Differential implication of proinflammatory cytokine interleukin-6 in the development of cephalic versus extracephalic neuropathic pain in rats

J Neurosci. 2008 Aug 20;28(34):8489-501. doi: 10.1523/JNEUROSCI.2552-08.2008.


Responses resulting from injury to the trigeminal nerve exhibit differences compared with those caused by lesion of other peripheral nerves. With the aim of elucidating the physiopathological mechanisms underlying cephalic versus extracephalic neuropathic pain, we determined the time course expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1beta, neuronal injury (ATF3), macrophage/microglial (OX-42), and satellite cells/astrocyte (GFAP) markers in central and ganglion tissues in rats that underwent unilateral chronic constriction injury (CCI) to either infraorbital nerve (IoN) (cephalic area) or sciatic nerve (SN) (extracephalic area). Whereas CCI induced microglial activation in both models, we observed a concomitant upregulation of IL-6 and ATF3 in the ipsilateral dorsal horn of the lumbar cord in SN-CCI rats but not in the ipsilateral spinal nucleus of the trigeminal nerve (Sp5c) in IoN-CCI rats. Preemptive treatment with minocycline (daily administration of 20 mg/kg, i.p., for 2 weeks) partially prevented pain behavior and microglial activation in SN-CCI rats but was ineffective in IoN-CCI rats. We show that IL-6 can upregulate OX-42 and ATF3 expression in cultured microglia and neurons from spinal cord, respectively, as well as in the dorsal horn after acute intrathecal administration of the cytokine. We propose that IL-6 could be one of the promoters of the signaling cascade leading to abnormal pain behavior in SN-CCI but not IoN-CCI rats. Our data further support the idea that different pathophysiological mechanisms contribute to the development of cephalic versus extracephalic neuropathic pain.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / genetics
  • Animals
  • Antigens, Differentiation / genetics
  • Behavior, Animal / drug effects
  • Biomarkers / metabolism
  • Constriction, Pathologic
  • Cytokines / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Ganglia, Sensory / metabolism
  • Glial Fibrillary Acidic Protein / genetics
  • Hyperesthesia / etiology
  • Hyperesthesia / psychology
  • Immunohistochemistry
  • Inflammation Mediators / metabolism*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Male
  • Minocycline / pharmacology
  • Neuralgia / etiology*
  • Neuralgia / metabolism*
  • Neuroglia / metabolism
  • Neurons / metabolism
  • Orbit / innervation*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sciatic Nerve* / injuries
  • Time Factors
  • Trauma, Nervous System / complications


  • Activating Transcription Factor 3
  • Antigens, Differentiation
  • Atf3 protein, rat
  • Biomarkers
  • Cytokines
  • Glial Fibrillary Acidic Protein
  • Inflammation Mediators
  • Interleukin-6
  • OX-62 antigen, rat
  • RNA, Messenger
  • Minocycline