1932

Abstract

Specialized pro-resolving mediators (SPMs), including resolvins, protectins, and maresins, are endogenous lipid mediators that are synthesized from omega-3 polyunsaturated fatty acids during the acute phase or resolution phase of inflammation. Synthetic SPMs possess broad safety profiles and exhibit potent actions in resolving inflammation in preclinical models. Accumulating evidence in the past decade has demonstrated powerful analgesia of exogenous SPMs in rodent models of inflammatory, neuropathic, and cancer pain. Furthermore, endogenous SPMs are produced by sham surgery and neuromodulation (e.g., vagus nerve stimulation). SPMs produce their beneficial actions through multiple G protein–coupled receptors, expressed by immune cells, glial cells, and neurons. Notably, loss of SPM receptors impairs the resolution of pain. I also highlight the emerging role of SPMs in the control of itch. Pharmacological targeting of SPMs or SPM receptors has the potential to lead to novel therapeutics for pain and itch as emerging approaches in resolution pharmacology.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-051921-084047
2023-01-20
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/63/1/annurev-pharmtox-051921-084047.html?itemId=/content/journals/10.1146/annurev-pharmtox-051921-084047&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Basbaum AI, Bautista DM, Scherrer G, Julius D 2009. Cellular and molecular mechanisms of pain. Cell 139:267–84
    [Google Scholar]
  2. 2.
    Ji RR, Chamessian A, Zhang YQ. 2016. Pain regulation by non-neuronal cells and inflammation. Science 354:572–77
    [Google Scholar]
  3. 3.
    Woolf CJ, Ma Q. 2007. Nociceptors—noxious stimulus detectors. Neuron 55:353–64
    [Google Scholar]
  4. 4.
    Ji RR, Lee SY. 2021. Molecular sensors of temperature, pressure, and pain with special focus on TRPV1, TRPM8, and PIEZO2 ion channels. Neurosci. Bull. 37:121745–49
    [Google Scholar]
  5. 5.
    Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D 1997. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–24
    [Google Scholar]
  6. 6.
    Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI et al. 2007. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448:204–8
    [Google Scholar]
  7. 7.
    Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A. 2007. TRPM8 is required for cold sensation in mice. Neuron 54:371–78
    [Google Scholar]
  8. 8.
    Kim SE, Coste B, Chadha A, Cook B, Patapoutian A. 2012. The role of Drosophila Piezo in mechanical nociception. Nature 483:209–12
    [Google Scholar]
  9. 9.
    Gold MS, Gebhart GF. 2010. Nociceptor sensitization in pain pathogenesis. Nat. Med. 16:1248–57
    [Google Scholar]
  10. 10.
    Ji RR, Xu ZZ, Gao YJ. 2014. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13:533–48
    [Google Scholar]
  11. 11.
    White FA, Sun J, Waters SM, Ma C, Ren D et al. 2005. Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. PNAS 102:14092–97
    [Google Scholar]
  12. 12.
    Luo X, Chen O, Wang Z, Bang S, Ji J et al. 2021. IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice. Neuron 109:2691–706.e5
    [Google Scholar]
  13. 13.
    Donnelly CR, Chen O, Ji RR. 2020. How do sensory neurons sense danger signals?. Trends Neurosci 43:822–38
    [Google Scholar]
  14. 14.
    Donnelly CR, Jiang C, Andriessen AS, Wang K, Wang Z et al. 2021. STING controls nociception via type I interferon signalling in sensory neurons. Nature 591:275–80
    [Google Scholar]
  15. 15.
    Cummins TR, Dib-Hajj SD, Black JA, Waxman SG. 2000. Sodium channels and the molecular pathophysiology of pain. Prog. Brain Res. 129:3–19
    [Google Scholar]
  16. 16.
    Moore C, Gupta R, Jordt SE, Chen Y, Liedtke WB. 2018. Regulation of pain and itch by TRP channels. Neurosci. Bull. 34:120–42
    [Google Scholar]
  17. 17.
    Hucho T, Levine JD. 2007. Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron 55:365–76
    [Google Scholar]
  18. 18.
