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

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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

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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

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