scholarly journals Tetrodotoxin-resistant voltage-dependent sodium channels in identified muscle afferent neurons

2012 ◽  
Vol 108 (8) ◽  
pp. 2230-2241 ◽  
Author(s):  
Renuka Ramachandra ◽  
Stephanie Y. McGrew ◽  
James C. Baxter ◽  
Esad Kiveric ◽  
Keith S. Elmslie
Keyword(s):  
Sodium Channels ◽  
Cardiovascular Responses ◽  
Muscle Afferents ◽  
Exercise Group ◽  
Afferent Neurons ◽  
Group Iii ◽  
Group I ◽  
Muscle Afferent ◽  
Voltage Dependent ◽  
Extracellular Sodium

Muscle afferents are critical regulators of motor function (Group I and II) and cardiovascular responses to exercise (Group III and IV). However, little is known regarding the expressed voltage-dependent ion channels. We identified muscle afferent neurons in dorsal root ganglia (DRGs), using retrograde labeling to examine voltage-dependent sodium (NaV) channels. In patch-clamp recordings, we found that the dominant NaV current in the majority of identified neurons was insensitive to tetrodotoxin (TTX-R), with NaV current in only a few (14%) neurons showing substantial (>50%) TTX sensitivity (TTX-S). The TTX-R current was sensitive to a NaV1.8 channel blocker, A803467. Immunocytochemistry demonstrated labeling of muscle afferent neurons by a NaV1.8 antibody, which further supported expression of these channels. A portion of the TTX-R NaV current appeared to be noninactivating during our 25-ms voltage steps, which suggested activity of NaV1.9 channels. The majority of the noninactivating current was insensitive to A803467 but sensitive to extracellular sodium. Immunocytochemistry showed labeling of muscle afferent neurons by a NaV1.9 channel antibody, which supports expression of these channels. Further examination of the muscle afferent neurons showed that functional TTX-S channels were expressed, but were largely inactivated at physiological membrane potentials. Immunocytochemistry showed expression of the TTX-S channels NaV1.6 and NaV1.7 but not NaV1.1. NaV1.8 and NaV1.9 appear to be the dominant functional sodium channels in small- to medium-diameter muscle afferent neurons. The expression of these channels is consistent with the identification of these neurons as Group III and IV, which mediate the exercise pressor reflex.

scholarly journals Identification of CaV channel types expressed in muscle afferent neurons

2013 ◽  
Vol 110 (7) ◽  
pp. 1535-1543 ◽  
Author(s):  
Renuka Ramachandra ◽  
Bassil Hassan ◽  
Stephanie G. McGrew ◽  
James Dompor ◽  
Mohamed Farrag ◽  
...  
Keyword(s):  
Charge Carrier ◽  
Muscle Afferents ◽  
Channel Blockers ◽  
Afferent Neurons ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Disease States ◽  
Increased Risk ◽  
Muscle Afferent ◽  
Voltage Dependent

Cardiovascular adjustments to exercise are partially mediated by group III/IV (small to medium) muscle afferents comprising the exercise pressor reflex (EPR). However, this reflex can be inappropriately activated in disease states (e.g., peripheral vascular disease), leading to increased risk of myocardial infarction. Here we investigate the voltage-dependent calcium (CaV) channels expressed in small to medium muscle afferent neurons as a first step toward determining their potential role in controlling the EPR. Using specific blockers and 5 mM Ba2+ as the charge carrier, we found the major calcium channel types to be CaV2.2 (N-type) > CaV2.1 (P/Q-type) > CaV1.2 (L-type). Surprisingly, the CaV2.3 channel (R-type) blocker SNX482 was without effect. However, R-type currents are more prominent when recorded in Ca2+ ( Liang and Elmslie 2001 ). We reexamined the channel types using 10 mM Ca2+ as the charge carrier, but results were similar to those in Ba2+. SNX482 was without effect even though ∼27% of the current was blocker insensitive. Using multiple methods, we demonstrate that CaV2.3 channels are functionally expressed in muscle afferent neurons. Finally, ATP is an important modulator of the EPR, and we examined the effect on CaV currents. ATP reduced CaV current primarily via G protein βγ-mediated inhibition of CaV2.2 channels. We conclude that small to medium muscle afferent neurons primarily express CaV2.2 > CaV2.1 ≥ CaV2.3 > CaV1.2 channels. As with chronic pain, CaV2.2 channel blockers may be useful in controlling inappropriate activation of the EPR.