    Ji RR, Gereau RW, Malcangio M, Strichartz GR. 2009. MAP kinase and pain. Brain Res. Rev. 60:135–48
    [Google Scholar]
  19. 19.
    Latremoliere A, Woolf CJ. 2009. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J. Pain 10:895–926
    [Google Scholar]
  20. 20.
    Ji RR, Kohno T, Moore KA, Woolf CJ. 2003. Central sensitization and LTP: Do pain and memory share similar mechanisms?. Trends Neurosci 26:696–705
    [Google Scholar]
  21. 21.
    Woolf CJ. 2011. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152:S2–15
    [Google Scholar]
  22. 22.
    Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. 2018. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology 129:2343–66
    [Google Scholar]
  23. 23.
    Yang Q, Wu Z, Hadden JK, Odem MA, Zuo Y et al. 2014. Persistent pain after spinal cord injury is maintained by primary afferent activity. J. Neurosci. 34:10765–69
    [Google Scholar]
  24. 24.
    Ellis A, Bennett DL. 2013. Neuroinflammation and the generation of neuropathic pain. Br. J. Anaesth. 111:26–37
    [Google Scholar]
  25. 25.
    Ji RR, Berta T, Nedergaard M. 2013. Glia and pain: Is chronic pain a gliopathy?. Pain 154:1S10–28
    [Google Scholar]
  26. 26.
    Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M et al. 2005. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–21
    [Google Scholar]
  27. 27.
    Kawasaki Y, Zhang L, Cheng JK, Ji RR 2008. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1β, interleukin-6, and tumor necrosis factor-α in regulating synaptic and neuronal activity in the superficial spinal cord. J. Neurosci. 28:5189–94
    [Google Scholar]
  28. 28.
    Luo H, Liu HZ, Zhang WW, Matsuda M, Lv N et al. 2019. Interleukin-17 regulates neuron-glial communications, synaptic transmission, and neuropathic pain after chemotherapy. Cell Rep 29:2384–97.e5
    [Google Scholar]
  29. 29.
    Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA. 1999. Inducible cyclooxygenase may have anti-inflammatory properties. Nat. Med. 5:698–701
    [Google Scholar]
  30. 30.
    Fullerton JN, Gilroy DW. 2016. Resolution of inflammation: a new therapeutic frontier. Nat. Rev. Drug Discov. 15:551–67
    [Google Scholar]
  31. 31.
    Ji RR, Xu ZZ, Strichartz G, Serhan CN. 2011. Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci 34:11599–609
    [Google Scholar]
  32. 32.
    Serhan CN, Dalli J, Karamnov S, Choi A, Park CK et al. 2012. Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J 26:1755–65
    [Google Scholar]
  33. 33.
    Bang S, Xie YK, Zhang ZJ, Wang Z, Xu ZZ, Ji RR 2018. GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain. J. Clin. Investig. 128:3568–82
    [Google Scholar]
  34. 34.
    Bang S, Donnelly CR, Luo X, Toro-Moreno M, Tao X et al. 2021. Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice. Nat. Commun. 12:1704
    [Google Scholar]
  35. 35.
    Krukowski K, Eijkelkamp N, Laumet G, Hack CE, Li Y et al. 2016. CD8+ T cells and endogenous IL-10 are required for resolution of chemotherapy-induced neuropathic pain. J. Neurosci. 36:11074–83
    [Google Scholar]
  36. 36.
    Chen G, Park CK, Xie RG, Ji RR 2015. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. J. Clin. Investig. 125:3226–40
    [Google Scholar]
  37. 37.
    Guo W, Wang H, Zou S, Gu M, Watanabe M et al. 2011. Bone marrow stromal cells produce long-term pain relief in rat models of persistent pain. Stem Cells 29:1294–303
    [Google Scholar]
  38. 38.
    Price TJ, Basbaum AI, Bresnahan J, Chambers JF, De Koninck Y et al. 2018. Transition to chronic pain: opportunities for novel therapeutics. Nat. Rev. Neurosci. 19:7383–84
    [Google Scholar]
  39. 39.
