Emerging targets in neuroinflammation-driven chronic pain

Nature Reviews Drug Discovery

Volumn 13, Issue 7, 2014, Pages 533-548

  Ji, Ru Rong ^a   Xu, Zhen Zhong ^a   Gao, Yong Jing ^b  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b NANTONG UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

CASPASE; CATHEPSIN S; CHEMOKINE; CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CX3CR1; CHEMOKINE RECEPTOR CXCR2; CXCL1 CHEMOKINE; FRACTALKINE; GELATINASE A; GELATINASE B; MONOCYTE CHEMOTACTIC PROTEIN 1; PROTEINASE; TRANSIENT RECEPTOR POTENTIAL CHANNEL; WNT PROTEIN; WNT3A PROTEIN; 1 (2 BROMOPHENYL) 3 (2 HYDROXY 4 NITROPHENYL)UREA; ANALGESIC AGENT; AZD 2423; AZD 8309; BRAIN DERIVED NEUROTROPHIC FACTOR; CASPASE 6; ELUBRIXIN; INTERFERON; INTERLEUKIN 10; INTERLEUKIN 4; MARAVIROC; MONOCYTE CHEMOTACTIC PROTEIN 3; NAVARIXIN; PLERIXAFOR; RAP 103; TRANSFORMING GROWTH FACTOR; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANILLOID RECEPTOR 1;

ASTROCYTE; CELL ACTIVATION; CELL INFILTRATION; CELL INTERACTION; CENTRAL NERVOUS SYSTEM SENSITIZATION; CHRONIC PAIN; DEGENERATIVE DISEASE; GLIA CELL; HUMAN; IMMUNOCOMPETENT CELL; INFLAMMATORY PAIN; INTRACELLULAR SIGNALING; MICROGLIA; MYELITIS; NERVE CELL PLASTICITY; NERVOUS SYSTEM INFLAMMATION; NEUROMODULATION; NEUROPATHIC PAIN; NEUROTRANSMISSION; NONHUMAN; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW; WNT SIGNALING PATHWAY; ENZYME SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MACROPHAGE; MALIGNANT NEOPLASTIC DISEASE; MENTAL DISEASE; NEUROLOGIC DISEASE; NEUROPATHY; PERIPHERAL NEUROPATHY; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; T LYMPHOCYTE; UPREGULATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; CHEMOKINES; CHRONIC PAIN; HUMANS; INFLAMMATION; NERVOUS SYSTEM DISEASES; PEPTIDE HYDROLASES; WNT PROTEINS;

EID: 84903814786     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4334     Document Type: Review

References (185)

1. Johannes, C. B., Le, T. K., Zhou, X., Johnston, J. A. & Dworkin, R. H. The prevalence of chronic pain in United States adults: Results of an Internet-based survey. J. Pain 11, 1230-1239 (2010
2. Stein, C., Millan, M. J. & Herz, A. Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: Alterations in behavior and nociceptive thresholds. Pharmacol. Biochem. Behav. 31, 455-451 (1988
3. Svensson, C. I., Zattoni, M. & Serhan, C. N. Lipoxins and aspirin-Triggered lipoxin inhibit inflammatory pain processing. J. Exp. Med. 204, 245-252 (2007
4. Honore, P. et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 98, 585-598 (2000
5. Xu, Q. et al. Peripheral TGF β1 signaling is a critical event in bone cancer-induced hyperalgesia in rodents. J. Neurosci. 33, 19099-19111 (2013
6. Decosterd, I. & Woolf, C. J. Spared nerve injury: An animal model of persistent peripheral neuropathic pain. Pain 87, 149-158 (2000
7. Costigan, M., Scholz, J. & Woolf, C. J. Neuropathic pain: A maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32, 1-32 (2009
8. Bennett, G. J. & Xie, Y. K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87-107 (1988
9. Kim, S. H. & Chung, J. M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355-363 (1992
10. Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267-284 (2009
11. Gold, M. S., Levine, J. D. & Correa, A. M. Modulation of TTX R INa by PKC and PKA and their role in PGE2 induced sensitization of rat sensory neurons in vitro. J. Neurosci. 18, 10345-10355 (1998
12. Aley, K. O. & Levine, J. D. Role of protein kinase A in the maintenance of inflammatory pain. J. Neurosci. 19, 2181-2186 (1999
