Highlights
- •IL-18 played a critical role in bone cancer-induced pain.
- •IL-18 could induced glutamate receptor 2B (GluN2B) activation during bone cancer pain.
- •IL-18 mediated microglia/astrocyte and microglia/neuron interactions in the dorsal horn.
Abstract
Glial cell hyperactivity has been proposed to be responsible for chronic pain, however,
the mechanisms remain unclear. Interleukin (IL)-18, released from glial cells, has
been reported to be involved in neuropathic pain. In this study, we investigated the
role of IL-18 in bone cancer pain. Bone cancer pain was mimicked by injecting Walker-256
mammary gland carcinoma cells into the intramedullary space of the tibia in rats.
Expression and location of IL-18 and the IL-18 receptor were tested. To investigate
the contribution of IL-18 signaling to bone cancer pain, IL-18 binding protein and
recombinant IL-18 were used. To investigate the mechanisms of glial cells effects,
MK801, N-methyl-D-aspartate (NMDA) receptor inhibitor, and Src kinase-specific inhibitor
PP1 were used. Tumor cell implantation (TCI) treatment increased expression of IL-18
and IL-18 receptor in spinal cord. The time course of IL-18 upregulation was correlated
with TCI-induced pain behaviors. Blocking the IL-18 signaling pathway prevented and
reversed bone cancer-related pain behaviors. Meanwhile, blocking IL-18 signaling also
suppressed TCI-induced glial cell hyperactivity, as well as activation of GluN2B and
subsequent Ca2+-dependent signaling. Spinal administration of recombinant IL-18 in naive rat induced
significant mechanical allodynia, as well as GluN2B activation. However, intrathecal
injection of MK801 failed to suppress recombinant IL–18-induced GluN2B phosphorylation,
whereas Src kinase inhibitor PP1 significantly inhibited IL-18-induced GluN2B activation.
IL–18-mediated glial-glia and glial-neuron interaction may facilitate bone cancer
pain. Blocking IL-18 signaling may effectively prevent and/or suppress bone cancer
pain.
Perspective
IL-18 signaling may be a new target for cancer pain therapy.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Interleukin 18 in the CNS.J Neuroinflammation. 2010; 7: 9
- Interleukin-18: A potent pro-inflammatory cytokine in atherosclerosis.Cardiovasc Res. 2012; 96: 172-175
- IL-18 in autoimmunity: Review.Eur Cytokine Netw. 2006; 17: 224-252
- Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury.J Neurosci. 2010; 30: 5437-5450
- Prevalence of pain in patients with cancer: A systematic review of the past 40 years.Ann Oncol. 2007; 18: 1437-1449
- IL-18: A key player in neuroinflammation and neurodegeneration?.Trends Neurosci. 2005; 28: 487-493
- New insights into neuron-glia communication.Science. 2002; 298: 556-562
- Targeting astrocyte signaling for chronic pain.Neurotherapeutics. 2010; 7: 482-493
- Involvement of BLT1 endocytosis and yes kinase activation in leukotriene B4-induced neutrophil degranulation.J Immunol. 2005; 174: 3617-3625
- Advances in understanding bone cancer pain.J Cell Biochem. 2005; 96: 682-688
- Glial cells and chronic pain.Neuroscientist. 2010; 16: 519-531
- Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade.Mol Pain. 2014; 10: 35
- Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain.J Neurosci. 2007; 27: 6006-6018
- Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain.Eur J Pain. 2009; 13: 138-145
- Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord.Nat Med. 2000; 6: 521-528
- Interleukin-18 stimulates synaptically released glutamate and enhances postsynaptic AMPA receptor responses in the CA1 region of mouse hippocampal slices.Brain Res. 2004; 1012: 190-193
- Oxycodone-induced analgesic effects in a bone cancer pain model in mice.Oncology. 2008; 74: 55-60
- The RS504393 influences the level of nociceptive factors and enhances opioid analgesic potency in neuropathic rats.J Neuroimmune Pharmacol. 2017; 12: 1-18