    Buckley CD, Gilroy DW, Serhan CN. 2014. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 40:315–27
    [Google Scholar]
  40. 40.
    Bannenberg G, Serhan CN. 2010. Specialized pro-resolving lipid mediators in the inflammatory response: an update. Biochim. Biophys. Acta 1801:1260–73
    [Google Scholar]
  41. 41.
    Chiang N, Serhan CN. 2020. Specialized pro-resolving mediator network: an update on production and actions. Essays Biochem 64:443–62
    [Google Scholar]
  42. 42.
    Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A et al. 2005. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Investig. 115:2774–83
    [Google Scholar]
  43. 43.
    Spite M, Norling LV, Summers L, Yang R, Cooper D et al. 2009. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461:1287–91
    [Google Scholar]
  44. 44.
    Sulciner ML, Serhan CN, Gilligan MM, Mudge DK, Chang J et al. 2018. Resolvins suppress tumor growth and enhance cancer therapy. J. Exp. Med. 215:115–40
    [Google Scholar]
  45. 45.
    Duffield JS, Hong S, Vaidya VS, Lu Y, Fredman G et al. 2006. Resolvin D series and protectin D1 mitigate acute kidney injury. J. Immunol. 177:5902–11
    [Google Scholar]
  46. 46.
    Zhang L, Terrando N, Xu ZZ, Bang S, Jordt SE et al. 2018. Distinct analgesic actions of DHA and DHA-derived specialized pro-resolving mediators on post-operative pain after bone fracture in mice. Front. Pharmacol. 9:412
    [Google Scholar]
  47. 47.
    Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A et al. 2001. Interleukin-1β-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410:471–75
    [Google Scholar]
  48. 48.
    Yaksh TL. 1999. Spinal systems and pain processing: development of novel analgesic drugs with mechanistically defined models. Trends Pharmacol. Sci. 20:329–37
    [Google Scholar]
  49. 49.
    Malmberg AB, Yaksh TL. 1995. Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: a microdialysis study in unanesthetized rats. J. Neurosci. 15:2768–76
    [Google Scholar]
  50. 50.
    Brigham NC, Ji RR, Becker ML 2021. Degradable polymeric vehicles for postoperative pain management. Nat. Commun. 12:1367
    [Google Scholar]
  51. 51.
    Brigham NC, Nofsinger R, Luo X, Dreger NZ, Abel AK et al. 2021. Controlled release of etoricoxib from poly(ester urea) films for post-operative pain management. J. Control. Release 329:316–27
    [Google Scholar]
  52. 52.
    Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. 2001. Lipid mediator class switching during acute inflammation: signals in resolution. Nat. Immunol. 2:612–19
    [Google Scholar]
  53. 53.
    Serhan CN, Chiang N, Van Dyke TE. 2008. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol. 8:349–61
    [Google Scholar]
  54. 54.
    Serhan CN. 2014. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510:92–101
    [Google Scholar]
  55. 55.
    Xu ZZ, Zhang L, Liu T, Park JY, Berta T et al. 2010. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nat. Med. 16:592–97
    [Google Scholar]
  56. 56.
    Patapoutian A, Tate S, Woolf CJ. 2009. Transient receptor potential channels: targeting pain at the source. Nat. Rev. Drug Discov. 8:55–68
    [Google Scholar]
  57. 57.
    Bang S, Yoo S, Yang TJ, Cho H, Kim YG, Hwang SW. 2010. Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception. Br. J. Pharmacol. 161:707–20
    [Google Scholar]
  58. 58.
    Park CK, Xu ZZ, Liu T, Lu N, Serhan CN, Ji RR 2011. 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. 31:18433–38
    [Google Scholar]
  59. 59.
    Park CK, Lu N, Xu ZZ, Liu T, Serhan CN, Ji RR 2011. Resolving TRPV1- and TNF-α-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J. Neurosci. 31:15072–85
    [Google Scholar]
  60. 60.