scholarly journals NaV1.9 channels in muscle afferent neurons and axons

2018 ◽  
Vol 120 (3) ◽  
pp. 1032-1044 ◽  
Author(s):  
Tyler L. Marler ◽  
Andrew B. Wright ◽  
Kristina L. Elmslie ◽  
Ankeeta K. Heier ◽  
Ethan Remily ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Muscle Activity ◽  
Muscle Blood Flow ◽  
Small Diameter ◽  
Muscle Afferents ◽  
Inactivation Kinetics ◽  
Afferent Neurons ◽  
Internal Solution ◽  
Group Iii ◽  
Muscle Afferent

The exercise pressor reflex (EPR) is activated by muscle contractions to increase heart rate and blood pressure during exercise. While this reflex is beneficial in healthy individuals, the reflex activity is exaggerated in patients with cardiovascular disease, which is associated with increased mortality. Group III and IV afferents mediate the EPR and have been shown to express both tetrodotoxin-sensitive (TTX-S, NaV1.6, and NaV1.7) and -resistant (TTX-R, NaV1.8, and NaV1.9) voltage-gated sodium (NaV) channels, but NaV1.9 current has not yet been demonstrated. Using a F−-containing internal solution, we found a NaV current in muscle afferent neurons that activates at around −70 mV with slow activation and inactivation kinetics, as expected from NaV1.9 current. However, this current ran down with time, which resulted, at least in part, from increased steady-state inactivation since it was slowed by both holding potential hyperpolarization and a depolarized shift of the gating properties. We further show that, following NaV1.9 current rundown (internal F−), application of the NaV1.8 channel blocker A803467 inhibited significantly more TTX-R current than we had previously observed (internal Cl−), which suggests that NaV1.9 current did not rundown with that internal solution. Using immunohistochemistry, we found that the majority of group IV somata and axons were NaV1.9 positive. The majority of small diameter myelinated afferent somata (putative group III) were also NaV1.9 positive, but myelinated muscle afferent axons were rarely labeled. The presence of NaV1.9 channels in muscle afferents supports a role for these channels in activation and maintenance of the EPR. NEW & NOTEWORTHY Small diameter muscle afferents signal pain and muscle activity levels. The muscle activity signals drive the cardiovascular system to increase muscle blood flow, but these signals can become exaggerated in cardiovascular disease to exacerbate cardiac damage. The voltage-dependent sodium channel NaV1.9 plays a unique role in controlling afferent excitability. We show that NaV1.9 channels are expressed in muscle afferents, which supports these channels as a target for drug development to control hyperactivity of these neurons.

scholarly journals Functional expression of α7-nicotinic acetylcholine receptors by muscle afferent neurons

2014 ◽  
Vol 112 (6) ◽  
pp. 1549-1558 ◽  
Author(s):  
James C. Baxter ◽  
Renuka Ramachandra ◽  
Dustin R. Mayne ◽  
Keith S. Elmslie
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Functional Expression ◽  
Muscle Afferents ◽  
Group Iv ◽  
Afferent Neurons ◽  
Sprague Dawley ◽  
Group Iii ◽  
Muscle Afferent ◽  
Exercise Induced

