Substance P (SP) may play an important role in the interactions between the nervous system and the immune system. Astrocytes carry receptors for SP on their surfaces. We examined whether ligand-induced receptor activation would lead to the release of arachidonic acid metabolites. SP (10−10-10−8 M) evokes the formation of prostaglandin E and thromboxane B2 in a dose-dependent manner. Structure-activity studies disclosed that the COOH-terminal peptide sequence of SP is primarily responsible for this biological activity. The generation by astrocytes of arachidonate-derived proinflammatory and immunoregulatory compounds in response to SP receptor activation may be relevant to immunoinflammatory responses within the central nervous system and emphasizes the concept of neuroimmunomodulation.— Hartung, H.-P.; Heininger, K.; Schäfer, B.; Toyka, K. V. Substance P and astrocytes: stimulation of the cyclooxygenase pathway of arachidonic acid metabolism. FASEB J. 2: 48-51; 1988.