    Perna E, Aguilera-Lizarraga J, Florens MV, Jain P, Theofanous SA et al. 2021. Effect of resolvins on sensitisation of TRPV1 and visceral hypersensitivity in IBS. Gut 70:1275–86
    [Google Scholar]
  61. 61.
    Huang J, Burston JJ, Li L, Ashraf S, Mapp PI et al. 2017. Targeting the D series resolvin receptor system for the treatment of osteoarthritis pain. Arthritis Rheumatol 69:996–1008
    [Google Scholar]
  62. 62.
    Xu ZZ, Ji RR. 2011. Resolvins are potent analgesics for arthritic pain. Br. J. Pharmacol. 164:274–77
    [Google Scholar]
  63. 63.
    Lima-Garcia JF, Dutra RC, da Silva K, Motta EM, Campos MM, Calixto JB. 2011. The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats. Br. J. Pharmacol. 164:278–93
    [Google Scholar]
  64. 64.
    Allen BL, Montague-Cardoso K, Simeoli R, Colas RA, Oggero S et al. 2020. Imbalance of pro-resolving lipid mediators in persistent allodynia dissociated from signs of clinical arthritis. Pain 161:92155–66
    [Google Scholar]
  65. 65.
    Falsetta ML, Wood RW, Linder MA, Bonham AD, Honn KV et al. 2021. Specialized pro-resolving mediators reduce pro-nociceptive inflammatory mediator production in models of localized provoked vulvodynia. J. Pain 22:1195–209
    [Google Scholar]
  66. 66.
    Park CK. 2015. Maresin 1 inhibits TRPV1 in temporomandibular joint-related trigeminal nociceptive neurons and TMJ inflammation-induced synaptic plasticity in the trigeminal nucleus. Mediators Inflamm 2015:275126
    [Google Scholar]
  67. 67.
    Serhan CN, Hamberg M, Samuelsson B. 1984. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. PNAS 81:5335–39
    [Google Scholar]
  68. 68.
    Svensson CI, Zattoni M, Serhan CN. 2007. Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing. J. Exp. Med. 204:245–52
    [Google Scholar]
  69. 69.
    Yaksh TL, Rudy TA. 1976. Analgesia mediated by a direct spinal action of narcotics. Science 192:1357–58
    [Google Scholar]
  70. 70.
    Hylden JL, Wilcox GL. 1980. Intrathecal morphine in mice: a new technique. Eur. J. Pharmacol. 67:313–16
    [Google Scholar]
  71. 71.
    Lu Q, Yang Y, Zhang H, Chen C, Zhao J et al. 2021. Activation of GPR18 by resolvin D2 relieves pain and improves bladder function in cyclophosphamide-induced cystitis through inhibiting TRPV1. Drug Des. Devel. Ther. 15:4687–99
    [Google Scholar]
  72. 72.
    Wang YH, Li Y, Wang JN, Zhao QX, Jin J et al. 2020. Maresin 1 attenuates radicular pain through the inhibition of NLRP3 inflammasome-induced pyroptosis via NF-κB signaling. Front. Neurosci. 14:831
    [Google Scholar]
  73. 73.
    Miao GS, Liu ZH, Wei SX, Luo JG, Fu ZJ, Sun T. 2015. Lipoxin A4 attenuates radicular pain possibly by inhibiting spinal ERK, JNK and NF-κB/p65 and cytokine signals, but not p38, in a rat model of non-compressive lumbar disc herniation. Neuroscience 300:10–18
    [Google Scholar]
  74. 74.
    Kharasch ED, Clark JD, Adams JM. 2022. Opioids and public health: the prescription opioid ecosystem and need for improved management. Anesthesiology 136:10–30
    [Google Scholar]
  75. 75.
    Brennan TJ. 2002. Frontiers in translational research: the etiology of incisional and postoperative pain. Anesthesiology 97:535–37
    [Google Scholar]
  76. 76.
    Kehlet H, Jensen TS, Woolf CJ. 2006. Persistent postsurgical pain: risk factors and prevention. Lancet 367:1618–25
    [Google Scholar]
  77. 77.