The exercise pressor reflex (EPR) is generated by group III and IV muscle afferents during exercise to increase cardiovascular function. Muscle contraction is triggered by ACh, which is metabolized into choline that could serve as a signal of exercise-induced activity. We demonstrate that ACh can induce current in muscle afferents neurons isolated from male Sprague-Dawley rats. The nicotinic ACh receptors (nAChRs) appear to be expressed by some group III-IV neurons since capsaicin (TRPV1) and/or ATP (P2X) induced current in 56% of ACh-responsive neurons. α7- And α4β2-nAChRs have been shown to be expressed in sensory neurons. An α7-nAChR antibody stained 83% of muscle afferent neurons. Functional expression was demonstrated by using the specific α7-nAChR blockers α-conotoxin ImI (IMI) and methyllycaconitine (MLA). MLA inhibited ACh responses in 100% of muscle afferent neurons, whereas IMI inhibited ACh responses in 54% of neurons. Dihydro-β-erythroidine, an α4β2-nAChR blocker, inhibited ACh responses in 50% of muscle afferent neurons, but recovery from block was not observed. Choline, an α7-nAChR agonist, elicited a response in 60% of ACh-responsive neurons. Finally, we demonstrated the expression of α7-nAChR by peripherin labeled (group IV) afferent fibers within gastrocnemius muscles. Some of these α7-nAChR-positive fibers were also positive for P2X3 receptors. Thus choline could serve as an activator of the EPR by opening α7-nAChR expressed by group IV (and possible group III) afferents. nAChRs could become pharmacological targets for suppressing the excessive EPR activation in patients with peripheral vascular disease.

scholarly journals Effect of Fiber Rich Product on Childhood Obesity and Lipid Profile Aged 10-12 Years

2021 ◽  
Vol 9 (3) ◽  
pp. 87-90
Author(s):  
A. Jyoth ◽  
Keyword(s):  
Exercise Group ◽  
Control Group ◽  
Group Iii ◽  
Group I ◽  
Diet Survey ◽  
Group Ii ◽  
And Control ◽  
Experimental Group ◽  
Positive Results ◽  
Green Peas

The effect of fiber rich product on child hood obesity studied with 60 sample which were collected randomly among 10-12 years and categorized into 2 groups i.e, experimental group and control group. Experimental group further categorized into three groups i.e, supplementation with exercise (n=15), only supplementation group (n=15), only exercise group (n=15) and control group consists of (n=15).Anthropometric, and diet survey conducted as parameters. A fiber rich product was prepared and supplemented for 2 months to the selected subjects and it consists of whole Bengal gram, whole green gram, green peas, barley and jaggery. Positive results were obtained in three experimental groups. Significant decrease observed inweight, and BMI, Total cholesterol, Triglycerides, LDL, VLDL significant increase observed in HDL in group I II and III. The results were (51.60-48.26kg, 24.7-23.1, 195.2-152.3 mg/dl, 168.2-145.0 mg/dl, 52.2-54.13 mg/dl, 109.4- 69.4mg/dl, 33.6-28.7mg/dl) in group I, In group II the results are (50.3-49.86kg, 23.7-23.4, 168.6-161.0mg/dl, 145.4-129.6mg/dl, 44.2-45.2 mg/dl, 95.3-90.0mg/dl, 29.1-28.3mg/dl).In group III the tesults aere (50.7-49.6kg, 24.5-23.9, 143.2-139.3mg/dl, 139-134.5mg/dl, 38.2-38.7mg/dl 76.8-74.1 mg/dl, 25.6-28.1mg/dl) .From the results it was clear that when compared to group II and III group I has shown better results.

Reflex cardiovascular responses evoked by selective activation of skeletal muscle ergoreceptors

2001 ◽  
Vol 90 (1) ◽  
pp. 308-316 ◽  
Author(s):  
B. G. Leshnower ◽  
J. T. Potts ◽  
M. G. Garry ◽  
J. H. Mitchell
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Cardiovascular Response ◽  
Afferent Fiber ◽  
Cardiovascular Responses ◽  
Muscle Afferents ◽  
Triceps Surae ◽  
Muscle Stretch ◽  
Group Iii ◽  
Passive Muscle

