Administration of capsaicin (8-methyl-N-vanillyl-6-nonenamide) to neonatal rats gives a long-lasting insensitivity to chemical irritants, and its potential as a specific toxin for peripheral C-fibers has made it of particular interest to neurobiologists concerned with pain mechanisms. The existence of capsaicin receptor on primary afferent sensory neurons is now evident. To deduce a receptor model for capsaicin, and propose the possible molecular interactions at the site of action, we prepared more than 50 capsaicin congeners (capsaicinoids). With these capsaicinoids, we investigated the role of functional groups in producing the long-lasting analgesia by phenylquinone writhing test and Randall-Selitto's method with ICR mice and SD rats. The structure-activity relationship of capsaicin in producing analgesia was established as follows: proper length of hydrophobic alkyl chain is 8-18 carbon atoms; 3-methoxy group of aromatic ring plays an important role but not essential; the presence of phenolic-OH is indispensable and the most suitable site is para-position; acyl amide linkage is dispensable; the linkage of amide bond bridged to the ring with CH2 is appropriate. Depletion of substance P from spinal cord and dorsal horn of rats by capsaicinoids was proved by RIA and immunohistochemistry. We succeeded in eliminating a potent acute toxicity shown by capsaicin through its structural modification.