USA 107, 1660–1665.10.1073/pnas.0907342107Search in Google Scholar PubMed PubMed Central

Li, Y., Dalli, J., Chiang, N., Baron, R.M., Quintana, C., and Serhan, C.N. (2013). Plasticity of leukocytic exudates in resolving acute inflammation is regulated by microRNA and proresolving mediators. Immunity 39, 885–898.10.1016/j.immuni.2013.10.011Search in Google Scholar PubMed PubMed Central

Li, R., Wang, Y., Zhao, E., Wu, K., Li, W., Shi, L., Wang, D., Xie, G., Yin, Y., Deng, M., et al. (2016). Maresin 1, a proresolving lipid mediator, mitigates carbon tetrachloride-induced liver injury in mice. Oxid. Med. Cell Longev. 2016, 9203716.10.1155/2016/9203716Search in Google Scholar PubMed PubMed Central

Liu, Z.H., Miao, G.S., Wang, J.N., Yang, C.X., Fu, Z.J., and Sun, T. (2016). Resolvin D1 inhibits mechanical hypersensitivity in sciatica by modulating the expression of nuclear factor-κB, phospho-extracellular signal-regulated kinase, and pro- and antiinflammatory cytokines in the spinal cord and dorsal root ganglion. Anesthesiology 124, 934–944.10.1097/ALN.0000000000001010Search in Google Scholar PubMed

Marcon, R., Bento, A.F., Dutra, R.C., Bicca, M.A., Leite, D.F., and Calixto, J.B. (2013). Maresin 1, a proresolving lipid mediator derived from omega-3 polyunsaturated fatty acids, exerts protective actions in murine models of colitis. J. Immunol. 191, 4288–4298.10.4049/jimmunol.1202743Search in Google Scholar PubMed

Martin, C.R., Zaman, M.M., Gilkey, C., Salguero, M.V., Hasturk, H., Kantarci, A., Van Dyke, T.E., and Freedman, S.D. (2014). Resolvin D1 and lipoxin A4 improve alveolarization and normalize septal wall thickness in a neonatal murine model of hyperoxia-induced lung injury. PLoS One 9, e98773.10.1371/journal.pone.0098773Search in Google Scholar PubMed PubMed Central

Martindale, R.G., Warren, M.M., and McClave, S.A. (2016). Does the use of specialized proresolving molecules in critical care offer a more focused approach to controlling inflammation than that of fish oils? Curr. Opin. Clin. Nutr. Metab. Care 19, 151–154.10.1097/MCO.0000000000000250Search in Google Scholar PubMed

Martini, A.C., Berta, T., Forner, S., Chen, G., Bento, A.F., Ji, R.R., and Rae, G.A. (2016). Lipoxin A4 inhibits microglial activation and reduces neuroinflammation and neuropathic pain after spinal cord hemisection. J. Neuroinflamm. 13, 75.10.1186/s12974-016-0540-8Search in Google Scholar PubMed PubMed Central

Meesawatsom, P., Burston, J., Hathway, G., Bennett, A., and Chapman, V. (2016). Inhibitory effects of aspirin-triggered resolvin D1 on spinal nociceptive processing in rat pain models. J. Neuroinflamm. 13, 233.10.1186/s12974-016-0676-6Search in Google Scholar PubMed PubMed Central

Meng, F., Mambetsariev, I., Tian, Y., Beckham, Y., Meliton, A., Leff, A., Gardel, M.L., Allen, M.J., Birukov, K.G., and Birukova, A.A. (2015). Attenuation of lipopolysaccharide-induced lung vascular stiffening by lipoxin reduces lung inflammation. Am. J. Respir. Cell Mol. Biol. 52, 152–161.10.1165/rcmb.2013-0468OCSearch in Google Scholar PubMed PubMed Central

Miao, G.S., Liu, Z.H., Wei, S.X., Luo, J.G., Fu, Z.J., and Sun, T. (2015). Lipoxin A4 attenuates radicular pain possibly by inhibiting spinal ERK, JNK and NF-kappaB/p65 and cytokine signals, but not p38, in a rat model of non-compressive lumbar disc herniation. Neuroscience 300, 10–18.10.1016/j.neuroscience.2015.04.060Search in Google Scholar PubMed

