QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, May 14, 2008, 28(20):5189-5194; doi:10.1523/JNEUROSCI.3338-07.2008

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (24) Citing Articles via Google Scholar Google Scholar Articles by Kawasaki, Y. Articles by Ji, R.-R. Search for Related Content PubMed PubMed Citation Articles by Kawasaki, Y. Articles by Ji, R.-R. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Pain

 Previous Article  |  Next Article 

Brief Communications
Cytokine Mechanisms of Central Sensitization: Distinct and Overlapping Role of Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor- in Regulating Synaptic and Neuronal Activity in the Superficial Spinal Cord

Yasuhiko Kawasaki,^1 * Ling Zhang,^1,2 * Jen-Kun Cheng,^1,3 and Ru-Rong Ji¹

¹Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, ²Key Laboratory of Brain Functional Genomics, Ministry of Education and Science and Technology Committee of Shanghai Municipal Government, Shanghai Institute of Brain Functional Genomics, East China Normal University, Shanghai 200062, China, and ³Department of Anesthesiology, Mackay Memorial Hospital, Taipei 10449, Taiwan

Correspondence should be addressed to Dr. Ru-Rong Ji, Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital, 75 Francis Street, Medical Research Building, Room 502, Boston, MA 02125. Email: rrji{at}zeus.bwh.harvard.edu

Central sensitization, increased sensitivity in spinal cord dorsal horn neurons after injuries, plays an essential role in the induction and maintenance of chronic pain. However, synaptic mechanisms underlying central sensitization are incompletely known. Growing evidence suggests that proinflammatory cytokines (PICs), such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor- (TNF), are induced in the spinal cord under various injury conditions and contribute to pain hypersensitivity. Using patch-clamp recordings in lamina II neurons of isolated spinal cord slices, we compared the effects of IL-1β, IL-6, and TNF on excitatory and inhibitory synaptic transmission. Whereas TNF enhanced the frequency of spontaneous EPSCs (sEPSCs), IL-6 reduced the frequency of spontaneous IPSCs (sIPSCs). Notably, IL-1β both enhanced the frequency and amplitude of sEPSCs and reduced the frequency and amplitude of sIPSCs. Consistently, TNF and IL-1β enhanced AMPA- or NMDA-induced currents, and IL-1β and IL-6 suppressed GABA- and glycine-induced currents. Furthermore, all the PICs increased cAMP response element-binding protein (CREB) phosphorylation in superficial dorsal horn neurons and produced heat hyperalgesia after spinal injection. Surprisingly, soluble IL-6 receptor (sIL-6R) produced initial decrease of sEPSCs, followed by increase of sEPSCs and CREB phosphorylation. Spinal injection of sIL-6R also induced heat hyperalgesia that was potentiated by coadministration with IL-6. Together, our data have demonstrated that PICs induce central sensitization and hyperalgesia via distinct and overlapping synaptic mechanisms in superficial dorsal horn neurons either by increasing excitatory synaptic transmission or by decreasing inhibitory synaptic transmission. PICs may further induce long-term synaptic plasticity through CREB-mediated gene transcription. Blockade of PIC signaling could be an effective way to suppress central sensitization and alleviate chronic pain.

Key words: EPSC; IPSC; disinhibition; GABA; glycine; soluble IL-6 receptor; proinflammatory cytokines; PICs

---

Received July 23, 2007; revised March 24, 2008; accepted April 2, 2008.

Correspondence should be addressed to Dr. Ru-Rong Ji, Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital, 75 Francis Street, Medical Research Building, Room 502, Boston, MA 02125. Email: rrji{at}zeus.bwh.harvard.edu

This article has been cited by other articles:

				M. Andratsch, N. Mair, C. E. Constantin, N. Scherbakov, C. Benetti, S. Quarta, C. Vogl, C. A. Sailer, N. Uceyler, J. Brockhaus, et al. A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain J. Neurosci., October 28, 2009; 29(43): 13473 - 13483. [Abstract] [Full Text] [PDF]

				M. Melanson, P. Miao, D. Eisenstat, Y. Gong, X. Gu, K. Au, W. Zhu, F. Begum, E. Frost, and M. Namaka Experimental autoimmune encephalomyelitis-induced upregulation of tumor necrosis factor-alpha in the dorsal root ganglia Multiple Sclerosis, October 1, 2009; 15(10): 1135 - 1145. [Abstract] [PDF]

				Z. Wang, W. Ma, J.-G. Chabot, and R. Quirion Cell-type specific activation of p38 and ERK mediates calcitonin gene-related peptide involvement in tolerance to morphine-induced analgesia FASEB J, August 1, 2009; 23(8): 2576 - 2586. [Abstract] [Full Text] [PDF]

				E. Laboureyras, J. Chateauraynaud, P. Richebe, and G. Simonnet Long-Term Pain Vulnerability After Surgery in Rats: Prevention by Nefopam, an Analgesic with Antihyperalgesic Properties Anesth. Analg., August 1, 2009; 109(2): 623 - 631. [Abstract] [Full Text] [PDF]

				J. Sandkuhler Models and Mechanisms of Hyperalgesia and Allodynia Physiol Rev, April 1, 2009; 89(2): 707 - 758. [Abstract] [Full Text] [PDF]

				Y.-J. Gao, L. Zhang, O. A. Samad, M. R. Suter, K. Yasuhiko, Z.-Z. Xu, J.-Y. Park, A.-L. Lind, Q. Ma, and R.-R. Ji JNK-Induced MCP-1 Production in Spinal Cord Astrocytes Contributes to Central Sensitization and Neuropathic Pain J. Neurosci., April 1, 2009; 29(13): 4096 - 4108. [Abstract] [Full Text] [PDF]

				M. M. Behrens, S. S. Ali, and L. L. Dugan Interleukin-6 Mediates the Increase in NADPH-Oxidase in the Ketamine Model of Schizophrenia J. Neurosci., December 17, 2008; 28(51): 13957 - 13966. [Abstract] [Full Text] [PDF]

				K. Miyoshi, K. Obata, T. Kondo, H. Okamura, and K. Noguchi Interleukin-18-Mediated Microglia/Astrocyte Interaction in the Spinal Cord Enhances Neuropathic Pain Processing after Nerve Injury J. Neurosci., November 26, 2008; 28(48): 12775 - 12787. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help