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Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity

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.

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Figure 1: Cox-2 induction and PGE2 release in the CNS.
Figure 2: PLA2 activity in the CNS is not regulated by inflammation.
Figure 3: Afferent nerve activity and IL-1β-dependent Cox-2 induction.
Figure 4: Intrathecal but not intravenous administration of 30 µg of the Cox-2 inhibitor NS398 48 h after induction of CFA inflammation significantly attenuates mechanical hypersensitivity.

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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.).

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Correspondence to Clifford J. Woolf.

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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

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