The factors regulating substance P (SP) synthesis and quantity of transport in the sensory vagus nerve are unknown. To examine this issue rats were administered ACTH or corticosterone or subjected to adrenalectomy, and the quantity of peripherally directed transported SP was measured in those animals as an indication of neuropeptide synthesis. ACTH treatment (12 U/day, sc, for 14 days) resulted in significant adrenal hypertrophy and increased corticosterone levels. The 24-h accumulation of SP proximal to ligature in the cervical vagus was significantly reduced [mean net proximal segment content: controls, 529 +/- 42 (+/- SEM) pg/3 mm segment; ACTH, 282 +/- 44]. The content in the unligated nerve, one sixth or less than that proximal to ligature, was not different in the two groups. In a separate experiment, ACTH (6 U/day for 14 days) had no effect compared to controls, whereas 16 U/day reduced transported SP. The content in the unligated nerve was again not different in the two groups. In the same experiment, corticosterone (2.5 mg/100 g BW, sc, for 14 days) reduced the quantity of transported SP. Total protein content in proximal segments was reduced only in the corticosterone group and was identical in all groups in unligated nerve. Adrenalectomy modestly increased transport by 20% and contralateral unligated nerve content by a similar percentage. The quantity of transported somatostatin, another vagal neuropeptide partly derived from sensory cell bodies, was either increased or unaltered by the experimental manipulations. In summary, these studies demonstrate that the chronic administration of ACTH or corticosterone significantly decreases the quantity of peripherally transported SP in the sensory vagus nerve and, presumably, synthesis within the vagal sensory ganglia. Down-regulation of synthesized/transported neuropeptide suggests a mechanism by which the ACTH-adrenal axis, acting through visceral sensory nerves, may modulate autonomic or central nervous system vagally mediated reflex arcs.