In dogs, an acoustic stress (A.S.) produced by hearing of intense music (less than or equal to 90 dB) through earpieces for 1 h induced a 520% maximal rise in plasma cortisol 15-30 min after the beginning of stress. Oral administration of the specific kappa agonists, U-50488 (0.1 mg/kg) and PD 117302 (0.05 mg/kg), 30 min before the A.S. session reduced significantly (P less than 0.01) by 71.2% and 80.9% the maximal increase of plasma cortisol but did not affect the increase observed after intracerebroventricular administration of ovineCRF (100 ng/kg). These effects which are not reproduced by intravenous administration of the drugs at similar doses, were blocked by previous treatment with MR 2266 (0.1 mg/kg) or local anesthesia and vagotomy, suggesting that kappa opioid agonists inhibit the stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) system by acting selectively on specific receptors located in the wall of the proximal gut.