Interleukin‐1β Induces Substance P Release from Primary Afferent Neurons Through the Cyclooxygenase‐2 System

Substance P (SP) is synthesized in the dorsal root ganglion (DRG) and released from primary afferent neurons to convey information regarding noxious stimuli. The effects of the proinflammatory cytokine interleukin-1 (IL-1) beta on the release of SP were investigated using primary cultured rat DRG cells. Recombinant mouse IL-1 beta added to the cells at 0.1 ng/ml increased the SP-like immunoreactivity (SPLI) in the culture medium after incubation for 6 h by similar to 50% as compared with that of nontreated DRG cells. The effect of IL-1 beta was Ca super(2+)-dependent and significantly inhibited by 100 ng/ml IL-1 receptor-specific antagonist (IL-1r antagonist), cyclooxygenase (COX) inhibitors such as 0.1 mM aspirin, 1 mu g/ml indomethacin, and 1 mu M NS-398 (specific for COX-2), and 1 mu M dexamethasone. Furthermore, a 1-h incubation with IL-1 beta markedly increased the inducible COX-2 mRNA level, which was inhibited by an IL-1r antagonist and dexamethasone, whereas IL-1 beta showed no effect on the level of constitutive COX-1 mRNA. These observations indicated that IL-1 beta induced the release of SP from the DRG cells via specific IL-1 receptors, the mechanism of which might involve prostanoid systems produced by COX-2. This could be responsible for the hyperalgesic action with reference to inflammatory pain in the primary afferent neuron to spinal cord pathway.