Abstract
Inflammation causes the induction of cyclooxygenase-2 (Cox-2)1, leading to the release of prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity2. Peripheral inflammation also generates pain hypersensitivity in neighbouring uninjured tissue (secondary hyperalgesia), because of increased neuronal excitability in the spinal cord (central sensitization)3, and a syndrome comprising diffuse muscle and joint pain, fever, lethargy and anorexia4. Here we show that Cox-2 may be involved in these central nervous system (CNS) responses, by finding a widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the CNS, elevating prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is interleukin-1β in the CNS, and as basal phospholipase A2 activity in the CNS does not change with peripheral inflammation, Cox-2 levels must regulate central prostanoid production. Intraspinal administration of an interleukin-converting enzyme or Cox-2 inhibitor decreases inflammation-induced central PGE2 levels and mechanical hyperalgesia. Thus, preventing central prostanoid production by inhibiting the interleukin-1β-mediated induction of Cox-2 in neurons or by inhibiting central Cox-2 activity reduces centrally generated inflammatory pain hypersensitivity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Vane, J. R., Bakhle, Y. S. & Botting, R. M. Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 38, 97–120 (1998).
McCleskey, E. W. & Gold, M. S. Ion channels of nociception. Annu. Rev. Physiol. 61, 835–856 (1999).
Woolf, C. J. & Salter, M. W. Neuronal plasticity-increasing the gain in pain. Science 288, 1765–1768 (2000).
Dantzer, R. et al. Molecular basis of sickness behavior. Ann. NY Acad. Sci. 856, 132–138 (1998).
O'Banion, M. K. Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology. Crit. Rev. Neurobiol. 13, 45–82 (1999).
Maier, J. A. M., Hlas, T. & Maciag, T. Cyclooxygenase is an immediate early gene induced by interleukin-1 in human endothelial cells. J. Biol. Chem. 265, 10805–10808 (1990).
Muth-Selbach, U. S., Tegeder, I., Brune, K. & Geisslinger, G. Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation. Anesthesiology 91, 231–239 (1999).
Smith, C. J. et al. Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc. Natl Acad. Sci. USA 95, 13313–13318 (1998).
Minami, T. et al. Characterization of EP-receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E2 to mice. Br. J. Pharmacol. 112, 735–740 (1994).
Beiche, F., Scheuerer, S., Brune, K., Geisslinger, G. & Goppelt-Struebe, M. Up-regulation of cyclooxygenase-2 mRNA in the rat spinal cord following peripheral inflammation. FEBS Lett. 390, 165–169 (1996).
Hay, C. H., Trevethick, M. A., Wheeldon, A., Bowers, J. S. & de Belleroche, J. S. The potential role of spinal cord cyclooxygenase-2 in the development of Freund's complete adjuvant-induced changes in hyperalgesia and allodynia. Neuroscience 78, 843–850 (1997).
Beiche, F., Brune, K., Geisslinger, G. & Goppelt-Struebe, M. Expression of cyclooxygenase isoforms in the rat spinal cord and their regulation during adjuvant-induced arthritis. Inflamm. Res. 47, 482–487 (1998).
Hietaranta, A. et al. Extracellular phospholipases A2 in relation to systemic inflammatory response syndrome (SIRS) and systemic complications in severe acute pancreatitis. Pancreas 18, 385–391 (1999).
Levy, R., Lowenthal, A. & Dana, R. Cytosolic phospholipase A2 is required for the activation of the NADPH oxidase associated H+ channel in phagocyte-like. Adv. Exp. Med. Biol. 479, 125–135 (2000).
Saunders, M. A. et al. Mechanisms of prostaglandin E2 release by intact cells expressing cyclooxygenase-2: evidence for a ‘two-component’ model. J. Pharmacol. Exp. Ther. 288, 1101–1106 (1999).
Safieh-Garabedian, B., Poole, S., Allchorne, A., Winter, J. & Woolf, C. J. Contribution of interleukin-1β to the inflammation-induced increase in nerve growth factor levels and inflammatory hyperalgesia. Br. J. Pharmacol. 115, 1265–1275 (1995).