13. Woolf, C. J. Evidence for a central component of post-injury pain hypersensitivity. Nature 306, 686-688 (1983
14. Ossipov, M. H., Dussor, G. O. & Porreca, F. Central modulation of pain. J. Clin. Invest. 120, 3779-3787 (2010
15. Chiu, I. M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52-57 (2013
16. Park, C. K. et al. Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron 82, 47-54 (2014
17. Woolf, C. J. & Salter, M. W. Neuronal plasticity: Increasing the gain in pain. Science 288, 1765-1769 (2000
18. Hylden, J. L., Nahin, R. L., Traub, R. J. & Dubner, R. Expansion of receptive fields of spinal lamina I projection neurons in rats with unilateral adjuvant-induced inflammation: The contribution of dorsal horn mechanisms. Pain 37, 229-243 (1989
19. Ji, R. R., Baba, H., Brenner, G. J. & Woolf, C. J. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nature Neurosci. 2, 1114-1119 (1999
20. Liu, X. J. et al. Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nature Med. 14, 1325-1332 (2008
21. Karim, F., Wang, C. C. & Gereau, R. W. Metabotropic glutamate receptor subtypes 1 and 5 are activators of extracellular signal-regulated kinase signaling required for inflammatory pain in mice. J. Neurosci. 21, 3771-3779 (2001
22. Christianson, C. A. et al. Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-Transferred arthritis. Pain 152, 2881-2891 (2011
23. Gao, Y. J. & Ji, R. R. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol. Ther. 126, 56-68 (2010
24. Kawasaki, Y., Zhang, L., Cheng, J. K. & Ji, R. R. 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, 5189-5194 (2008
25. Rivest, S. Regulation of innate immune responses in the brain. Nature Rev. Immunol. 9, 429-439 (2009
26. Grace, P. M., Hutchinson, M. R., Maier, S. F. & Watkins, L. R. Pathological pain and the neuroimmune interface. Nature Rev. Immunol. 14, 217-231 (2014
27. Kigerl, K. A. et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 29, 13435-13444 (2009
28. Costigan, M. et al. T cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J. Neurosci. 29, 14415-14422 (2009
29. Old, E. A. et al. Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain. J. Clin. Invest. 124, 2023-2036 (2014
30. Ellis, A. & Bennett, D. L. Neuroinflammation and the generation of neuropathic pain. Br. J. Anaesth. 111, 26-37 (2013
31. Ji, R. R., Berta, T. & Nedergaard, M. Glia and pain: Is chronic pain a gliopathy?. Pain 154 (Suppl. 1), 10-28 (2013
32. Raghavendra, V., Tanga, F. & DeLeo, J. A. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 306, 624-630 (2003
33. Zhang, J. & De Koninck, Y. Spatial and temporal relationship between monocyte chemoattractant protein 1 expression and spinal glial activation following peripheral nerve injury. J. Neurochem. 97, 772-783 (2006
34. Katsura, H. et al. Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury. J. Neurosci. 26, 8680-8690 (2006
35. Uceyler, N. et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 136, 1857-1867 (2013
36. Shi, Y., Gelman, B. B., Lisinicchia, J. G. & Tang, S. J. Chronic-pain-Associated astrocytic reaction in the spinal cord dorsal horn of human immunodeficiency virus-infected patients. J. Neurosci. 32, 10833-10840 (2012
37. Xanthos, D. N. & Sandkuhler, J. Neurogenic neuroinflammation: Inflammatory CNS reactions in response to neuronal activity. Nature Rev. Neurosci. 15, 43-53 (2014
38. Hathway, G. J., Vega-Avelaira, D., Moss, A., Ingram, R. & Fitzgerald, M. Brief, low frequency stimulation of rat peripheral C fibres evokes prolonged microglial-induced central sensitization in adults but not in neonates. Pain 144, 110-118 (2009