Mika, J., Zychowska, M., Popiolek-Barczyk, K., Rojewska, E., and Przewlocka, B. (2013). Importance of glial activation in neuropathic pain. Eur. J. Pharmacol. 716, 106–119.10.1016/j.ejphar.2013.01.072Search in Google Scholar PubMed

Norling, L.V., Dalli, J., Flower, R.J., Serhan, C.N., and Perretti, M. (2012). Resolvin D1 limits polymorphonuclear leukocyte recruitment to inflammatory loci: receptor-dependent actions. Arterioscler. Thromb. Vasc. Biol. 32, 1970–1978.10.1161/ATVBAHA.112.249508Search in Google Scholar PubMed PubMed Central

Norling, L.V., Headland, S.E., Dalli, J., Arnardottir, H.H., Haworth, O., Jones, H.R., Irimia, D., Serhan, C.N., and Perretti, M. (2016). Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis. JCI Insight 1, e85922.10.1172/jci.insight.85922Search in Google Scholar PubMed PubMed Central

Norris, P.C., Arnardottir, H., Sanger, J.M., Fichtner, D., Keyes, G.S., and Serhan, C.N. (2016). Resolvin D3 multi-level proresolving actions are host protective during infection. Prostaglandins Leukot. Essent. Fatty Acids. DOI: 10.1016/j.plefa.2016. in Google Scholar PubMed PubMed Central

Oehler, B., Mohammadi, M., Perpina Viciano, C., Hackel, D., Hoffmann, C., Brack, A., and Rittner, H.L. (2017). Peripheral Interaction of resolvin D1 and E1 with opioid receptor antagonists for antinociception in inflammatory pain in rats. Front Mol Neurosci 10, 242.10.3389/fnmol.2017.00242Search in Google Scholar PubMed PubMed Central

Pagadala, P., Park, C.K., Bang, S., Xu, Z.Z., Xie, R.G., Liu, T., Han, B.X., Tracey, W.D., Jr., Wang, F., and Ji, R.R. (2013). Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca2+-activated small conductance potassium channels. J Neurosci. 33, 13425–13430.10.1523/JNEUROSCI.0454-13.2013Search in Google Scholar PubMed PubMed Central

Park, C.K. (2015). Maresin 1 inhibits TRPV1 in temporomandibular joint-related trigeminal nociceptive neurons and TMJ inflammation-induced synaptic plasticity in the trigeminal nucleus. Mediat. Inflamm. 2015, 275126.10.1155/2015/275126Search in Google Scholar PubMed PubMed Central

Park, C.K., Lu, N., Xu, Z.Z., Liu, T., Serhan, C.N., and Ji, R.R. (2011a). Resolving TRPV1- and TNFα-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J. Neurosci. 31, 15072–15085.10.1523/JNEUROSCI.2443-11.2011Search in Google Scholar PubMed PubMed Central

Park, C.K., Xu, Z.Z., Liu, T., Lu, N., Serhan, C.N., and Ji, R.R. (2011b). Resolvin D2 is a potent endogenous inhibitor for transient receptor potential subtype V1/A1, inflammatory pain, and spinal cord synaptic plasticity in mice: distinct roles of resolvin D1, D2, and E1. J Neurosci, 31, 18433–18438.10.1523/JNEUROSCI.4192-11.2011Search in Google Scholar PubMed PubMed Central

Piovezan, A.P., Batisti, A.P., Benevides, M., Turnes, B.L., Martins, D.F., Kanis, L., Duarte, E.C.W., Cavalheiro, A.J., Bueno, P.C.P., Seed, M.P., et al. (2017). Hydroalcoholic crude extract of Casearia sylvestris Sw. reduces chronic post-ischemic pain by activation of pro-resolving pathways. J. Ethnopharmacol. 204, 179–188.10.1016/j.jep.2017.03.059Search in Google Scholar PubMed

Pouliot, M., Clish, C.B., Petasis, N.A., Van Dyke, T.E., and Serhan, C.N. (2000). Lipoxin A(4) analogues inhibit leukocyte recruitment to Porphyromonas gingivalis: a role for cyclooxygenase-2 and lipoxins in periodontal disease. Biochemistry 39, 4761–4768.10.1021/bi992551bSearch in Google Scholar PubMed

