scholarly journals A dual role for peripheral GDNF signaling in nociception and cardiovascular reflexes

2019 ◽  
Author(s):  
Luis F. Queme ◽  
Alex A. Weyler ◽  
Elysia R. Cohen ◽  
Renita C Hudgins ◽  
Michael P. Jankowski
Keyword(s):  
Purinergic Receptor ◽  
Ischemia Reperfusion ◽  
Muscle Afferents ◽  
Dual Role ◽  
Cardiovascular Reflexes ◽  
Creb Binding Protein ◽  
Group Iii ◽  
Muscle Afferent ◽  
Sympathetic Reflexes ◽  
Pressor Reflexes

AbstractGroup III/IV muscle afferents transduce nociceptive signals and modulate exercise pressor reflexes (EPR). However, the mechanisms governing afferent responsiveness to dually modulate these processes are not well characterized. We and others have shown that ischemic injury can induce both nociception-related behaviors and exacerbated EPRs in the same mice. This correlated with primary muscle afferent sensitization and increased expression of glial cell line-derived neurotrophic factor (GDNF) in injured muscle and increased expression of GDNF family receptor α1 (GFRα1) in DRGs. Here we report that increased GDNF/GFRα1 signaling to sensory neurons from ischemia/reperfusion affected muscle modulated nociceptive-like behaviors, increased EPRs, and group III/IV muscle afferent sensitization. This appeared to have taken effect through increased CREB/CREB-binding protein mediated expression of the purinergic receptor P2X5 in the DRGs. Muscle GDNF signaling to neurons may play an important dual role in nociception and sympathetic reflexes and could provide a novel therapeutic target for treating complications from ischemic injuries.

scholarly journals A dual role for peripheral GDNF signaling in nociception and cardiovascular reflexes in the mouse

2019 ◽  
Vol 117 (1) ◽  
pp. 698-707 ◽  
Author(s):  
Luis F. Queme ◽  
Alex A. Weyler ◽  
Elysia R. Cohen ◽  
Renita C. Hudgins ◽  
Michael P. Jankowski
Keyword(s):  
Purinergic Receptor ◽  
Ischemia Reperfusion ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Dual Role ◽  
Cardiovascular Reflexes ◽  
Creb Binding Protein ◽  
Group Iii ◽  
Muscle Afferent

Group III/IV muscle afferents transduce nociceptive signals and modulate exercise pressor reflexes (EPRs). However, the mechanisms governing afferent responsiveness to dually modulate these processes are not well characterized. We and others have shown that ischemic injury can induce both nociception-related behaviors and exacerbated EPRs in the same mice. This correlated with primary muscle afferent sensitization and increased expression of glial cell line-derived neurotrophic factor (GDNF) in injured muscle and increased expression of GDNF family receptor α1 (GFRα1) in dorsal root ganglia (DRG). Here, we report that increased GDNF/GFRα1 signaling to sensory neurons from ischemia/reperfusion-affected muscle directly modulated nociceptive-like behaviors and increased exercise-mediated reflexes and group III/IV muscle afferent sensitization. This appeared to have taken effect through increased cyclic adenosine monophosphate (cAMP) response element binding (CREB)/CREB binding protein-mediated expression of the purinergic receptor P2X5 in the DRGs. Muscle GDNF signaling to neurons may, therefore, play an important dual role in nociception and sympathetic reflexes and could provide a therapeutic target for treating complications from ischemic injuries.

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 knockout of the ASIC3 on cardiovascular reflexes arising from hindlimb muscle in decerebrated rats

2019 ◽  
Vol 317 (5) ◽  
pp. R641-R648 ◽  
Author(s):  
Joyce S. Kim ◽  
Jonathan E. Harms ◽  
Victor Ruiz-Velasco ◽  
Marc P. Kaufman
Keyword(s):  
Lactic Acid ◽  
Muscle Afferents ◽  
Cardiovascular Reflexes ◽  
Calcaneal Tendon ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Arterial Blood ◽  
Pressor Responses ◽  
Alternative Approach ◽  
Pressor Reflex

The exercise pressor reflex is initiated by the contraction-induced activation of group III and IV muscle afferents. The reflex is manifested by increases in arterial blood pressure and cardiac output, which, in turn, are generated by increases in the sympathetic outflow to the heart and vasculature and decreases in the vagal outflow to the heart. In previous experiments, we used a pharmacological approach to assess the role played by the acid-sensing ion channel 3 (ASIC3) on group III and IV afferents in evoking the exercise pressor reflex. In the present experiments, we used an alternative approach, namely functional knockout (KO) of the ASIC3 gene, to confirm and extend our previous finding that pharmacological blockade of the ASIC3 had only a small impact on the expression of the exercise pressor reflex when the arterial supply to the contracting hindlimb muscles of rats was patent. Using this alternative approach, we compared the magnitude of the exercise pressor reflex evoked in ASIC3 KO rats with that evoked in their wild-type (WT) counterparts. We found both WT and ASIC3 KO rats displayed similar pressor responses to static contraction (WT, n = 10, +12 ± 2 mmHg; KO, n = 9, +11 ± 2 mmHg) and calcaneal tendon stretch (WT, n = 9, +13 ± 2 mmHg; KO, n = 7, +11 ± 2 mmHg). Likewise, both WT and ASIC3 KO displayed similar pressor responses to intra-arterial injection of 12 mM lactic acid (WT, n = 9, +14 ± 3 mmHg; KO, n = 8, +18 ± 5 mmHg), 24 mM lactic acid (WT, n = 9,+24 ± 2 mmHg; KO, n = 8, +20 ± 5 mmHg), capsaicin (WT, n = 9,+27 ± 5 mmHg; KO, n = 10, +29 ± 5 mmHg), and diprotonated phosphate ([Formula: see text]; WT, n = 6,+22 ± 3 mmHg; KO, n = 6, +32 ± 6 mmHg). We conclude that redundant receptors are responsible for evoking the pressor reflexes arising from group III and IV afferents.