39. Wen, Y. R. et al. Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-Activated protein kinase in spinal microglia in the rat spared nerve injury model. Anesthesiology 107, 312-321 (2007
40. White, F. A., Bhangoo, S. K. & Miller, R. J. Chemokines: Integrators of pain and inflammation. Nature Rev. Drug Discov. 4, 834-844 (2005
41. Zhang, J. et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J. Neurosci. 27, 12396-12406 (2007
42. Echeverry, S., Shi, X. Q., Rivest, S. & Zhang, J. Peripheral nerve injury alters blood-spinal cord barrier functional and molecular integrity through a selective inflammatory pathway. J. Neurosci. 31, 10819-10828 (2011
43. Beggs, S., Liu, X. J., Kwan, C. & Salter, M. W. Peripheral nerve injury and TRPV1 expressing primary afferent C fibers cause opening of the blood-brain barrier. Mol. Pain 6, 74 (2010
44. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318 (2005
45. McMahon, S. B. & Malcangio, M. Current challenges in glia-pain biology. Neuron 64, 46-54 (2009
46. Schafers, M., Geis, C., Svensson, C. I., Luo, Z. D. & Sommer, C. Selective increase of tumour necrosis factor-Alpha in injured and spared myelinated primary afferents after chronic constrictive injury of rat sciatic nerve. Eur. J. Neurosci. 17, 791-804 (2003
47. Xu, J. T., Xin, W. J., Zang, Y., Wu, C. Y. & Liu, X. G. The role of tumor necrosis factor-Alpha in the neuropathic pain induced by Lumbar 5 ventral root transection in rat. Pain 123, 306-321 (2006
48. Berta, T. et al. Extracellular caspase 6 drives murine inflammatory pain via microglial TNF-α secretion. J. Clin. Invest. 124, 1173-1186 (2014
49. Zhang, R. X. et al. Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia. Pain 118, 125-136 (2005
50. Clark, A. K. et al. P2X7 dependent release of interleukin 1β and nociception in the spinal cord following lipopolysaccharide. J. Neurosci. 30, 573-582 (2010
51. Miyoshi, K., Obata, K., Kondo, T., Okamura, H. & Noguchi, K. Interleukin 18 mediated microglia/ astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J. Neurosci. 28, 12775-12787 (2008
52. Chen, M. L. et al. Role of P2X7 receptor-mediated IL 18/IL 18R signaling in morphine tolerance: Multiple glial-neuronal dialogues in the rat spinal cord. J. Pain 13, 945-958 (2012
53. Imai, S. et al. Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain. Brain 136, 828-843 (2013
54. Gao, Y. J. et al. JNK-induced MCP 1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J. Neurosci. 29, 4096-4108 (2009
55. Zhang, Z. J., Cao, D. L., Zhang, X., Ji, R. R. & Gao, Y. J. Chemokine contribution to neuropathic pain: Respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain 154, 2185-2197 (2013
56. Lever, I. J. et al. Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation. J. Neurosci. 21, 4469-4477 (2001
57. Coull, J. A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017-1021 (2005
58. Ferrini, F. et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl- homeostasis. Nature Neurosci. 16, 183-192 (2013
59. Madiai, F. et al. Upregulation of FGF 2 in reactive spinal cord astrocytes following unilateral lumbar spinal nerve ligation. Exp. Brain Res. 148, 366-376 (2003
60. Milligan, E. D. et al. Intrathecal polymer-based interleukin 10 gene delivery for neuropathic pain. Neuron Glia Biol. 2, 293-308 (2006
61. Sloane, E. M. et al. Long-Term control of neuropathic pain in a non-viral gene therapy paradigm. Gene Ther. 16, 470-475 (2009
62. Echeverry, S., Shi, X. Q. & Zhang, J. Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain. Pain 135, 37-47 (2008
