Regulation of proinflammatory cytokines gene expression by nociceptin/orphanin FQ in the spinal cord and the cultured astrocytes

Neuroscience. 2007 Jan 5;144(1):275-85. doi: 10.1016/j.neuroscience.2006.09.016. Epub 2006 Oct 25.


Peripheral inflammation induces central sensitization characterized by the development of allodynia and hyperalgesia to thermal stimuli. Recent evidence suggests that activation of glial cells and a subsequent increase in proinflammatory cytokines contribute to the development of behavioral hypersensitivity after nerve injury or peripheral inflammation. The neuropeptide nociceptin/orphanin FQ (N/OFQ), the endogenous agonist of the N/OFQ peptide receptor (ORL1 receptor), has been demonstrated to play an important role in modulation of nociceptive signals. In the present study, we investigated: (1) astrocyte activation and proinflammatory cytokine expression at the lumbar spinal cord following intraplantar administration of complete Freund's adjuvant (CFA) in rats; (2) the mechanism of N/OFQ on nociception modulation, the relationship between N/OFQ and cytokines in the rat CNS in vivo and in vitro. The results showed: (1) CFA-induced peripheral inflammation evoked robust astrocyte activation and proinflammatory cytokines spinally; (2) down-regulation of cytokine mRNA transcripts by intrathecal administration of N/OFQ, the effects produced by N/OFQ were abolished by combination with ORL1 receptor-specific antagonist [Nphe(1)]N/OFQ(1-13)NH2; (3) ORL1 receptor was expressed on astrocytes of rat spinal cord; (4) cytokine gene expression was inhibited in astrocyte cultures exposed to N/OFQ, the inhibiting effects of N/OFQ were significantly blocked by [Nphe(1)]N/OFQ(1-13)NH2. The present data demonstrated that astrocyte activation and enhanced cytokine expression at the CNS had a role in eliciting behavioral hypersensitivity; the anti-nociception function of N/OFQ might be dependent on cytokines derived from astrocytes, the effects were attributable to the ORL1 receptor pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Behavior, Animal / drug effects
  • Blotting, Western
  • Cells, Cultured
  • Cytokines / biosynthesis*
  • Cytokines / genetics*
  • Foot
  • Freund's Adjuvant / administration & dosage
  • Gene Expression Regulation / drug effects*
  • Glial Fibrillary Acidic Protein / biosynthesis
  • Hot Temperature
  • Immunohistochemistry
  • In Vitro Techniques
  • Inflammation / genetics*
  • Inflammation / metabolism*
  • Injections
  • Injections, Spinal
  • Interleukin-1beta / biosynthesis
  • Interleukin-6 / biosynthesis
  • Male
  • Opioid Peptides / administration & dosage
  • Opioid Peptides / pharmacology*
  • Pain Threshold / drug effects
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid / biosynthesis
  • Receptors, Opioid / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spinal Cord / cytology
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism*
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Cytokines
  • Glial Fibrillary Acidic Protein
  • Interleukin-1beta
  • Interleukin-6
  • Opioid Peptides
  • RNA, Messenger
  • Receptors, Opioid
  • Tumor Necrosis Factor-alpha
  • nociceptin
  • Freund's Adjuvant
  • nociceptin receptor