Substance P (SP) and calcitonin gene-related peptide (CGRP) constitute the main sensory peptides in the trigeminal ganglion (TG). The objective of this study was to characterize peptidergic changes in the streptozotocin-induced diabetes mellitus rat model both quantitatively and qualitatively. Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (65 mg/kg) and the levels of SP and CGRP were measured by means of radioimmunoassay (RIA) in a time-dependent manner. Peptide immunoreactivities were characterized by high pressure liquid chromatography (HPLC). The expression of both neuropeptides was examined 5 weeks after streptozotocin injection using in situ hybridization with 35S-labelled oligonucleotides. Saline-injected rats served as controls. SP was significantly decreased in the diabetic rat TG, i.e. , a 44.6% (+/-10.9) decrease after 1 week, 40.2% (+/-11.8) after 3 weeks and 72.3% (+/-14.6) after 5 weeks. CGRP was decreased only after 5 weeks (19.6% decrease +/-3.9), whereas at later stages, both peptide levels returned to normal values. HPLC revealed one major peak coeluting with the synthetic peptides. By using in situ hybridization, a significantly increased signal of both peptide-encoding mRNAs was found (43.8%), which seems to act to restore a diabetes-associated depletion of neuropeptides in the diabetic rat TG. The decreased SP- and CGRP levels in the diabetic rat TG reflect a diabetes-associated deficit which may be clinically relevant. Diabetes mellitus is associated with a variety of ocular complications, even corneal complications, including decreased corneal sensitivity, which in many ways resemble those after interruption of the normal trophic innervation of the eye. Our results point to reduced availability of neuropeptides for corneal innervation and may thus support the idea of a partial loss of trophic influences from the trigeminal nerve in diabetics.