- Blocking EphB1 receptor forward signaling in spinal cord relieves bone cancer pain and rescues analgesic effect of morphine treatment in rodents.Cancer Res. 2011; 71: 4392-4402
- EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord.Pain. 2013; 154: 2823-2835
- A rat model of bone cancer pain.Pain. 2002; 96: 129-140
- Pathological and protective roles of glia in chronic pain.Nat Rev Neurosci. 2009; 10: 23-36
- Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury.J Neurosci. 2008; 28: 12775-12787
- Spinal astrocytes as therapeutic targets for pathological pain.J Pharmacol Sci. 2010; 114: 347-353
- The role of interleukin-18, oxidative stress and metabolic syndrome in Alzheimer's disease.J Clin Med. 2017; 6: 55
- Murine microglial cells produce and respond to interleukin-18.J Neurochem. 2008; 72: 2215-2218
- Intrathecal injection of metabotropic glutamate receptor subtype 3 and 5 agonist/antagonist attenuates bone cancer pain by inhibition of spinal astrocyte activation in a mouse model.Anesthesiology. 2012; 116: 122-132
- Neuron-glia crosstalk gets serious: Role in pain hypersensitivity.Curr Opin Anaesthesiol. 2008; 21: 570-579
- Interactions between the immune and nervous systems in pain.Nat Med. 2010; 16: 1267-1276
- Involvement of pro- and antinociceptive factors in minocycline analgesia in rat neuropathic pain model.J Neuroimmunol. 2014; 277: 57-66
- A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain.Brain Res. 2008; 1219: 116-126
- Src kinases: A hub for NMDA receptor regulation.Nat Rev Neurosci. 2004; 5: 317
- The neuropathic pain triad: Neurons, immune cells and glia.Nat Neurosci. 2007; 10: 1361-1368
- Immune responses of microglia in the spinal cord: Contribution to pain states.Exp Neurol. 2012; 234: 262-270
- Interleukin-18: Biology and role in the immunotherapy of cancer.Curr Med Chem. 2010; 17: 3353-3357
- Regulation of IL-18 production by IFNγ and PGE2 in mouse microglial cells: Involvement of NF-kB pathway in the regulatory processes.Immunol Lett. 2001; 77: 79-85
- Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain.Neurochem Int. 2004; 45: 397-407
- Role of IL-18 in overt pain-like behaviour in mice.Eur J Pharmacol. 2008; 588: 207-212
- Minocycline-induced reduction of brain-derived neurotrophic factor expression in relation to cancer-induced bone pain in rats.J Neurosci Res. 2012; 90: 672-681
- Neuronal plasticity: Increasing the gain in pain.Science. 1765–1768; 288: 2000
- Robust increase of cutaneous sensitivity, cytokine production and sympathetic sprouting in rats with localized inflammatory irritation of the spinal ganglia.Neuroscience. 2006; 142: 809-822
- Delayed activation of spinal microglia contributes to the maintenance of bone cancer pain in female Wistar rats via P2X7 receptor and IL-18.J Neurosci. 2015; 35: 7950-7963
- Antiallodynic effects of propentofylline elicited by interrupting spinal glial function in a rat model of bone cancer pain.J Neurosci Res. 1877–1886; 89: 2011
- Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia.Pain. 2005; 118: 125-136
- WNT signaling underlies the pathogenesis of neuropathic pain in rodents.J Clin Invest. 2013; 123: 2268-2286
- Peripheral NMDA receptors are involved in long-term hyperalgesia and spinal microglia activation induced by formalin injection.FASEB J. 2006; 20: A776
Article info
Publication history
Published online: October 25, 2017
Accepted:
October 12,
2017
Received in revised form:
October 4,
2017
Received:
May 5,
2017
Footnotes
S.L., Y.-p.L., and Y.L. contributed equally to this work.
This work was supported by grants from National Natural Science Foundation of China (NSFC-81371242, 81671084), Qing Lan Project of Jiangsu province, and Nature Science Foundation of Jiangsu province (BK20161175).
The authors have no conflicts of interest to declare.
Identification
Copyright
© 2017 by the American Pain Society
