The normal heart rate present in healthy animals and humans is determined primarily by the activity of parasympathetic cardiac neurons in the brainstem. Previous work has unequivocally demonstrated that the tonic parasympathetic activity that innervates the heart, and reflex changes in cardiac vagal activity, play an essential role in normal cardiovascular function. However in some hypotensive cardiovascular challenges, such as septic and hemorrhagic shock, there is a paradoxical increase in cardiac vagal activity and bradycardia which is detrimental to survival. This abnormal increase in cardiac vagal activity involves activation of central opioid receptors. The overall hypothesis guiding the current proposal is that activation of opioid receptors increase the excitability of cardiac vagal neurons by modulating critical synaptic inputs as well as directly altering voltage gated currents in cardiac vagal neurons. This hypothesis is supported both by our preliminary electrophysiological observations as well as our immunohistochemical and collaborative electron microscopic work. We will specifically 1) test whether activation of opioid receptors alters the critical synaptic innervation of cardiac vagal neurons. 2) examine whether activation of postsynaptic opioid receptors modifies the properties of voltage gated currents in cardiac vagal neurons, 3) identify the source of opioid pathways to cardiac vagal neurons and 4) characterize the electrophysiological properties of the opioid-containing neurons that monosynaptically project to cardiac vagal neurons. The anticipated results will provide information fundamental to understanding the basis and mechanisms of cardiac vagal activity that originate in the medulla, and will also suggest which receptors and processes could be involved in paradoxical and detrimental responses of the cardiovascular system.
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