The presence of adrenomedullin (AM) and of an AM receptor were investigated in highly enriched primary cultures of Schwann cells and perineural fibroblasts of newborn and adult rats. AM was released into the conditioned medium of adult perineural fibroblasts (1749+/-629 pgeq/10(5) cells per 24 h). mRNA encoding AM was also predominantly expressed in adult perineural fibroblasts. mRNA encoding the calcitonin receptor-like receptor (CRLR) and the receptor-activity-modifying proteins (RAMP) 1, -2 and -3 were demonstrated in all the primary cells, but the levels of RAMP1 mRNA relative to 18s rRNA were 10-fold lower than those of CRLR and RAMP2 and -3 encoding mRNA. The results are consistent with the expression of CRLR/RAMP2 and CRLR/RAMP3 heterodimeric AM receptors in all the primary cells examined. AM stimulated cAMP accumulation in newborn (EC(50) 0.62+/-0.29 nM) and adult (EC(50) 0.45+/-0.03 nM) rat Schwann cells and in newborn (EC(50) 0.79+/-0.50 nM) and adult (EC(50) 1.06+/-0.72 nM) rat perineural fibroblasts. The EC(50) of calcitonin gene-related peptide stimulated cAMP production was 93- to 100-fold higher than those of AM in the four types of primary cells studied. The co-expression of AM and its receptor in perineural fibroblasts and the expression of an AM receptor in Schwann cells suggest autocrine and/or paracrine modes of action of AM in peripheral nerves.