ABSTRACT The purpose of this study was to identify sites of central neuronal activation resulting from stimulation of cardiac ischemic-sensitive afferent neurons and to determine whether electrical stimulation of afferent fibers in the left vagus modified the pattern of neuronal activation. It has previously been determined that most of the afferent fibers associated with cardiac ischemic pain travel in sympathetic nerves via dorsal root ganglion neurons to higher central neurons. Fos expression (Fos-like immunoreactivity, Fos-LI) was used as an index of neuronal activation in selected levels of the cervical and thoracic spinal cord and the brainstem. Adult Sprague-Dawley rats were anesthetized with urethane and underwent either intra-pericardial infusion of a solution containing algogenic substances that are released during periods of ischemia (10mM of adenosine, bradykinin, prostaglandin E₂, and 5-hydroxytryptamine; i.e., 'inflammatory exudate solution', IES) or occlusion of the left anterior descending coronary artery (CoAO) to activate cardiac ischemic-sensitive (nociceptive) afferent fibers. Both IES and CoAO increased Fos expression above resting levels in dorsal horns in laminae I - V in cervical 2 and thoracic 4 spinal segments and in the caudal NTS. Dorsal rhizotomy virtually eliminated the Fos-LI in the spinal cord as well as the brainstem. Electro-neuromodulation of the cardiac ischemic afferent signal by electrical stimulation of the central end of the left thoracic vagus, excited neurons at the cervical and brainstem level but inhibited neurons at the thoracic spinal cord during IES or CoAO. These results suggest that stimulation of the left thoracic vagus, an example of one form of electro-neuromodulatory therapy used to alleviate the discomfort associated with cardiac ischemia, excites descending inhibitory pathways. The inhibition exerted at the thoracic spinal level that effectively suppresses the ischemic (nociceptive) input signal, may occur by either a short-loop descending pathway via signals from cervical propriospinal circuits, and/or alternatively, a longer-loop descending pathway via signals from the NTS.