    Flatters SJ. 2008. Characterization of a model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR). Pain 135:119–30
    [Google Scholar]
  78. 78.
    Huang L, Wang CF, Serhan CN, Strichartz G. 2011. Enduring prevention and transient reduction of postoperative pain by intrathecal resolvin D1. Pain 152:557–65
    [Google Scholar]
  79. 79.
    Wang JC, Strichartz GR. 2017. Prevention of chronic post-thoracotomy pain in rats by intrathecal resolvin D1 and D2: effectiveness of perioperative and delayed drug delivery. J. Pain 18:5535–45
    [Google Scholar]
  80. 80.
    Ji RR, Donnelly CR, Nedergaard M. 2019. Astrocytes in chronic pain and itch. Nat. Rev. Neurosci. 20:667–85
    [Google Scholar]
  81. 81.
    Terrando N, Gomez-Galan M, Yang T, Carlstrom M, Gustavsson D et al. 2013. Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline. FASEB J 27:3564–71
    [Google Scholar]
  82. 82.
    Costigan M, Scholz J, Woolf CJ. 2009. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32:1–32
    [Google Scholar]
  83. 83.
    Xu ZZ, Berta T, Ji RR 2013. Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury. J. Neuroimmune Pharmacol. 8:37–41
    [Google Scholar]
  84. 84.
    Luo X, Gu Y, Tao X, Serhan CN, Ji RR 2019. Resolvin D5 inhibits neuropathic and inflammatory pain in male but not female mice: distinct actions of D-series resolvins in chemotherapy-induced peripheral neuropathy. Front. Pharmacol. 10:745
    [Google Scholar]
  85. 85.
    Nesman JI, Chen O, Luo X, Ji RR, Serhan CN, Hansen TV. 2021. A new synthetic protectin D1 analog 3-oxa-PD1n-3 DPA reduces neuropathic pain and chronic itch in mice. Org. Biomol. Chem. 19:2744–52
    [Google Scholar]
  86. 86.
    Martini AC, Berta T, Forner S, Chen G, Bento AF et al. 2016. Lipoxin A4 inhibits microglial activation and reduces neuroinflammation and neuropathic pain after spinal cord hemisection. J. Neuroinflamm. 13:75
    [Google Scholar]
  87. 87.
    Wei J, Su W, Zhao Y, Wei Z, Hua Y et al. 2022. Maresin 1 promotes nerve regeneration and alleviates neuropathic pain after nerve injury. J. Neuroinflamm. 19:32
    [Google Scholar]
  88. 88.
    Xu ZZ, Liu XJ, Berta T, Park CK, Lu N et al. 2013. Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma. Ann. Neurol. 74:490–95
    [Google Scholar]
  89. 89.
    Ruscheweyh R, Wilder-Smith O, Drdla R, Liu XG, Sandkuhler J. 2011. Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol. Pain 7:20
    [Google Scholar]
  90. 90.
    Gao J, Tang C, Tai LW, Ouyang Y, Li N et al. 2018. Pro-resolving mediator maresin 1 ameliorates pain hypersensitivity in a rat spinal nerve ligation model of neuropathic pain. J. Pain Res. 11:1511–19
    [Google Scholar]
  91. 91.
    Li Y, Zhang H, Zhang H, Kosturakis AK, Jawad AB, Dougherty PM. 2014. Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy. J. Pain 15:712–25
    [Google Scholar]
  92. 92.
    Flatters SJ, Bennett GJ. 2004. Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain 109:150–61
    [Google Scholar]
  93. 93.
    Gwak YS, Kang J, Unabia GC, Hulsebosch CE. 2012. Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats. Exp. Neurol. 234:362–72
    [Google Scholar]
  94. 94.
    Schmidt BL. 2014. The neurobiology of cancer pain. Neuroscientist 20:546–62
    [Google Scholar]
  95. 95.
    Khasabova IA, Golovko MY, Golovko SA, Simone DA, Khasabov SG. 2020. Intrathecal administration of resolvin D1 and E1 decreases hyperalgesia in mice with bone cancer pain: involvement of endocannabinoid signaling. Prostaglandins Other Lipid Mediat. 151:106479
    [Google Scholar]
  96. 96.
