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-l (IL-l) 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-I beta was Ca2+-dependent and significantly inhibited by 100 ng/ml II-I receptor-specific antagonist (II-lr antagonist), cyclooxygenase (COX) inhibitors such as 0.1 mM aspirin, I mu g/ml indomethacin, and I mu M NS-398 (specific for COX-2), and 1 mu M dexamethasone. Furthermore, a I-h incubation with IL-I beta markedly increased We inducible COX-2 mRNA level, which was inhibited by an IL-lr 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-l 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.