Pain regulation by non-neuronal cells and inflammation

Acute pain is protective and a cardinal feature of inflammation. Chronic pain after arthritis, nerve injury, cancer, and chemotherapy is associated with chronic neuroinflammation, a local inflammation in the peripheral or central nervous system. Accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells, and stem cells play active roles in the pathogenesis and resolution of pain. We review how non-neuronal cells interact with nociceptive neurons by secreting neuroactive signaling molecules that modulate pain. Recent studies also suggest that bacterial infections regulate pain through direct actions on sensory neurons, and specific receptors are present in nociceptors to detect danger signals from infections. We also discuss new therapeutic strategies to control neuroinflammation for the prevention and treatment of chronic pain.

[1]  J. Deleo,et al.  The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[2]  D. Bennett,et al.  The role of the immune system in the generation of neuropathic pain , 2012, The Lancet Neurology.

[3]  Charles N Serhan,et al.  Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions , 2010, Nature Medicine.

[4]  I. Vetter,et al.  Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target , 2016, Molecular pain.

[5]  K. Sluka,et al.  IL-10 Cytokine Released from M2 Macrophages Is Crucial for Analgesic and Anti-inflammatory Effects of Acupuncture in a Model of Inflammatory Muscle Pain , 2014, Molecular Neurobiology.

[6]  Y. Chen,et al.  Neuronal somatic ATP release triggers neuron–satellite glial cell communication in dorsal root ganglia , 2007, Proceedings of the National Academy of Sciences.

[7]  A. Didangelos,et al.  Persistent Alterations in Microglial Enhancers in a Model of Chronic Pain. , 2016, Cell reports.

[8]  G. Yehia,et al.  Dopamine mediates vagal modulation of the immune system by electroacupuncture , 2014, Nature Medicine.

[9]  J. Sandkühler,et al.  Selective Activation of Microglia Facilitates Synaptic Strength , 2015, The Journal of Neuroscience.

[10]  D. Ginty,et al.  The gentle touch receptors of mammalian skin , 2014, Science.

[11]  Nan Marie Jokerst,et al.  UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling , 2013, Proceedings of the National Academy of Sciences.

[12]  David E. Strochlic,et al.  The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase , 2015, Nature Medicine.

[13]  Maria Fitzgerald,et al.  T-Cell Infiltration and Signaling in the Adult Dorsal Spinal Cord Is a Major Contributor to Neuropathic Pain-Like Hypersensitivity , 2009, The Journal of Neuroscience.

[14]  Kshitij Srivastava,et al.  A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain , 2015, Cancer cell.

[15]  M. Gold,et al.  Nociceptor sensitization in pain pathogenesis , 2010, Nature Medicine.

[16]  J. Sandkühler,et al.  Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity , 2013, Nature Reviews Neuroscience.

[17]  Zhen-Zhong Xu,et al.  Emerging targets in neuroinflammation-driven chronic pain , 2014, Nature Reviews Drug Discovery.

[18]  S. Hwang,et al.  Bacteria activate sensory neurons that modulate pain and inflammation , 2013, Nature.

[19]  Zhen-Zhong Xu,et al.  Extracellular MicroRNAs Activate Nociceptor Neurons to Elicit Pain via TLR7 and TRPA1 , 2014, Neuron.

[20]  S. Koizumi,et al.  P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury , 2003, Nature.

[21]  J. Rubenstein,et al.  Forebrain GABAergic Neuron Precursors Integrate into Adult Spinal Cord and Reduce Injury-Induced Neuropathic Pain , 2012, Neuron.

[22]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[23]  Wei Liu,et al.  Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture , 2010, Nature Neuroscience.

[24]  M. Mack,et al.  Monocytes/Macrophages control resolution of transient inflammatory pain. , 2014, The journal of pain : official journal of the American Pain Society.

[25]  Shao-Jun Tang,et al.  Oligodendrocytes in HIV-associated pain pathogenesis , 2016, Molecular pain.

[26]  Simmie L. Foster,et al.  Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation , 2015, Neuron.

[27]  J. Levine,et al.  Critical role of nociceptor plasticity in chronic pain , 2009, Trends in Neurosciences.

[28]  O. Steward,et al.  Thrombospondin-4 Contributes to Spinal Sensitization and Neuropathic Pain States , 2012, The Journal of Neuroscience.

[29]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[30]  E. Dennis,et al.  Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis , 2011, PAIN.

[31]  S. Bevan,et al.  Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain. , 2014, The Journal of clinical investigation.

[32]  L. Allen Stem cells. , 2003, The New England journal of medicine.

[33]  Zhi-jun Zhang,et al.  CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5. , 2016, The Journal of clinical investigation.

[34]  Antoine G. Godin,et al.  Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl− homeostasis , 2013, Nature Neuroscience.

[35]  K. Tracey,et al.  Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin , 2000, Nature.

[36]  Zhen-Zhong Xu,et al.  Toll-like receptor 7 mediates pruritus , 2010, Nature Neuroscience.

