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

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-α (TNFα), 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 TNFα on excitatory and inhibitory synaptic transmission. Whereas TNFα 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, TNFα 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.

[1]  A. Dickenson,et al.  Spinal interleukin-6 (IL-6) inhibits nociceptive transmission following neuropathy , 2003, Brain Research.

[2]  R. Malenka,et al.  Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-α , 2005, The Journal of Neuroscience.

[3]  W. Guo,et al.  Glial–Cytokine–Neuronal Interactions Underlying the Mechanisms of Persistent Pain , 2007, The Journal of Neuroscience.

[4]  J. Lopshire,et al.  Tumor Necrosis Factor Enhances the Capsaicin Sensitivity of Rat Sensory Neurons , 1997, The Journal of Neuroscience.

[5]  M. Vasko,et al.  Tumor necrosis factor a and interleukin-1b stimulate the expression of cyclooxygenase II but do not alter prostaglandin E2 receptor mRNA levels in cultured dorsal root ganglia cells , 2004 .

[6]  C. Woolf,et al.  Central sensitization and LTP: do pain and memory share similar mechanisms? , 2003, Trends in Neurosciences.

[7]  Adam Sapirstein,et al.  Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity , 2001, Nature.

[8]  C. Woolf,et al.  Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumour necrosis factor α , 1997, British journal of pharmacology.

[9]  C. Woolf,et al.  Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn , 2003, Molecular and Cellular Neuroscience.

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

[11]  C. Sommer,et al.  Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia , 2004, Neuroscience Letters.

[12]  C. Woolf,et al.  ERK MAP Kinase Activation in Superficial Spinal Cord Neurons Induces Prodynorphin and NK-1 Upregulation and Contributes to Persistent Inflammatory Pain Hypersensitivity , 2002, The Journal of Neuroscience.

[13]  L. Sorkin,et al.  Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. , 1997, Neuroscience.

[14]  Hiroshi Baba,et al.  Partial Peripheral Nerve Injury Promotes a Selective Loss of GABAergic Inhibition in the Superficial Dorsal Horn of the Spinal Cord , 2002, The Journal of Neuroscience.

[15]  C L Galli,et al.  Interleukin-1β Enhances NMDA Receptor-Mediated Intracellular Calcium Increase through Activation of the Src Family of Kinases , 2003, The Journal of Neuroscience.

[16]  C. Woolf,et al.  Peripheral axonal injury results in reduced μ opioid receptor pre- and post-synaptic action in the spinal cord , 2005, Pain.

[17]  A. Reeve,et al.  Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat , 2000, European journal of pain.

[18]  R. Yezierski,et al.  The role of neuroinflammation and neuroimmune activation in persistent pain , 2001, Pain.

[19]  Robert W. Gereau,et al.  Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α , 2006, The Journal of Neuroscience.

[20]  H. Zeilhofer.  The glycinergic control of spinal pain processing , 2005, Cellular and Molecular Life Sciences CMLS.

[21]  H. Schaible,et al.  Acute and long‐term effects of IL‐6 on cultured dorsal root ganglion neurones from adult rat , 2005, Journal of neurochemistry.

[22]  R Wagner,et al.  Tumour necrosis factor-α induces ectopic activity in nociceptive primary afferent fibres , 1997, Neuroscience.

[23]  C. Woolf,et al.  Ionotropic and Metabotropic Receptors, Protein Kinase A, Protein Kinase C, and Src Contribute to C-Fiber-Induced ERK Activation and cAMP Response Element-Binding Protein Phosphorylation in Dorsal Horn Neurons, Leading to Central Sensitization , 2004, The Journal of Neuroscience.

[24]  Steven F. Maier,et al.  Glial activation: a driving force for pathological pain , 2001, Trends in Neurosciences.

[25]  E. Kumamoto,et al.  Capsaicin facilitates excitatory but not inhibitory synaptic transmission in substantia gelatinosa of the rat spinal cord , 1998, Neuroscience Letters.

[26]  S. Rose-John,et al.  Neural activities of IL‐6‐type cytokines often depend on soluble cytokine receptors , 1999, The European journal of neuroscience.

[27]  V. Derkach,et al.  Excitatory interneurons dominate sensory processing in the spinal substantia gelatinosa of rat , 2007, The Journal of physiology.

[28]  L. Sorkin,et al.  Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-α after Spinal Nerve Ligation , 2003, The Journal of Neuroscience.

[29]  M. Kress,et al.  Involvement of the Proinflammatory Cytokines Tumor Necrosis Factor-α, IL-1β, and IL-6 But Not IL-8 in the Development of Heat Hyperalgesia: Effects on Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin , 2000, The Journal of Neuroscience.

[30]  A. Todd,et al.  Loss of Neurons from Laminas I-III of the Spinal Dorsal Horn Is Not Required for Development of Tactile Allodynia in the Spared Nerve Injury Model of Neuropathic Pain , 2005, The Journal of Neuroscience.

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