Qi, W., Li, H., Cai, X.H., Gu, J.Q., Meng, J., Xie, H.Q., Zhang, J.L., Chen, J., Jin, X.G., Tang, Q., et al. (2015). Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury. Lab. Invest. 95, 1258–1268.10.1038/labinvest.2015.109Search in Google Scholar PubMed

Quan-Xin, F., Fan, F., Xiang-Ying, F., Shu-Jun, L., Shi-Qi, W., Zhao-Xu, L., Xu-Jie, Z., Qing-Chuan, Z., and Wei, W. (2012). Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia, phosphorylation of NMDA receptors, and cytokines expression in the thoracic spinal dorsal horn. BMC Gastroenterol. 12, 148.10.1186/1471-230X-12-148Search in Google Scholar PubMed PubMed Central

Rajaraman, G., Simcocks, A., Hryciw, D.H., Hutchinson, D.S., and McAinch, A.J. (2016). G protein coupled receptor 18: a potential role for endocannabinoid signaling in metabolic dysfunction. Mol. Nutr. Food Res. 60, 92–102.10.1002/mnfr.201500449Search in Google Scholar PubMed

Recchiuti, A. and Serhan, C.N. (2012). Pro-resolving lipid mediators (SPMs) and their actions in regulating miRNA in novel resolution circuits in inflammation. Front. Immunol. 3, 298.10.3389/fimmu.2012.00298Search in Google Scholar PubMed PubMed Central

Recchiuti, A., Krishnamoorthy, S., Fredman, G., Chiang, N., and Serhan, C.N. (2011). MicroRNAs in resolution of acute inflammation: identification of novel resolvin D1-miRNA circuits. FASEB J. 25, 544–560.10.1096/fj.10-169599Search in Google Scholar PubMed PubMed Central

Ren, K. and Dubner, R. (2010). Interactions between the immune and nervous systems in pain. Nat. Med. 16, 1267–1276.10.1038/nm.2234Search in Google Scholar PubMed PubMed Central

Ruscheweyh, R., Wilder-Smith, O., Drdla, R., Liu, X.G., and Sandkuhler, J. (2011). Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol. Pain 7, 20.10.1186/1744-8069-7-20Search in Google Scholar PubMed PubMed Central

Saito, T., Hasegawa-Moriyama, M., Kurimoto, T., Yamada, T., Inada, E., and Kanmura, Y. (2015). Resolution of inflammation by resolvin D1 is essential for peroxisome proliferator-activated receptor-γ-mediated analgesia during postincisional pain development in Type 2 diabetes. Anesthesiology 123, 1420–1434.10.1097/ALN.0000000000000892Search in Google Scholar PubMed

Sawada, Y., Honda, T., Hanakawa, S., Nakamizo, S., Murata, T., Ueharaguchi-Tanada, Y., Ono, S., Amano, W., Nakajima, S., Egawa, G., et al. (2015). Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses. J. Exp. Med. 212, 1921–1930.10.1084/jem.20150381Search in Google Scholar PubMed PubMed Central

Scholz, J. and Woolf, C.J. (2007). The neuropathic pain triad: neurons, immune cells and glia. Nat. Neurosci. 10, 1361–1368.10.1038/nn1992Search in Google Scholar PubMed

Schwab, J.M., Chiang, N., Arita, M., and Serhan, C.N. (2007). Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874.10.1038/nature05877Search in Google Scholar PubMed PubMed Central

Serhan, C.N. (2008). Systems approach with inflammatory exudates uncovers novel anti-inflammatory and pro-resolving mediators. Prostaglandins Leukot. Essent. Fatty Acids 79, 157–163.10.1016/j.plefa.2008.09.012Search in Google Scholar PubMed PubMed Central

Serhan, C.N. (2017a). Discovery of specialized pro-resolving mediators marks the dawn of resolution physiology and pharmacology. Mol. Aspects Med. 58, 1–11.10.1016/j.mam.2017.03.001Search in Google Scholar PubMed PubMed Central

Serhan, C.N. (2017b). Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J. 31, 1273–1288.10.1096/fj.201601222RSearch in Google Scholar PubMed PubMed Central