63. Tsuda, M. et al. JAK STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain 134, 1127-1139 (2011
64. Zhang, H., Nei, H. & Dougherty, P. M. A p38 mitogen-Activated protein kinase-dependent mechanism of disinhibition in spinal synaptic transmission induced by tumor necrosis factor-α. J. Neurosci. 30, 12844-12855 (2010
65. Garraway, S. M., Petruska, J. C. & Mendell, L. M. BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs. Eur. J. Neurosci. 18, 2467-2476 (2003
66. Park, C. K. et al. Resolving TRPV1- And TNF α mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J. Neurosci. 31, 15072-15085 (2011
67. Zeilhofer, H. U., Benke, D. & Yevenes, G. E. Chronic pain states: Pharmacological strategies to restore diminished inhibitory spinal pain control. Annu. Rev. Pharmacol. Toxicol. 52, 111-133 (2012
68. Lu, Y. et al. A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia. J. Clin. Invest. 123, 4050-4062 (2013
69. Guo, W. et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J. Neurosci. 27, 6006-6018 (2007
70. Calvo, M. et al. Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J. Neurosci. 30, 5437-5450 (2010
71. Oh, S. B. et al. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J. Neurosci. 21, 5027-5035 (2001
72. Verge, G. M. et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur. J. Neurosci. 20, 1150-1160 (2004
73. Clark, A. K. et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl Acad. Sci. USA 104, 10655-10660 (2007
74. Zhuang, Z. Y. et al. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav. Immun. 21, 642-651 (2007
75. Milligan, E. D. et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur. J. Neurosci. 20, 2294-2302 (2004
76. Dorgham, K. et al. An engineered CX3CR1 antagonist endowed with anti-inflammatory activity. J. Leukoc. Biol. 86, 903-911 (2009
77. Abbadie, C. et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl Acad. Sci. USA 100, 7947-7952 (2003
78. Thacker, M. A. et al. CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur. J. Pain 13, 263-272 (2009
79. Guo, W., Wang, H., Zou, S., Dubner, R. & Ren, K. Chemokine signaling involving chemokine (C C motif) ligand 2 plays a role in Descending pain facilitation. Neurosci. Bull. 28, 193-207 (2012
80. Zhang, Z. J. et al. Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain. J. Neuroinflamm. 9, 136 (2012
81. Menetski, J. et al. Mice overexpressing chemokine ligand 2 (CCL2) in astrocytes display enhanced nociceptive responses. Neuroscience 149, 706-714 (2007
82. Omari, K. M., John, G., Lango, R. & Raine, C. S. Role for CXCR2 and CXCL1 on glia in multiple sclerosis. Glia 53, 24-31 (2006
83. Li, H., Xie, W., Strong, J. A. & Zhang, J. M. Systemic antiinflammatory corticosteroid reduces mechanical pain behavior, sympathetic sprouting, and elevation of proinflammatory cytokines in a rat model of neuropathic pain. Anesthesiology 107, 469-477 (2007
84. Pineau, I., Sun, L., Bastien, D. & Lacroix, S. Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL 1 receptor/ MyD88 dependent fashion. Brain Behav. Immun. 24, 540-553 (2010
85. Zhao, P., Waxman, S. G. & Hains, B. C. Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21. J. Neurosci. 27, 8893-8902 (2007
86. Biber, K. et al. Neuronal CCL21 up regulates microglia P2X4 expression and initiates neuropathic pain Development. EMBO J. 30, 1864-1873 (2011
87. Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778-783 (2003
88. Bhangoo, S. K. et al. CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy. Brain Behav. Immun. 21, 581-591 (2007
