Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord.

Full Abstract

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-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha), 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-1beta, IL-6, and TNFalpha on excitatory and inhibitory synaptic transmission. Whereas TNFalpha enhanced the frequency of spontaneous EPSCs (sEPSCs), IL-6 reduced the frequency of spontaneous IPSCs (sIPSCs). Notably, IL-1beta both enhanced the frequency and amplitude of sEPSCs and reduced the frequency and amplitude of sIPSCs. Consistently, TNFalpha and IL-1beta enhanced AMPA- or NMDA-induced currents, and IL-1beta 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.

Author information

Author/s: Kawasaki, Yasuhiko (Y); Zhang, Ling (L); Cheng, Jen-Kun (JK); Ji, Ru-Rong (RR);

Affiliation: Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Grants: DE17794 (Agency:NIDCR NIH HHS) ; NS 54932 (Agency:NINDS NIH HHS) ; R01 DE017794-02 (Agency:NIDCR NIH HHS) ; R01 DE017794-03 (Agency:NIDCR NIH HHS) ; R01 NS040698-04 (Agency:NINDS NIH HHS) ; R01 NS054932-01A1 (Agency:NINDS NIH HHS) ; R01 NS054932-02 (Agency:NINDS NIH HHS) ; R03 TW007180-03 (Agency:FIC NIH HHS) ; TW7180 (Agency:FIC NIH HHS)

Journal and publication information

Publication Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2008-May; vol 28 (issue 20) : pp 5189-94

Dates: Created 2008/05/15; Completed 2008/06/19; Revised 2009/02/12;

PMID: 18480275, status: MEDLINE (last retrieved date: 2/18/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Organ Culture Techniques
Pain - chemically induced; metabolism
Patch-Clamp Techniques
Posterior Horn Cells - drug effects; metabolism; physiology
Rats
Rats, Sprague-Dawley
Receptors, GABA - drug effects; metabolism
Receptors, Glutamate - drug effects; metabolism
Spinal Cord - cytology; metabolism; physiology
Synaptic Transmission - drug effects; physiology
Tumor Necrosis Factor-alpha - metabolism; pharmacology; physiology

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Cyclic AMP Response Element-Binding Protein (0) ; Cytokines (0) ; Interleukin-1beta (0) ; Interleukin-6 (0) ; Receptors, GABA (0) ; Receptors, Glutamate (0) ; Tumor Necrosis Factor-alpha (0)

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