Serhan, C.N. and Chiang, N. (2013). Resolution phase lipid mediators of inflammation: agonists of resolution. Curr. Opin. Pharmacol. 13, 632–640.10.1016/j.coph.2013.05.012Search in Google Scholar PubMed PubMed Central

Serhan, C.N., Hamberg, M., and Samuelsson, B. (1984). Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Proc. Natl. Acad. Sci. USA 81, 5335–5339.10.1073/pnas.81.17.5335Search in Google Scholar PubMed PubMed Central

Serhan, C.N., Jain, A., Marleau, S., Clish, C., Kantarci, A., Behbehani, B., Colgan, S.P., Stahl, G.L., Merched, A., Petasis, N.A., et al. (2003). Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J. Immunol. 171, 6856–6865.10.4049/jimmunol.171.12.6856Search in Google Scholar PubMed

Serhan, C.N., Yang, R., Martinod, K., Kasuga, K., Pillai, P.S., Porter, T.F., Oh, S.F., and Spite, M. (2009). Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J. Exp. Med. 206, 15–23.10.1084/jem.20081880Search in Google Scholar PubMed PubMed Central

Serhan, C.N., Dalli, J., Karamnov, S., Choi, A., Park, C.K., Xu, Z.Z., Ji, R.R., Zhu, M., and Petasis, N.A. (2012). Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J. 26, 1755–1765.10.1096/fj.11-201442Search in Google Scholar PubMed PubMed Central

Serhan, C.N., Chiang, N., and Dalli, J. (2015a). The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution. Semin. Immunol. 27, 200–215.10.1016/j.smim.2015.03.004Search in Google Scholar PubMed PubMed Central

Serhan, C.N., Dalli, J., Colas, R.A., Winkler, J.W., and Chiang, N. (2015b). Protectins and maresins: new pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome. Biochim. Biophys. Acta 1851, 397–413.10.1016/j.bbalip.2014.08.006Search in Google Scholar PubMed PubMed Central

Singh, A., Rahman, T., Bartiss, R., Arabshahi, A., Prasain, J., Barnes, S., Musteata, F.M., and Sellati, T.J. (2017). Lipoxin A4, a 5-lipoxygenase pathway metabolite, modulates immune response during acute respiratory tularemia. J. Leukoc. Biol. 101, 531–542.10.1189/jlb.4A0815-365RRSearch in Google Scholar PubMed PubMed Central

Sommer, C. and Birklein, F. (2010). Fighting off pain with resolvins. Nat. Med. 16, 518–520.10.1038/nm0510-518Search in Google Scholar PubMed

Spite, M., Norling, L.V., Summers, L., Yang, R., Cooper, D., Petasis, N.A., Flower, R.J., Perretti, M., and Serhan, C.N. (2009). Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461, 1287–1291.10.1038/nature08541Search in Google Scholar PubMed PubMed Central

Sun, T., Yu, E., Yu, L., Luo, J., Li, H., and Fu, Z. (2012). LipoxinA(4) induced antinociception and decreased expression of NF-κB and pro-inflammatory cytokines after chronic dorsal root ganglia compression in rats. Eur. J. Pain 16, 18–27.10.1016/j.ejpain.2011.05.005Search in Google Scholar PubMed

Svensson, C.I., Zattoni, M., and Serhan, C.N. (2007). Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing. J. Exp. Med. 204, 245–252.10.1084/jem.20061826Search in Google Scholar PubMed PubMed Central

Tang, H., Liu, Y., Yan, C., Petasis, N.A., Serhan, C.N., and Gao, H. (2014). Protective actions of aspirin-triggered (17R) resolvin D1 and its analogue, 17R-hydroxy-19-para-fluorophenoxy-resolvin D1 methyl ester, in C5a-dependent IgG immune complex-induced inflammation and lung injury. J. Immunol. 193, 3769–3778.10.4049/jimmunol.1400942Search in Google Scholar PubMed PubMed Central

Tian, Y., Liu, M., Mao-Ying, Q.L., Liu, H., Wang, Z.F., Zhang, M.T., Wang, J., Li, Q., Liu, S.B., Mi, W.L., et al. (2015). Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: involvement of PI3k/Akt signaling pathway. Brain Behav. Immun. 50, 63–77.10.1016/j.bbi.2015.06.016Search in Google Scholar PubMed

