The major goal of this application is to understand the interplay between receptors and channels that control excitability of the thin fiber muscle afferents that evoke the exercise pressor reflex as well as transduce the sensation of pain. The exercise pressor reflex, which arises from the contraction of skeletal muscles, is one of the two neural mechanisms that evoke the cardiovascular adjustments to exercise. These adjustments, which serve to support the ability of skeletal muscles to contract by increasing blood flow and oxygen to exercising muscles, include reflex increases in arterial blood pressure, cardiac output and ventilation. With respect to thin fiber muscle afferents, we propose to combine the power of the in vitro whole-cell patch- clamp technique, which will determine the mechanisms of afferent excitability, with the physiological insights provided by in vivo electrophysiology, which will determine how these mechanisms translate into increased excitability. For in vitro experiments, muscle afferents will be identified by retrograde labeling DRG neurons with DiI that has been injected into the triceps surae muscles. Particular attention will be paid to afferents that have tetradotoxin resistant channels, which will identify them as group IV muscle afferents. For in vivo experiments, thin fiber triceps surae muscle afferents will be identified by their conduction velocities and their receptive fields. In both in vitro and in vivo experiments, particular attention will be paid to the effects two peptides, namely bradykinin and DAMGO, on the membrane and discharge properties of the afferents. The former peptide is expected to be stimulatory and to act on B2 receptors, whereas the latter peptide, which is a <-opioid receptor agonist, is expected to be inhibitory. The proposed experiments are anticipated to providing new information about the mechanisms effecting the excitatory of the afferents comprising the sensory arm of the exercise pressor reflex.

Public Health Relevance

Static (i.e., weight lifting) exercise is well known to stimulate thin fiber sensory nerves, which in turn activate the sympathetic nervous system, an effect which in turn causes vasoconstriction in the heart, kidneys and the skeletal muscles. In hearts whose coronary arteries are narrowed by disease, this vasoconstriction can cause chest pain and fatal arrhythmias. Likewise, in muscles, whose arteries are narrowed by disease, exercise can cause excessive stimulation of the sensory nerves that reflexively activate the sympathetic nervous system muscle pain (i.e., claudication).

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Boyce, Amanda T
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Pennsylvania State University
Internal Medicine/Medicine
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Stone, Audrey J; Kaufman, Marc P (2015) The exercise pressor reflex and peripheral artery disease. Auton Neurosci 188:69-73
Copp, Steven W; Stone, Audrey J; Yamauchi, Katsuya et al. (2014) Effects of peripheral and spinal ?-opioid receptor stimulation on the exercise pressor reflex in decerebrate rats. Am J Physiol Regul Integr Comp Physiol 307:R281-9
Baxter, James C; Ramachandra, Renuka; Mayne, Dustin R et al. (2014) Functional expression of ?7-nicotinic acetylcholine receptors by muscle afferent neurons. J Neurophysiol 112:1549-58
Yamauchi, Katsuya; Stone, Audrey J; Kaufman, Marc P (2014) Hindlimb venous distention evokes a pressor reflex in decerebrated rats. Physiol Rep 2:
Stone, A J; Copp, S W; Kaufman, M P (2014) Role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrated rats. Neuroscience 277:26-35
Stone, Audrey J; Yamauchi, Katsuya; Kaufman, Marc P (2014) Purinergic 2X receptors play a role in evoking the exercise pressor reflex in rats with peripheral artery insufficiency. Am J Physiol Heart Circ Physiol 306:H396-404
Leal, Anna K; Yamauchi, Katsuya; Kim, Joyce et al. (2013) Peripheral ?-opioid receptors attenuate the exercise pressor reflex. Am J Physiol Heart Circ Physiol 305:H1246-55
Ramachandra, Renuka; McGrew, Stephanie Y; Baxter, James C et al. (2013) NaV1.8 channels are expressed in large, as well as small, diameter sensory afferent neurons. Channels (Austin) 7:34-7
Yamauchi, Katsuya; Kim, Joyce S; Stone, Audrey J et al. (2013) Endoperoxide 4 receptors play a role in evoking the exercise pressor reflex in rats with simulated peripheral artery disease. J Physiol 591:2949-62
Hassan, Bassil; Ruiz-Velasco, Victor (2013) The *-opioid receptor agonist U-50488 blocks Ca2+ channels in a voltage- and G protein-independent manner in sensory neurons. Reg Anesth Pain Med 38:21-7

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