Cartmell, T., Poole, S., Turnbull, A. V., Rothwell, N. J. & Luheshi, G. N. Circulating interleukin-6 mediates the febrile response to localised inflammation in rats. J. Physiol. 526, 653–661 (2000).
Fantuzzi, G. & Dinarello, C. A. Interleukin-18 and interleukin-1 beta: two cytokine substrates for ICE (caspase-1). J. Clin. Immunol. 19, 1–11 (1999).
Lashbrook, J. M. et al. Synergistic antiallodynic effects of spinal morphine with ketorolac and selective COX1- and COX2-inhibitors in nerve-injured rats. Pain 82, 65–72 (1999).
Yaksh, T. L. & Rudy, T. A. Analgesia mediated by a direct spinal action of narcotics. Science 192, 1357–1358 (1976).
Dirig, D. M., Konin, G. P., Isakson, P. C. & Yaksh, T. L. Effect of spinal cyclooxygenase inhibitors in rat using the formalin test and in vitro prostaglandin E2 release. Eur. J. Pharmacol. 331, 155–160 (1997).
Southall, M. D., Michael, R. L. & Vasko, M. R. Intrathecal NSAIDS attenuate inflammation-induced neuropeptide release from spinal cord slices. Pain 78, 39–48 (1998).
Yamamoto, T. & Sakashita, Y. COX-2 inhibitor prevents the development of hyperalgesia induced by intrathecal NMDA or AMPA. NeuroReport 9, 3869–3873 (1998).
Malmberg, A. B. & Yaksh, T. L. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science 257, 1276–1279 (1992).
Swiergiel, A. H., Smagin, G. N., Johnson, L. J. & Dunn, A. J. The role of cytokines in the behavioral responses to endotoxin and influenza virus infection in mice: effects of acute and chronic administration of the interleukin-1-receptor antagonist (IL-1ra). Brain Res. 776, 96–104 (1997).
Yao, J. H. et al. Mice deficient in interleukin-1beta converting enzyme resist anorexia induced by central lipopolysaccaride. Am. J. Physiol. 277, R1435–R1443 (1999).
Amaya, F. et al. Diversity of expression of the sensory neuron specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2. Mol. Cell. Neurosci. 15, 331–342 (2000).
Curley, J. et al. Injectable biodegradable bupivacaine/polyester microspheres. Anesthesiology 84, 1401–1410 (1996).
Bingham, C. O. et al. Low molecular weight group IIA and group V phospholipase A(2) enzymes have different intracellular locations in mouse bone marrow-derived mast cells. J. Biol. Chem. 274, 31476–31484 (1999).
Sapirstein, A., Spech, R. A., Witzgall, R. & Bonventre, J. V. Cytosolic phospholipase A2 (PLA2), but not secretory PLA2, potentiates hydrogen peroxide cytotoxicity in kidney epithelial cells. J. Biol. Chem. 271, 21505–21513 (1996).
Acknowledgements
We thank H. Baba, C. Van der Meer, M. Costigan, R.-R. Ji, K. Befort, D. Borsook and L. Kobierski for assistance and advice and C. Berde for the microspheres. Financial support was provided by NIH and Pfizer (C.J.W.). Cytokine reagents generated by EC CYBRAINET Biomed II and TMR Programme (S.P.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Samad, T., Moore, K., Sapirstein, A. et al. Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410, 471–475 (2001). https://doi.org/10.1038/35068566
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/35068566
This article is cited by
-
Antinociceptive and anti-inflammatory activity of extracts and α-pyrones isolated from Cantinoa stricta
Inflammopharmacology (2024)
-
TRPV1+ neurons alter Staphylococcus aureus skin infection outcomes by affecting macrophage polarization and neutrophil recruitment
BMC Immunology (2023)
-
Repeated closed-head mild traumatic brain injury-induced inflammation is associated with nociceptive sensitization
Journal of Neuroinflammation (2023)
-
Long-term changes of Th17 and regulatory T cells in peripheral blood of dogs with spinal cord injury after intervertebral disc herniation
BMC Veterinary Research (2023)
-
LncRNA MALAT1 functions as a biomarker of no-reflow phenomenon in ST-segment elevation myocardial infarction patients receiving primary percutaneous coronary intervention
Scientific Reports (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.