    Ye Y, Scheff NN, Bernabe D, Salvo E, Ono K et al. 2018. Anti-cancer and analgesic effects of resolvin D2 in oral squamous cell carcinoma. Neuropharmacology 139:182–93
    [Google Scholar]
  97. 97.
    Fishbein A, Hammock BD, Serhan CN, Panigrahy D. 2021. Carcinogenesis: failure of resolution of inflammation?. Pharmacol. Ther. 218:107670
    [Google Scholar]
  98. 98.
    Gilligan MM, Gartung A, Sulciner ML, Norris PC, Sukhatme VP et al. 2019. Aspirin-triggered proresolving mediators stimulate resolution in cancer. PNAS 116:6292–97
    [Google Scholar]
  99. 99.
    Wang K, Gu Y, Liao Y, Bang S, Donnelly CR et al. 2020. PD-1 blockade inhibits osteoclast formation and murine bone cancer pain. J. Clin. Investig. 130:73603–20
    [Google Scholar]
  100. 100.
    Wang K, Donnelly CR, Jiang C, Liao Y, Luo X et al. 2021. STING suppresses bone cancer pain via immune and neuronal modulation. Nat. Commun. 12:4558
    [Google Scholar]
  101. 101.
    Bennett DL, Woods CG. 2014. Painful and painless channelopathies. Lancet Neurol 13:587–99
    [Google Scholar]
  102. 102.
    Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H et al. 2010. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142:687–98
    [Google Scholar]
  103. 103.
    Mogil JS. 2020. Qualitative sex differences in pain processing: emerging evidence of a biased literature. Nat. Rev. Neurosci. 21:353–65
    [Google Scholar]
  104. 104.
    Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL 3rd. 2009. Sex, gender, and pain: a review of recent clinical and experimental findings. J. Pain 10:447–85
    [Google Scholar]
  105. 105.
    Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S et al. 2015. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat. Neurosci. 18:1081–83
    [Google Scholar]
  106. 106.
    Chen G, Zhang YQ, Qadri YJ, Serhan CN, Ji RR 2018. Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron 100:1292–311
    [Google Scholar]
  107. 107.
    Chiang N, Fredman G, Backhed F, Oh SF, Vickery T et al. 2012. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484:524–28
    [Google Scholar]
  108. 108.
    Chiang N, Dalli J, Colas RA, Serhan CN. 2015. Identification of resolvin D2 receptor mediating resolution of infections and organ protection. J. Exp. Med. 212:1203–17
    [Google Scholar]
  109. 109.
    Krishnamoorthy S, Recchiuti A, Chiang N, Yacoubian S, Lee CH et al. 2010. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. PNAS 107:1660–65
    [Google Scholar]
  110. 110.
    Thion MS, Low D, Silvin A, Chen J, Grisel P et al. 2018. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172:500–16.e16
    [Google Scholar]
  111. 111.
    Arita M, Bianchini F, Aliberti J, Sher A, Chiang N et al. 2005. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201:713–22
    [Google Scholar]
  112. 112.
    Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. 2007. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J. Immunol. 178:3912–17
    [Google Scholar]
  113. 113.
    Xie YK, Luo H, Qiu XY, Xu ZZ. 2021. Resolution of inflammatory pain by endogenous chemerin and G protein-coupled receptor ChemR23. Neurosci. Bull. 37:1351–56
    [Google Scholar]
  114. 114.
    Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J et al. 2007. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat. Med. 13:868–73
    [Google Scholar]
  115. 115.
    Doyle JR, Krishnaji ST, Zhu G, Xu ZZ, Heller D et al. 2014. Development of a membrane-anchored chemerin receptor agonist as a novel modulator of allergic airway inflammation and neuropathic pain. J. Biol. Chem. 289:13385–96
    [Google Scholar]
  116. 116.
    Qu L, Caterina MJ. 2018. Accelerating the reversal of inflammatory pain with NPD1 and its receptor GPR37. J. Clin. Investig. 128:3246–49
    [Google Scholar]
  117. 117.