89. Kiguchi, N., Maeda, T., Kobayashi, Y., Fukazawa, Y. & Kishioka, S. Macrophage inflammatory protein 1α mediates the development of neuropathic pain following peripheral nerve injury through interleukin 1β up regulation. Pain 149, 305-315 (2010
90. Matsushita, K. et al. Chemokine (C C motif) receptor 5 is an important pathological regulator in the development and maintenance of neuropathic pain. Anesthesiology 120, 1491-1503 (2014
91. Weitzenfeld, P. & Ben-Baruch, A. The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. Cancer Lett. http://dx.doi.org/10.1016/j. canlet.2013.10.006 (2013
92. White, F. A. et al. Excitatory monocyte chemoattractant protein 1 signaling is up regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc. Natl Acad. Sci. USA 102, 14092-14097 (2005
93. Kalliomaki, J. et al. A randomized, double-blind, placebo-controlled trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain 154, 761-767 (2013
94. Padi, S. S. et al. Attenuation of rodent neuropathic pain by an orally active peptide, RAP 103, which potently blocks CCR2- And CCR5-mediated monocyte chemotaxis and inflammation. Pain 153, 95-106 (2012
95. Virtala, R., Ekman, A. K., Jansson, L., Westin, U. & Cardell, L. O. Airway inflammation evaluated in a human nasal lipopolysaccharide challenge model by investigating the effect of a CXCR2 inhibitor. Clin. Exp. Allergy 42, 590-596 (2012
96. Lazaar, A. L. et al. SB 656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans. Br. J. Clin. Pharmacol. 72, 282-293 (2011
97. Holz, O. et al. SCH527123, a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur. Respir. J. 35, 564-570 (2010
98. Xu, Z. Z. et al. Neuroprotectin/protectin D1 protects neuropathic pain in mice after nerve trauma. Ann. Neurol. 74, 490-495 (2013
99. Xu, Z. Z. et al. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nature Med. 16, 592-597 (2010
100. Connor, K. M. et al. Increased dietary intake of omega 3 polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nature Med. 13, 868-873 (2007
101. Ji, R. R., Xu, Z. Z., Strichartz, G. & Serhan, C. N. Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci. 34, 599-609 (2011
102. Serhan, C. N. et al. Resolvins: A family of bioactive products of omega 3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025-1037 (2002
103. Hong, S., Gronert, K., Devchand, P. R., Moussignac, R. L. & Serhan, C. N. Novel docosatrienes and 17S resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J. Biol. Chem. 278, 14677-14687 (2003
104. Arita, M. et al. Resolvin E1, an endogenous lipid mediator derived from omega 3 eicosapentaenoic acid, protects against 2,4,6 trinitrobenzene sulfonic acid-induced colitis. Proc. Natl Acad. Sci. USA 102, 7671-7676 (2005
105. Seki, H. et al. The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury. J. Immunol. 184, 836-843 (2010
106. Duffield, J. S. et al. Resolvin D series and protectin D1 mitigate acute kidney injury. J. Immunol. 177, 5902-5911 (2006
107. Mukherjee, P. K., Marcheselli, V. L., Serhan, C. N. & Bazan, N. G. Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc. Natl Acad. Sci. USA 101, 8491-8496 (2004
108. Lukiw, W. J. et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774-2783 (2005
109. Bazan, N. G. Neuroprotectin D1 mediated anti-inflammatory and survival signaling in stroke, retinal degenerations, and Alzheimer's disease. J. Lipid Res. 50, S400-S405 (2009
110. Bazan, N. G., Calandria, J. M. & Serhan, C. N. Rescue and repair during photoreceptor cell renewal mediated by docosahexaenoic acid-derived neuroprotectin D1. J. Lipid Res. 51, 2018-2031 (2010
111. Palacios-Pelaez, R., Lukiw, W. J. & Bazan, N. G. Omega 3 essential fatty acids modulate initiation and progression of neurodegenerative disease. Mol. Neurobiol. 41, 367-374 (2010