[37]  C. Gravel,et al.  BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain , 2005, Nature.

[38]  W. Guo,et al.  Bone Marrow Stromal Cells Produce Long‐Term Pain Relief in Rat Models of Persistent Pain , 2011, Stem cells.

[39]  Daniel Zeller,et al.  Small fibre pathology in patients with fibromyalgia syndrome. , 2013, Brain : a journal of neurology.

[40]  A. Basbaum,et al.  Injured sensory neuron-derived CSF1 induces microglia proliferation and DAP12-dependent pain , 2015, Nature Neuroscience.

[41]  B. Ryffel,et al.  Spinal cord oligodendrocyte‐derived alarmin IL‐33 mediates neuropathic pain , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  R. LaMotte,et al.  Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Zhen-Zhong Xu,et al.  Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion. , 2014, The Journal of clinical investigation.

[44]  M. Nedergaard,et al.  Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice. , 2014, Brain : a journal of neurology.

[45]  Derek W. Gilroy,et al.  Resolution of inflammation: a new therapeutic frontier , 2016, Nature Reviews Drug Discovery.

[46]  T. Jessell PAIN , 1982, The Lancet.

[47]  S. Maier,et al.  Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation , 2016, Proceedings of the National Academy of Sciences.

[48]  C. Woolf,et al.  Neuronal plasticity: increasing the gain in pain. , 2000, Science.

[49]  C. Sommer,et al.  Intraneural injection of interleukin-1β and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain , 2005, Pain.

[50]  R. Ji,et al.  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 , 2008, The Journal of Neuroscience.

[51]  R. Ji,et al.  Delayed Activation of Spinal Microglia Contributes to the Maintenance of Bone Cancer Pain in Female Wistar Rats via P2X7 Receptor and IL-18 , 2015, The Journal of Neuroscience.

[52]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[53]  S. Maier,et al.  Pathological pain and the neuroimmune interface , 2014, Nature Reviews Immunology.

[54]  Ryan M. Cassidy,et al.  The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4 , 2015, The Journal of Neuroscience.

[55]  A. Akopian,et al.  LPS Sensitizes TRPV1 via Activation of TLR4 in Trigeminal Sensory Neurons , 2011, Journal of dental research.

[56]  Sarah E Ross,et al.  Keratinocytes can modulate and directly initiate nociceptive responses , 2015, eLife.

[57]  A. Chadli THE CANCER CELL , 1924, La Presse medicale.

[58]  C. Serhan,et al.  Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma , 2013, Annals of neurology.

[59]  David Julius,et al.  Cellular and Molecular Mechanisms of Pain , 2009, Cell.

[60]  K. C. Robinson,et al.  Skin β-Endorphin Mediates Addiction to UV Light , 2014, Cell.

[61]  Zhen-Zhong Xu,et al.  Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter , 2014, Cell Research.

[62]  P. Mantyh Bone cancer pain: Causes, consequences, and therapeutic opportunities , 2013, PAIN®.

[63]  K. Nave,et al.  Oligodendrocyte ablation triggers central pain independently of innate or adaptive immune responses in mice , 2014, Nature Communications.

[64]  Loren J. Martin,et al.  Different immune cells mediate mechanical pain hypersensitivity in male and female mice , 2015, Nature Neuroscience.

[65]  L. Christophorou Science , 2018, Emerging Dynamics: Science, Energy, Society and Values.

[66]  L. Huang,et al.  Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons , 2008, Proceedings of the National Academy of Sciences.

[67]  Daniel Henrion,et al.  Mycobacterial Toxin Induces Analgesia in Buruli Ulcer by Targeting the Angiotensin Pathways , 2014, Cell.

[68]  Maiken Nedergaard,et al.  Glia and pain: Is chronic pain a gliopathy? , 2013, PAIN®.

[69]  Xiuting Gu,et al.  Peripheral TGF-β1 Signaling Is a Critical Event in Bone Cancer-Induced Hyperalgesia in Rodents , 2013, The Journal of Neuroscience.

[70]  J. Julien,et al.  CD11b+Ly6G− myeloid cells mediate mechanical inflammatory pain hypersensitivity , 2015, Proceedings of the National Academy of Sciences.

[71]  S. Bevan,et al.  Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain , 2007, Proceedings of the National Academy of Sciences.

[72]  J. Winn,et al.  Brain , 1878, The Lancet.

[73]  C. Woolf,et al.  Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology , 2012, Nature Neuroscience.

[74]  Yong Ho Kim,et al.  Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade , 2015, Nature Medicine.

[75]  R. Ji,et al.  Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. , 2015, The Journal of clinical investigation.

[76]  E. Shigetomi,et al.  Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain. , 2016, The Journal of clinical investigation.

[77]  William G. Wadsworth,et al.  This copy is for your personal, non-commercial use only. , 2014 .

[78]  W. Gan,et al.  Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury , 2016, Nature Communications.