    Renthal W, Tochitsky I, Yang L, Cheng YC, Li E et al. 2020. Transcriptional reprogramming of distinct peripheral sensory neuron subtypes after axonal injury. Neuron 108:128–44.e9
    [Google Scholar]
  118. 118.
    Kupari J, Usoskin D, Parisien M, Lou D, Hu Y et al. 2021. Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain. Nat. Commun. 12:1510
    [Google Scholar]
  119. 119.
    Chiang N, Libreros S, Norris PC, de la Rosa X, Serhan CN. 2019. Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions. J. Clin. Investig. 129:5294–311
    [Google Scholar]
  120. 120.
    Khedgikar V, Charles JF, Lehoczky JA. 2022. Mouse LGR6 regulates osteogenesis in vitro and in vivo through differential ligand use. Bone 155:116267
    [Google Scholar]
  121. 121.
    Han YH, Shin KO, Kim JY, Khadka DB, Kim HJ et al. 2019. A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis. J. Clin. Investig. 129:1684–98
    [Google Scholar]
  122. 122.
    Serhan CN, Dalli J, Karamnov S, Choi A, Park CK et al. 2012. Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J 26:1755–65
    [Google Scholar]
  123. 123.
    Fabisiak A, Fabisiak N, Mokrowiecka A, Malecka-Panas E, Jacenik D et al. 2021. Novel selective agonist of GPR18, PSB-KK-1415 exerts potent anti-inflammatory and anti-nociceptive activities in animal models of intestinal inflammation and inflammatory pain. Neurogastroenterol. Motil. 33:e14003
    [Google Scholar]
  124. 124.
    Lee SH, Tonello R, Im ST, Jeon H, Park J et al. 2020. Resolvin D3 controls mouse and human TRPV1-positive neurons and preclinical progression of psoriasis. Theranostics 10:12111–26
    [Google Scholar]
  125. 125.
    Payrits M, Horvath A, Biro-Suto T, Erostyak J, Makkai G et al. 2020. Resolvin D1 and D2 inhibit transient receptor potential vanilloid 1 and ankyrin 1 ion channel activation on sensory neurons via lipid raft modification. Int. J. Mol. Sci. 21:5019
    [Google Scholar]
  126. 126.
    Ikeda H, Heinke B, Ruscheweyh R, Sandkuhler J. 2003. Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299:1237–40
    [Google Scholar]
  127. 127.
    LaMotte RH, Dong X, Ringkamp M. 2014. Sensory neurons and circuits mediating itch. Nat. Rev. Neurosci. 15:19–31
    [Google Scholar]
  128. 128.
    Wu SH, Chen XQ, Liu B, Wu HJ, Dong L. 2013. Efficacy and safety of 15(R/S)-methyl-lipoxin A4 in topical treatment of infantile eczema. Br. J. Dermatol. 168:172–78
    [Google Scholar]
  129. 129.
    Liu X, Wang X, Duan X, Poorun D, Xu J et al. 2017. Lipoxin A4 and its analog suppress inflammation by modulating HMGB1 translocation and expression in psoriasis. Sci. Rep. 7:7100
    [Google Scholar]
  130. 130.
    Sawada Y, Honda T, Nakamizo S, Otsuka A, Ogawa N et al. 2018. Resolvin E1 attenuates murine psoriatic dermatitis. Sci. Rep. 8:11873
    [Google Scholar]
  131. 131.
    Han Q, Liu D, Convertino M, Wang Z, Jiang C et al. 2018. miRNA-711 binds and activates TRPA1 extracellularly to evoke acute and chronic pruritus. Neuron 99:449–63.e6
    [Google Scholar]
  132. 132.
    Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A et al. 2009. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139:71353–65
    [Google Scholar]
  133. 133.
    Cao C, Kang HJ, Singh I, Chen H, Zhang C et al. 2021. Structure, function and pharmacology of human itch GPCRs. Nature 600:7887170–75
    [Google Scholar]
  134. 134.
