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 (10−10‐10−8M) evokes the formation of prostaglandin E and thromboxane B2in 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.