In dogs under light thiopentobarbital anesthesia, intracarotid injection of bradykinin (BK) causes a dose-dependent "pain response" represented by hyperpnea, bradycardia, vocalization and ipsilateral contraction of the sternocephalic muscle. These events result from the activation of primary afferent nerves located in the wall of the carotid vessels distributed mainly in occipital artery territory. We present evidence indicating that these BK-induced reflex phenomena are 1) mediated by the activation of B2 receptors; 2) potentiated by prostaglandin E2 (PGE2) and serotonin (5-HT) the latter acting via sub-type 5-HT3 receptors; 3) reduced by indomethacin and/or NG-nitroarginine, and 4) abolished by methylene blue. These results suggest that 5-HT plays a modulatory role on BK action; the latter depends on the release of prostaglandins and nitric oxide or a related compound and includes the activation of guanylate cyclase which appears to be involved in primary afferent excitation.