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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR059397-03
Application #
8212538
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Boyce, Amanda T
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$474,681
Indirect Cost
$154,722
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
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
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
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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