It is well known that the exercise pressor reflex (EPR) is mediated by group III and IV skeletal muscle afferent fibers, which exhibit unique discharge responses to mechanical and chemical stimuli. Based on the difference in discharge patterns of group III and IV muscle afferents, we hypothesized that activation of mechanically sensitive (MS) fibers would evoke a different pattern of cardiovascular responses compared with activation of both MS and chemosensitive (CS) fibers. Experiments were conducted in chloralose-urethane-anesthetized cats ( n = 10). Passive muscle stretch was used to activate MS afferents, and electrically evoked contraction of the triceps surae was used to activate both MS and CS muscle afferents. No significant differences were shown in reflex heart rate and mean arterial pressure (MAP) responses between passive muscle stretch and evoked muscle contraction. However, when the reflex responses were matched according to tension-time index (TTI), the peak MAP response (67 ± 4 vs. 56 ± 4 mmHg, P < 0.05) was significantly greater at higher TTI (427 ± 18 vs. 304 ± 13 kg · s, high vs. low TTI, P < 0.05), despite different modes of afferent fiber activation. When the same mode of afferent fiber activation was compared, the peak MAP response (65 ± 7 vs. 55 ± 5 mmHg, P < 0.05) was again predicted by the magnitude of TTI (422 ± 24 vs. 298 ± 19 kg · s, high vs. low TTI, P < 0.05). Total sensory input from skeletal muscle ergoreceptors, as predicted by TTI and not the modality of afferent fiber activation (muscle contraction vs. passive stretch), is suggested to be the primary determinant of the magnitude of the EPR-evoked cardiovascular response.

scholarly journals Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans

2015 ◽  
Vol 309 (9) ◽  
pp. H1479-H1489 ◽  
Author(s):  
Simranjit K. Sidhu ◽  
Joshua C. Weavil ◽  
Massimo Venturelli ◽  
Matthew J. Rossman ◽  
Benjamin S. Gmelch ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Cardiovascular Response ◽  
Knee Extensor ◽  
Cardiovascular Responses ◽  
Muscle Afferents ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Pressor Reflex ◽  
Exercise Induced ◽  
The Impact

We investigated the influence of aging on the group III/IV muscle afferents in the exercise pressor reflex-mediated cardiovascular response to rhythmic exercise. Nine old (OLD; 68 ± 2 yr) and nine young (YNG; 24 ± 2 yr) males performed single-leg knee extensor exercise (15 W, 30 W, 80% max) under control conditions and with lumbar intrathecal fentanyl impairing feedback from group III/IV leg muscle afferents. Mean arterial pressure (MAP), cardiac output, leg blood flow (QL), systemic (SVC) and leg vascular conductance (LVC) were continuously determined. With no hemodynamic effect at rest, fentanyl blockade during exercise attenuated both cardiac output and QL ∼17% in YNG, while the decrease in cardiac output in OLD (∼5%) was significantly smaller with no impact on QL ( P = 0.8). Therefore, in the face of similar significant ∼7% reduction in MAP during exercise with fentanyl blockade in both groups, LVC significantly increased ∼11% in OLD, but decreased ∼8% in YNG. The opposing direction of change was reflected in SVC with a significant ∼5% increase in OLD and a ∼12% decrease in YNG. Thus while cardiac output seems to account for the majority of group III/IV-mediated MAP responses in YNG, the impact of neural feedback on the heart may decrease with age and alterations in SVC become more prominent in mediating the similar exercise pressor reflex in OLD. Interestingly, in terms of peripheral hemodynamics, while group III/IV-mediated feedback plays a clear role in increasing LVC during exercise in the YNG, these afferents seem to actually reduce LVC in OLD. These peripheral findings may help explain the limited exercise-induced peripheral vasodilation often associated with aging.

scholarly journals Study of effect of various treatments in clinically diagnosed patients of Carpal tunnel syndrome

2020 ◽  
Vol 11 (3) ◽  
pp. 3105-3113
Author(s):  
Sahoo J.K. ◽  
Joshi A.G
Keyword(s):  
Treatment Group ◽  
Carpal Tunnel Syndrome ◽  
Exercise Group ◽  
Group Iv ◽  
Significant Group ◽  
Group Iii ◽  
Group I ◽  
Medicinal Treatment ◽  
Before And After ◽  
Tunnel Syndrome