112. Serhan, C. N. et al. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: Assignments of dihydroxy-containing docosatrienes. J. Immunol. 176, 1848-1859 (2006
113. Samad, T. A. et al. Interleukin 1β mediated induction of Cox 2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410, 471-475 (2001
114. Arita, M. et al. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J. Immunol. 178, 3912-3917 (2007
115. Krishnamoorthy, S. et al. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc. Natl Acad. Sci. USA 107, 1660-1665 (2010
116. Kehlet, H., Jensen, T. S. & Woolf, C. J. Persistent postsurgical pain: Risk factors and prevention. Lancet 367, 1618-1625 (2006
117. Bian, D., Nichols, M. L., Ossipov, M. H., Lai, J. & Porreca, F. Characterization of the antiallodynic efficacy of morphine in a model of neuropathic pain in rats. Neuroreport 6, 1981-1984 (1995
118. Kohno, T. et al. Peripheral axonal injury results in reduced μ opioid receptor pre- And post-synaptic action in the spinal cord. Pain 117, 77-87 (2005
119. Boucher, T. J. et al. Potent analgesic effects of GDNF in neuropathic pain states. Science 290, 124-127 (2000
120. Gardell, L. R. et al. Multiple actions of systemic artemin in experimental neuropathy. Nature Med. 9, 1383-1389 (2003
121. Xu, Z. Z., Berta, T. & Ji, R. R. Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury. J. Neuroimmune Pharmacol. 8, 37-41 (2013
122. Tsujino, H. et al. Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury. Mol. Cell Neurosci. 15, 170-182 (2000
123. Park, C. K. et al. 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 (2011
124. Lima-Garcia, J. F. et al. 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, 278-293 (2011
125. Patapoutian, A., Tate, S. & Woolf, C. J. Transient receptor potential channels: Targeting pain at the source. Nature Rev. Drug Discov. 8, 55-68 (2009
126. Caterina, M. J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306-313 (2000
127. Chen, Y. et al. Temporomandibular joint pain: A critical role for Trpv4 in the trigeminal ganglion. Pain 154, 1295-1304 (2013
128. Patwardhan, A. M. et al. Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents. J. Clin. Invest. 120, 1617-1626 (2010
129. Sisignano, M., Bennett, D. L., Geisslinger, G. & Scholich, K. TRP-channels as key integrators of lipid pathways in nociceptive neurons. Prog. Lipid Res. 53, 93-107 (2013
130. Bang, S. et al. Resolvin D1 attenuates activation of sensory transient receptor potential channels leading to multiple anti-nociception. Br. J. Pharmacol. 161, 707-720 (2010
131. Serhan, C. N. et al. Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J. 26, 1755-1765 (2012
132. Finnerup, N. B., Sindrup, S. H. & Jensen, T. S. The evidence for pharmacological treatment of neuropathic pain. Pain 150, 573-581 (2010
133. Sommer, C. & Birklein, F. Fighting off pain with resolvins. Nature Med. 16, 518-520 (2010
134. Nikolajsen, L., Ilkjaer, S., Christensen, J. H., Kroner, K. & Jensen, T. S. Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet 350, 1353-1357 (1997
135. Ramsden, C. E. et al. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: A randomized trial. Pain 154, 2441-2451 (2013
136. Chiang, N., Bermudez, E. A., Ridker, P. M., Hurwitz, S. & Serhan, C. N. Aspirin triggers antiinflammatory 15 epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc. Natl Acad. Sci. USA 101, 15178-15183 (2004
137. Morris, T. et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J. Immunol. 183, 2089-2096 (2009