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 Role of TRPV1 in acupuncture modulation of reflex excitatory cardiovascular responses

2018 ◽  
Vol 314 (5) ◽  
pp. R655-R666 ◽  
Author(s):  
Zhi-Ling Guo ◽  
Liang-Wu Fu ◽  
Hou-Fen Su ◽  
Stephanie C. Tjen-A-Looi ◽  
John C. Longhurst
Keyword(s):  
Intracellular Signaling ◽  
Intrathecal Injection ◽  
Sensory Nerve ◽  
Cardiovascular Responses ◽  
Nerve Fibers ◽  
Cardiovascular Reflexes ◽  
Transient Receptor Potential Vanilloid ◽  
Group Iii ◽  
Afferent Nerves ◽  
Pressor Reflexes

We have shown that acupuncture, including manual and electroacupuncture (MA and EA), at the P5–6 acupoints stimulates afferent fibers in the median nerve (MN) to modulate sympathoexcitatory cardiovascular reflexes through central regulation of autonomic function. However, the mechanisms underlying acupuncture activation of these sensory afferent nerves and their cell bodies in the dorsal root ganglia (DRG) are unclear. Transient receptor potential vanilloid type 1 (TRPV1) is present in sensory nerve fibers distributed in the general region of acupoints like ST36 and BL 40 located in the hindlimb. However, the contribution of TRPV1 to activation of sensory nerves by acupuncture, leading to modulation of pressor responses, has not been studied. We hypothesized that TRPV1 participates in acupuncture’s activation of sensory afferents and their associated cell bodies in the DRG to modulate pressor reflexes. Local injection of iodoresiniferatoxin (Iodo-RTX; a selective TRPV1 antagonist), but not 5% DMSO (vehicle), into the P6 acupoint on the forelimb reversed the MA’s inhibition of pressor reflexes induced by gastric distension (GD). Conversely, inhibition of GD-induced sympathoexcitatory responses by EA at P5–6 was unchanged after administration of Iodo-RTX into P5–6. Single-unit activity of Group III or IV bimodal afferents sensitive to both mechanical and capsaicin stimuli responded to MA stimulation at P6. MA-evoked activity was attenuated significantly ( P < 0.05) by local administration of Iodo-RTX ( n = 12) but not by 5% DMSO ( n = 12) into the region of the P6 acupoint in rats. Administration of Iodo-RTX into P5–6 did not reduce bimodal afferent activity evoked by EA stimulation ( n = 8). Finally, MA at P6 and EA at P5–6 induced phosphorylation of extracellular signal-regulated kinases (ERK; an intracellular signaling messenger involved in cellular excitation) in DRG neurons located at C7–8 spinal levels receiving MN inputs. After TRPV1 was knocked down in the DRG at these spinal levels with intrathecal injection of TRPV1-siRNA, expression of phosphorylated ERK in the DRG neuron was reduced in MA-treated, but not EA-treated animals. These data suggest that TRPV1 in Group III and IV bimodal sensory afferent nerves contributes to acupuncture inhibition of reflex increases in blood pressure and specifically plays an important role during MA but not EA.

Identification of muscle afferents subserving sensation of deep pain in humans

1994 ◽  
Vol 72 (2) ◽  
pp. 883-889 ◽  
Author(s):  
D. A. Simone ◽  
P. Marchettini ◽  
G. Caputi ◽  
J. L. Ochoa
Keyword(s):  
Conduction Velocity ◽  
Receptive Fields ◽  
Extensor Tendon ◽  
Common Peroneal Nerve ◽  
Muscle Afferents ◽  
Group Iv ◽  
High Threshold ◽  
Group Iii ◽  
Muscle Afferent ◽  
Afferent Unit

1. Intraneural microstimulation (INMS) and microneurography were used in combination to stimulate and record from muscle nociceptor primary afferent fibers of the common peroneal nerve of healthy volunteers. When pain evoked by INMS was projected to muscle, afferent activity could be evoked by innocuous and noxious pressure applied within the projected painful area. Conduction velocity of single fibers was determined by stimulating the receptive fields (RFs) electrically via needle electrodes inserted into the RF and measuring conduction latency and distance between the RF and recording electrode. 2. Pain projected to muscle during INMS trains 5–10 s in duration at threshold intensity for pain sensation was typically described as cramping and was well localized. Subjects mapped the area of the painful projected field (PF) over the skin using a pointer. 3. Fourteen slowly adaping mechanoreceptors with RF in muscle and with moderate to high receptor threshold were identified within or near the painful PF. Conduction velocities were in the range of Group III (n = 8) and Group IV (n = 6) fibers. Mean RF areas of Group III and Group IV afferents, determined by applying pressure percutaneously, were 2.71 +/- 1.14 (SE) cm2 and 3.40 +/- 1.08 (SE) cm2, respectively. Only one Group III afferent unit exhibited spontaneous activity (< 1 Hz). 4. One additional high-threshold mechanoreceptor was identified, with its RF located in the extensor tendon at the base of the big toe. This fiber had a conduction velocity of 32 m/s. During INMS, a well-localized sharp pain was projected to the tendon.(ABSTRACT TRUNCATED AT 250 WORDS)

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