Carpal tunnel syndrome is the compression neuropathy in upper extremity. Several researches have been done to see the effect of various treatments separately. But very little research work is available for comparison of treatments. So the study was aimed to study the clinical and electrophysiological findings and their Comparision before and after various treatments. NCS was carried out in 200 CTS patients before and after 6weeks of treatment. Patients were divided into 4 groups. Group I- operative, Group II-medicinal treatment, Group III-exercise, Group IV-medicine+exercise. Clinical and electrophysiological parameters all groups were compared before and after treatment. Group (I), showed significant changes in all parameters except SNAP in operated Rt. Hand as compared to Lt. Hand. Group-II showed significant changes in DML,DML(diff.),DSL,DSL(Diff.)except CMAP,SNAP,&SCV in Rt. Hand but in Lt. hand DML,DML(diff.)DSL showed significant changes where as DSL(Diff.) CMAP,SNAP,&SCV were non-significant. Group-III showed significant changes in DML, DML(diff.),DSL,DSL(Diff.) but SCV,SNAP and CMAP were non-significant in Rt. hand but in Lt. hand only DML(diff.) was significant . Group-IV showed significant changes in all parameters except SCV in Rt. hand but in Lt. hand DML, DML (diff.),DSL, DSL(Diff.) were significant , where as SNAP, CMAP, and SCV were non-significant. It was concluded that maximum improvement was observed in clinical and electrophysiological parameters in operative group, then Medicine + exercise Group, then exercise Group and minimum in Medicinal treatment Group. So operative method is the method of choice for CTS; however the duration of treatment should be more so that further improvements can be seen in all parameters.

Increasing gracilis muscle interstitial potassium concentrations stimulate group III and IV afferents

1985 ◽  
Vol 58 (3) ◽  
pp. 936-941 ◽  
Author(s):  
K. J. Rybicki ◽  
T. G. Waldrop ◽  
M. P. Kaufman
Keyword(s):  
Pressor Response ◽  
Cardiovascular Responses ◽  
Muscular Contraction ◽  
Muscle Afferents ◽  
Group Iv ◽  
Gracilis Muscle ◽  
Group Iii ◽  
Arterial Blood ◽  
Static Contraction ◽  
Anesthetized Dogs

Static muscular contraction reflexly increases arterial blood pressure and heart rate. One possible mechanism evoking this reflex is that potassium accumulates in the interstitial space of a working muscle to stimulate group III and IV afferents whose activation in turn evokes a pressor response. The responses of group III and IV muscle afferents to increases in interstitial potassium concentrations within the range evoked by static contraction are unknown. Thus we injected potassium chloride into the gracilis artery of anesthetized dogs while we measured both gracilis muscle interstitial potassium concentrations with potassium-selective electrodes and the impulse activity of afferents in the gracilis nerve. We found that increasing interstitial potassium concentrations to levels similar to those seen during static contraction stimulated 14 of 16 group III and 29 of 31 group IV afferents. The responses of the afferents to potassium were concentration dependent. The typical response to potassium consisted of a burst of impulses, an effect that returned to control firing rates within 26 s, even though interstitial potassium concentrations remained elevated for several minutes. Although our results suggest that potassium may play a role in initiating the reflex cardiovascular responses to static muscular contraction, the accumulation of this ion does not appear to be solely responsible for maintaining the pressor response for the duration of the contraction.

Regenerating sprouts of axotomized cat muscle afferents express characteristic firing patterns to mechanical stimulation

1991 ◽  
Vol 66 (6) ◽  
pp. 2155-2158 ◽  
Author(s):  
R. D. Johnson ◽  
J. B. Munson
Keyword(s):  
Muscle Afferents ◽  
Triceps Surae ◽  
Cutaneous Afferents ◽  
Spontaneous Discharge ◽  
Firing Patterns ◽  
Group I ◽  
Afferent Fibers ◽  
Physiological Properties ◽  
Muscle Afferent ◽  
Group Ii

1. In cats, we studied the physiological properties of regenerating sprouts of muscle afferent fibers and compared them with sprouts from cutaneous afferent fibers. 2. Muscle nerves to the triceps surae and cutaneous sural nerves were axotomized in the popliteal fossa, and the proximal ends were inserted into nerve cuffs. Six days later, we recorded action potentials from single Groups I and II muscle and mostly Group II cutaneous afferents driven by mechanostimulation of the cuff. 3. Most muscle afferent sprouts (91%) had a regular slowly adapting discharge in response to sustained mechanical displacement of the cuff, particularly to sustained stretch stimuli, whereas most cutaneous afferents (92%) did not. Muscle afferents were more likely to have a spontaneous discharge and afterdischarge. 4. Group II muscle afferent sprouts had lower stretch thresholds and a higher incidence of spontaneous discharge compared with Group I fiber sprouts, whereas Group I fibers had a higher incidence of high-frequency afterdischarge to mechanical stimuli. 5. We conclude that, 6 days after axotomy, regenerating sprouts of muscle afferents, particularly Group II afferents, have become mechanosensitive in the absence of a receptor target and exhibit physiological properties similar to those found when innervating their native muscle but significantly different from sprouts of cutaneous afferents. Expression of these native muscle afferent firing patterns after the inappropriate reinnervation of hairy skin may be due to inherent properties of the muscle afferent fiber.