    Yang F, Guo L, Li Y, Wang G, Wang J et al. 2021. Structure, function and pharmacology of human itch receptor complexes. Nature 600:7887164–69
    [Google Scholar]
  135. 135.
    Chávez-Castillo M, Ortega A, Cudris-Torres L, Duran P, Rojas M et al. 2021. Specialized pro-resolving lipid mediators: the future of chronic pain therapy?. Int. J. Mol. Sci. 22:10370
    [Google Scholar]
  136. 136.
    Ramsden CE, Faurot KR, Zamora D, Suchindran CM, Macintosh BA et al. 2013. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Pain 154:2441–51
    [Google Scholar]
  137. 137.
    Ramsden CE, Faurot KR, Zamora D, Palsson OS, MacIntosh BA et al. 2015. Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: a secondary analysis of a randomized trial. Pain 156:587–96
    [Google Scholar]
  138. 138.
    Hasturk H, Schulte F, Martins M, Sherzai H, Floros C et al. 2021. Safety and preliminary efficacy of a novel host-modulatory therapy for reducing gingival inflammation. Front. Immunol. 12:704163
    [Google Scholar]
  139. 139.
    Arita M, Oh SF, Chonan T, Hong S, Elangovan S et al. 2006. Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. J. Biol. Chem. 281:22847–54
    [Google Scholar]
  140. 140.
    Norling LV, Spite M, Yang R, Flower RJ, Perretti M, Serhan CN. 2011. Cutting edge: humanized nano-proresolving medicines mimic inflammation-resolution and enhance wound healing. J. Immunol. 186:5543–47
    [Google Scholar]
  141. 141.
    Brigham NC, Ji RR, Becker ML 2021. Degradable polymeric vehicles for postoperative pain management. Nat. Commun. 12:1367
    [Google Scholar]
  142. 142.
    Serhan CN, de la Rosa X, Jouvene C. 2019. Novel mediators and mechanisms in the resolution of infectious inflammation: evidence for vagus regulation. J. Intern. Med. 286:240–58
    [Google Scholar]
  143. 143.
    Tao X, Lee MS, Donnelly CR, Ji RR 2020. Neuromodulation, specialized pro-resolving mediators, and resolution of pain. Neurotherapeutics 17:3886–99
    [Google Scholar]
  144. 144.
    Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN. 2014. Vagus nerve controls resolution and pro-resolving mediators of inflammation. J. Exp. Med. 211:1037–48
    [Google Scholar]
  145. 145.
    Serhan CN, de la Rosa X, Jouvene CC. 2018. Cutting edge: Human vagus produces specialized proresolving mediators of inflammation with electrical stimulation reducing proinflammatory eicosanoids. J. Immunol. 201:3161–65
    [Google Scholar]
  146. 146.
    Tao X, Luo X, Zhang T, Hershey B, Esteller R, Ji RR 2021. Spinal cord stimulation attenuates mechanical allodynia and increases central resolvin D1 levels in rats with spared nerve injury. Front. Physiol. 12:687046
    [Google Scholar]
  147. 147.
    Volkow ND, Collins FS. 2017. The role of science in addressing the opioid crisis. N. Engl. J. Med. 377:391–94
    [Google Scholar]
  148. 148.
    Perretti M, Leroy X, Bland EJ, Montero-Melendez T 2015. Resolution pharmacology: opportunities for therapeutic innovation in inflammation. Trends Pharmacol. Sci. 36:737–55
    [Google Scholar]
  149. 149.
    Kantarci A, Aytan N, Palaska I, Stephens D, Crabtree L, Benincasa C et al. 2018. Combined administration of resolvin E1 and lipoxin A4 resolves inflammation in a murine model of Alzheimer's disease. Exp. Neurol. 300:111–20
    [Google Scholar]
  150. 150.
    Tao X, Lee MS, Donnelly CR, Ji R-R. 2020. Neuromodulation, specialized proresolving mediators, and resolution of pain. Neurotherapeutics 17:886–99
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-051921-084047
Loading
/content/journals/10.1146/annurev-pharmtox-051921-084047
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error