Substance P (SP) antiserum was administered to rats on the second day of life. Three months later, the content of SP was significantly decreased in the dorsal part of the spinal cord and in the periaqueductal gray matter of these animals, as compared to control rats receiving a neonatal treatment of non-specific immunoglobulins. Further, the levels of Met-enkephalin and 5-hydroxyindole acetic acid (5-HIAA) were concomitantly increased in the same regions. SP receptor binding sites and opioid receptors, which appear earlier in development, were not modified in the two regions studied. On the other hand, the antinociceptive response to intracerebroventricular (i.c.v.) injection of SP or of the synthetic enkephalin analog D-Ala2,D-Leu5-enkephalin, as well as the hypertensive response to i.c.v. SP were blocked. The results suggest that, after administration to newborn rats, the antiserum is able to penetrate into SP neurons, producing a long-lasting SP suppression and a subsensitivity to the pharmacological effects of the neuropeptide. The modifications in the content of Met-enkephalin and 5-HIAA are possibly compensatory changes which subserve the functionality of central cardiovascular and pain regulatory systems after the immunolesion.