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 (EPR) as well as transduce the sensation of pain. The EPR, which arises from contraction of skeletal muscle, is one of two key neural mechanisms that evoke the cardiovascular adjustments to exercise. These adjustments, which support the ability of skeletal muscles to contract by increasing blood flow and oxygen to exercising muscles, include increases in systemic blood pressure, cardiac output and ventilation. With respect to the thin fiber muscle afferents that mediate the EPR, we combine the power of the in vitro whole-cell patch-clamp technique to determine the mechanisms of afferent excitability, with the physiological insights provided by in vivo electrophysiology to 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 small afferent neurons that express channels known to elicit the EPR (e.g. ASIC, TRPV1, P2X and TRPA1). 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, we will concentrat on the mechanisms by which two receptors, the opioid (Aim 1) and -opioid (Aim 2) receptors, inhibit the EPR. Additional experiments will investigate the role of two voltage depend ion channels, KV7 (Aim 3) and NaV1.
7 (Aim 4) in controlling the excitability of the EPR. The proposed experiments are natural extensions from those of our previous funding period and will greatly increase our understanding of the mechanisms affecting the excitatory afferents comprising the sensory arm of the EPR.

Public Health Relevance

The focus of our study is to examine the mechanisms by which sensory nerves stimulate sympathetic nerves, which leads to vasoconstriction in the heart, kidneys and skeletal muscles. It is well known that in skeletal muscle, the arteries supplying this tissue are chronically narrowed by disease, and the stimulation of the sensory nerves and activation of the sympathetic nervous system leads to muscle pain (i.e. claudication).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR059397-06
Application #
8895672
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Boyce, Amanda T
Project Start
2010-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Estrada, Juan A; Kaufman, Marc P (2018) µ-Opioid receptors inhibit the exercise pressor reflex by closing N-type calcium channels but not by opening GIRK channels in rats. Am J Physiol Regul Integr Comp Physiol 314:R693-R699
Farrag, Mohamed; Drobish, Julie K; Puhl, Henry L et al. (2017) Endomorphins potentiate acid-sensing ion channel currents and enhance the lactic acid-mediated increase in arterial blood pressure: effects amplified in hindlimb ischaemia. J Physiol 595:7167-7183
Romero, Haylie K; Christensen, Sean B; Di Cesare Mannelli, Lorenzo et al. (2017) Inhibition of ?9?10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain. Proc Natl Acad Sci U S A 114:E1825-E1832
Harms, Jonathan E; Copp, Steven W; Kaufman, Marc P (2016) Low-frequency stimulation of group III and IV hind limb afferents evokes reflex pressor responses in decerebrate rats. Physiol Rep 4:
Copp, Steven W; Kim, Joyce S; Ruiz-Velasco, Victor et al. (2016) The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in rats with ligated femoral arteries. Am J Physiol Heart Circ Physiol 310:H1233-41
Ramachandra, Renuka; Elmslie, Keith S (2016) EXPRESS: Voltage-dependent sodium (NaV) channels in group IV sensory afferents. Mol Pain 12:
Mahmoud, Saifeldin; Farrag, Mohamed; Ruiz-Velasco, Victor (2016) G?7 proteins contribute to coupling of nociceptin/orphanin FQ peptide (NOP) opioid receptors and voltage-gated Ca(2+) channels in rat stellate ganglion neurons. Neurosci Lett 627:77-83
Sugino, Shigekazu; Farrag, Mohamed; Ruiz-Velasco, Victor (2016) G?14 subunit-mediated inhibition of voltage-gated Ca2+ and K+ channels via neurokinin-1 receptors in rat celiac-superior mesenteric ganglion neurons. J Neurophysiol 115:1577-86
Copp, Steven W; Kim, Joyce S; Ruiz-Velasco, Victor et al. (2016) The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats. J Physiol 594:641-55
Freet, Christopher S; Ballard, Sarah M; Alexander, Danielle N et al. (2015) Cocaine-induced suppression of saccharin intake and morphine modulation of Ca²? channel currents in sensory neurons of OPRM1 A118G mice. Physiol Behav 139:216-23

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