138. Kawasaki, Y. et al. Distinct roles of matrix metalloproteases in the early- And late-phase development of neuropathic pain. Nature Med. 14, 331-336 (2008
139. Clark, A. K. & Malcangio, M. Microglial signalling mechanisms: Cathepsin S and fractalkine. Exp. Neurol. 234, 283-292 (2012
140. Guo, S. L. et al. Cystatin C in cerebrospinal fluid is upregulated in elderly patients with chronic osteoarthritis pain and modulated through matrix metalloproteinase 9 specific pathway. Clin. J. Pain 30, 331-339 (2013
141. Christianson, C. A. et al. Spinal matrix metalloproteinase 3 mediates inflammatory hyperalgesia via a tumor necrosis factor-dependent mechanism. Neuroscience 200, 199-210 (2012
142. Zhao, B. Q. et al. Role of matrix metalloproteinases in Delayed cortical responses after stroke. Nature Med. 12, 441-445 (2006
143. Bissett, D. et al. Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer. J. Clin. Oncol. 23, 842-849 (2005
144. Miller, K. D. et al. A randomized phase II feasibility trial of BMS 275291 in patients with early stage breast cancer. Clin. Cancer Res. 10, 1971-1975 (2004
145. Hu, J., Van Den Steen, P. E., Sang, Q. X. & Opdenakker, G. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nature Rev. Drug Discov. 6, 480-498 (2007
146. Williams, J. M. et al. Evaluation of metalloprotease inhibitors on hypertension and diabetic nephropathy. Am. J. Physiol. Renal Physiol. 300, F983-F998 (2011
147. Clark, A. K., Yip, P. K. & Malcangio, M. The liberation of fractalkine in the dorsal horn requires microglial cathepsin S. J. Neurosci. 29, 6945-6954 (2009
148. Zhang, Y. K. et al. WNT signaling underlies the pathogenesis of neuropathic pain in rodents. J. Clin. Invest. 123, 2268-2286 (2013
149. Tang, S. J. Synaptic activity-regulated Wnt signaling in synaptic plasticity, glial function and chronic pain. CNS Neurol. Disord. Drug Targets 22 Dec 2013 [epub ahead of print].
150. Yuan, S., Shi, Y. & Tang, S. J. Wnt signaling in the pathogenesis of multiple sclerosis-Associated chronic pain. J. Neuroimmune. Pharmacol. 7, 904-913 (2012
151. Shi, Y., Shu, J., Gelman, B. B., Lisinicchia, J. G. & Tang, S. J. Wnt signaling in the pathogenesis of human HIV-Associated pain syndromes. J. Neuroimmune. Pharmacol. 8, 956-964 (2013
152. Chen, J., Park, C. S. & Tang, S. J. Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation. J. Biol. Chem. 281, 11910-11916 (2006
153. Watkins, L. R. & Maier, S. F. Glia: A novel drug discovery target for clinical pain. Nature Rev. Drug Discov. 2, 973-985 (2003
154. Woolf, C. J. Overcoming obstacles to developing new analgesics. Nature Med. 16, 1241-1247 (2010
155. Mogil, J. S. Animal models of pain: Progress and challenges. Nature Rev. Neurosci. 10, 283-294 (2009
156. King, T. et al. Unmasking the tonic-Aversive state in neuropathic pain. Nature Neurosci. 12, 1364-1366 (2009
157. Morgan, P. et al. Can the flow of medicines be improved?. Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov. Today 17, 419-424 (2012
158. Chiang, N. et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524-528 (2012
159. Morita, M. et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell 153, 112-125 (2013
160. Vargas, D. L., Nascimbene, C., Krishnan, C., Zimmerman, A. W. & Pardo, C. A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57, 67-81 (2005
161. Polgar, E., Gray, S., Riddell, J. S. & Todd, A. J. Lack of evidence for significant neuronal loss in laminae I III of the spinal dorsal horn of the rat in the chronic constriction injury model. Pain 111, 144-150 (2004
162. Scholz, J. et al. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J. Neurosci. 25, 7317-7323 (2005
