Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity.
Inflammation causes the induction of cyclooxygenase-2 (Cox-2), leading to the release of prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. Peripheral inflammation also generates pain hypersensitivity in neighbouring uninjured tissue (secondary hyperalgesia), because of increased neuronal excitability in the spinal cord (central sensitization), and a syndrome comprising diffuse muscle and joint pain, fever, lethargy and anorexia. 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-1beta 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-1beta-mediated induction of Cox-2 in neurons or by inhibiting central Cox-2 activity reduces centrally generated inflammatory pain hypersensitivity.
Department of Anatomy, University College London, London WC1E 6BT, UK.
T A
TA
Samad
K A
KA
Moore
A
A
Sapirstein
S
S
Billet
A
A
Allchorne
S
S
Poole
J V
JV
Bonventre
C J
CJ
Woolf
D002490:Central Nervous System / Q000201:enzymology / Q000502:physiology*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000134:cerebrospinal fluid; D004790:Enzyme Induction; D005620:Freund's Adjuvant; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D007375:Interleukin-1 / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000502:physiology; D010146:Pain; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000201:enzymology / Q000502:physiology
D007375:Interleukin-1; D007527:Isoenzymes; D005620:Freund's Adjuvant; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone