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

Inflammation causes the induction of cyclooxygenase-2 (Cox-2)(1), leading t o the release of prostanoids, which sensitize peripheral nociceptor termina ls and produce localized pain hypersensitivity(2). Peripheral inflammation also generates pain hypersensitivity in neighbouring uninjured tissue (seco ndary hyperalgesia), because of increased neuronal excitability in the spin al cord (central sensitization)(3), and a syndrome comprising diffuse muscl e and joint pain, fever, lethargy and anorexia(4). 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 o ther regions of the CNS, elevating prostaglandin E-2 (PGE(2)) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is in terleukin-1 beta in the CNS, and as basal phospholipase A(2) activity in th e CNS does not change with peripheral inflammation, Cox-2 levels must regul ate central prostanoid production. Intraspinal administration of an interle ukin-converting enzyme or Cox-2 inhibitor decreases inflammation-induced ce ntral PGE(2) levels and mechanical hyperalgesia. Thus, preventing central p rostanoid production by inhibiting the interleukin-1 beta -mediated inducti on of Cox-2 in neurons or by inhibiting central Cox-2 activity reduces cent rally generated inflammatory pain hypersensitivity.