163. Vereker, E., O'Donnell, E. & Lynch, M. A. The inhibitory effect of interleukin 1β on long-Term potentiation is coupled with increased activity of stress-Activated protein kinases. J. Neurosci. 20, 6811-6819 (2000
164. Ren, W. J. et al. Peripheral nerve injury leads to working memory deficits and dysfunction of the hippocampus by upregulation of TNF-α in rodents. Neuropsychopharmacology 36, 979-992 (2011
165. Liu, Y. L. et al. Tumor necrosis factor-α induces long-Term potentiation of C fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: The role of NF kappa B, JNK and p38 MAPK. Neuropharmacology 52, 708-715 (2007
166. Choi, J. I., Svensson, C. I., Koehrn, F. J., Bhuskute, A. & Sorkin, L. S. Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior. Pain 149, 243-253 (2010
167. Hess, A. et al. Blockade of TNF-α rapidly inhibits pain responses in the central nervous system. Proc. Natl Acad. Sci. USA 108, 3731-3736 (2011
168. Calvo, M. & Bennett, D. L. The mechanisms of microgliosis and pain following peripheral nerve injury. Exp. Neurol. 234, 271-282 (2012
169. Garrison, C. J., Dougherty, P. M., Kajander, K. C. & Carlton, S. M. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res. 565, 1-7 (1991
170. Raghavendra, V., Tanga, F. Y. & DeLeo, J. A. Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur. J. Neurosci. 20, 467-473 (2004
171. Colburn, R. W. et al. Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J. Neuroimmunol. 79, 163-175 (1997
172. Moss, A. et al. Spinal microglia and neuropathic pain in young rats. Pain 128, 215-224 (2007
173. Ji, R. R., Gereau, R. W., Malcangio, M. & Strichartz, G. R. MAP kinase and pain. Brain Res. Rev. 60, 135-148 (2009
174. Zhuang, Z. Y., Gerner, P., Woolf, C. J. & Ji, R. R. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 114, 149-159 (2005
175. Zhuang, Z. Y. et al. A peptide c Jun N terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: Respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain Development and maintenance. J. Neurosci. 26, 3551-3560 (2006
176. Obata, K. et al. Roles of extracellular signal-regulated protein kinases 5 in spinal microglia and primary sensory neurons for neuropathic pain. J. Neurochem. 102, 1569-1584 (2007
177. Tozaki-Saitoh, H. et al. P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J. Neurosci. 28, 4949-4956 (2008
178. Kobayashi, K. et al. P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. J. Neurosci. 28, 2892-2902 (2008
179. Kobayashi, K., Yamanaka, H., Yanamoto, F., Okubo, M. & Noguchi, K. Multiple P2Y subtypes in spinal microglia are involved in neuropathic pain after peripheral nerve injury. Glia 60, 1529-1539 (2012
180. Sorge, R. E. et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nature Med. 18, 595-599 (2012
181. Cotrina, M. L., Lin, J. H., Lopez-Garcia, J. C., Naus, C. C. & Nedergaard, M. ATP-mediated glia signaling. J. Neurosci. 20, 2835-2844 (2000
182. Chen, M. J. et al. Astrocytic CX43 hemichannels and gap junctions play a crucial role in Development of chronic neuropathic pain following spinal cord injury. Glia 60, 1660-1670 (2012
183. Zhang, F. et al. Selective activation of microglia in spinal cord but not higher cortical regions following nerve injury in adult mouse. Mol. Pain 4, 15 (2008
184. Sung, B., Lim, G. & Mao, J. Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J. Neurosci. 23, 2899-2910 (2003
185. Tsuda, M., Inoue, K. & Salter, M. W. Neuropathic pain and spinal microglia: A big problem from molecules in "small" glia. Trends Neurosci. 28, 101-107 (2005