Tiwari, V., Guan, Y., and Raja, S.N. (2014). Modulating the delicate glial-neuronal interactions in neuropathic pain: promises and potential caveats. Neurosci. Biobehav. Rev 45, 19–27.10.1016/j.neubiorev.2014.05.002Search in Google Scholar PubMed PubMed Central

Tjonahen, E., Oh, S.F., Siegelman, J., Elangovan, S., Percarpio, K.B., Hong, S., Arita, M., and Serhan, C.N. (2006). Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis. Chem. Biol. 13, 1193–1202.10.1016/j.chembiol.2006.09.011Search in Google Scholar PubMed

Wang, Z.F., Li, Q., Liu, S.B., Mi, W.L., Hu, S., Zhao, J., Tian, Y., Mao-Ying, Q.L., Jiang, J.W., Ma, H.J., et al. (2014). Aspirin-triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal JAK2/STAT3 signaling in neuropathic pain in rats. Neuroscience 273, 65–78.10.1016/j.neuroscience.2014.04.052Search in Google Scholar PubMed

Winkler, J.W., Orr, S.K., Dalli, J., Cheng, C.Y., Sanger, J.M., Chiang, N., Petasis, N.A., and Serhan, C.N. (2016). Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance. Sci Rep 6, 18972.10.1038/srep18972Search in Google Scholar PubMed PubMed Central

Woolf, C.J. and Salter, M.W. (2000). Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1769.10.1126/science.288.5472.1765Search in Google Scholar PubMed

Woolf, C.J. and Ma, Q. (2007). Nociceptors – noxious stimulus detectors. Neuron 55, 353–364.10.1016/j.neuron.2007.07.016Search in Google Scholar PubMed

Wu, S.H., Chen, X.Q., Liu, B., Wu, H.J., and Dong, L. (2013). Efficacy and safety of 15(R/S)-methyl-lipoxin A(4) in topical treatment of infantile eczema. Br. J. Dermatol. 168, 172–178.10.1111/j.1365-2133.2012.11177.xSearch in Google Scholar PubMed

Xu, Z.Z. and Ji, R.R. (2011). Resolvins are potent analgesics for arthritic pain. Br. J. Pharmacol. 164, 274–277.10.1111/j.1476-5381.2011.01348.xSearch in Google Scholar PubMed PubMed Central

Xu, Z.Z., Zhang, L., Liu, T., Park, J.Y., Berta, T., Yang, R., Serhan, C.N., and Ji, R.R. (2010). Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nat. Med. 16, 592–597.10.1038/nm.2123Search in Google Scholar PubMed PubMed Central

Xu, Z.Z., Berta, T., and Ji, R.R. (2013a). Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury. J. Neuroimmune Pharmacol. 8, 37–41.10.1007/s11481-012-9394-8Search in Google Scholar PubMed PubMed Central

Xu, Z.Z., Liu, X.J., Berta, T., Park, C.K., Lu, N., Serhan, C.N., and Ji, R.R. (2013b). Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma. Ann. Neurol. 74, 490–495.10.1002/ana.23928Search in Google Scholar PubMed PubMed Central

Yoo, S., Lim, J.Y., and Hwang, S.W. (2013). Resolvins: endogenously-generated potent painkilling substances and their therapeutic perspectives. Curr. Neuropharmacol. 11, 664–676.10.2174/1570159X11311060009Search in Google Scholar PubMed PubMed Central

Zhang, G., Liu, X., Wang, C., Qu, L., Deng, J., Wang, H., and Qin, Z. (2013). Resolution of PMA-induced skin inflammation involves interaction of IFN-gamma and ALOX15. Mediators Inflamm. 2013, 930124.10.1155/2013/930124Search in Google Scholar PubMed PubMed Central

Zhang, Z.J., Jiang, B.C., and Gao, Y.J. (2017). Chemokines in neuron-glial cell interaction and pathogenesis of neuropathic pain. Cell Mol. Life Sci. 74, 3275–3291.10.1007/s00018-017-2513-1Search in Google Scholar PubMed

Received: 2017-08-24
Accepted: 2017-12-17
Published Online: 2018-02-08
Published in Print: 2018-08-28

©2018 Walter de Gruyter GmbH, Berlin/Boston

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