scholarly journals Modulation of Oligosynaptic Cutaneous and Muscle Afferent Reflex Pathways During Fictive Locomotion and Scratching in the Cat

1998 ◽  
Vol 79 (1) ◽  
pp. 447-463 ◽  
Author(s):  
A. M. Degtyarenko ◽  
E. S. Simon ◽  
T. Norden-Krichmar ◽  
R. E. Burke
Keyword(s):  
Membrane Potential ◽  
Central Pattern Generators ◽  
Muscle Afferents ◽  
Flexor Hallucis Longus ◽  
Fictive Locomotion ◽  
Postsynaptic Potentials ◽  
Cutaneous Reflex ◽  
Reflex Pathways ◽  
Group I ◽  
Muscle Afferent

Degtyarenko, A. M., E. S. Simon, T. Norden-Krichmar, and R. E. Burke. Modulation of oligosynaptic cutaneous and muscle afferent reflex pathways during fictive locomotion and scratching in the cat. J. Neurophysiol. 79: 447–463, 1998. We have compared state-dependent transmission through oligosynaptic (minimally disynaptic) reflex pathways from low-threshold cutaneous and muscle afferents to some flexor and extensor lumbosacral motoneurons during fictive locomotion and scratching in decerebrate unanesthetized cats. As reported in earlier work, oligosynaptic cutaneous excitatory postsynaptic potentials (EPSPs) in flexor digitorum longus (FDL) and inhibitory postsynaptic potentials (IPSPs) in extensor digitorum (EDL) longus motoneurons were enhanced markedly during the early flexion phase of fictive locomotion. We show in this paper that, in contrast, these cutaneous reflex pathways were depressed markedly during all phases of fictive scratching. On the other hand, disynaptic EPSPs produced by homonymous and synergist group I muscle afferents in flexor (tibialis anterior and EDL) motoneurons were present and strongly modulated during both fictive locomotion and scratching. During both actions, these disynaptic group I EPSPs appeared or exhibited the largest amplitude when the motoneuron membrane potential was most depolarized and the parent motor pool was active. There was an interesting exception to the simple pattern of coincident group I EPSP enhancement and motoneuron depolarization. During locomotion, disynaptic group I EPSPs in both FDL and flexor hallucis longus (FHL) motoneurons cells were facilitated during the extension phase, although FDL motoneurons were relatively hyperpolarized whereas FHL cells were depolarized. The reverse situation was found during fictive scratching; group I EPSPs were facilitated in both FDL and FHL cells during the flexion phase when FDL motoneurons were depolarized and FHL cells were relatively hyperpolarized. These observations suggest that the disynaptic EPSPs in these two motor nuclei are produced by common interneurons. Reciprocal disynaptic inhibitory pathways from group Ia muscle afferents to antagonist motoneurons were also active and subject to phase-dependent modulation during both fictive locomotion and scratching. In all but one cell tested, reciprocal disynaptic group Ia IPSPs were largest during those phases in which the motoneuron membrane potential was relatively hyperpolarized and the parent motor pool was inactive. Oligosynaptic PSPs in motoneurons produced by stimulation of the mesencephalic locomotor region (MLR) were modulated strongly during fictive locomotion but were suppressed powerfully throughout fictive scratching. Large cord dorsum potentials generated by MLR stimuli also were suppressed markedly during fictive scratching. These results allow certain inferences about the organization of interneurons in the pathways examined. They also suggest that the central pattern generators that produce fictive locomotion and scratching are organized differently.

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