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

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 hypersensitivity(2). 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 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 other regions of the CNS, elevating prostaglandin E(2) (PGE(2)) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is interleukin-1 beta in the CNS, and as basal phospholipase A(2) 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 PGE(2) levels and mechanical hyperalgesia. Thus, preventing central prostanoid production by inhibiting the interleukin-1 beta -mediated induction of Cox-2 in neurons or by inhibiting central Cox-2 activity reduces centrally generated inflammatory pain hypersensitivity.