Roles of ASIC3, TRPV1, and Na<sub>V</sub>1.8 in the Transition from Acute to Chronic Pain in a Mouse Model of Fibromyalgia

Chen, Wei Nan; Lee, Cheng‐Han; Lin, Sunny Jui-Shan; Wong, Chia Wen; Sun, Wei Hsin; Wood, John N.; Chen, Chih‐Cheng

doi:10.1186/1744-8069-10-40

Cited by 58 publications

(95 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies report that activating TRPV1 inhibits TTX-R current in primary sensory neurons, which may account for the analgesia of capsaicin [29,30]. However, the increased TRPV1 and TTX-R current is required for developing chronic hyperalgesia [31]. In the future study, more experiments are required to clarify whether the increased α-subunit expression upon the chronic TRPV4 activation will lead to an increased of I Na .…”

Section: Discussionmentioning

confidence: 95%

Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

et al. 2014

View full text Add to dashboard Cite

Transient receptor potential vanilloid 4 (TRPV4) is reported to control the resting membrane potential and increase excitability in many types of cells. Voltage-gated sodium channels (VGSCs) play an important role in initiating action potentials in neurons. However, whether VGSCs can be modulated by the activation of TRPV4 in hippocampal pyramidal neurons remains unknown. In this study, we tested the effect of TRPV4 agonists (GSK1016790A and 4α-PDD) on voltage-gated sodium current (I Na) in hippocampal CA1 pyramidal neurons and the protein levels of α/β-subunit of VGSCs in the hippocampus of mice subjected to intracerebroventricular (icv.) injection of GSK1016790A (GSK-injected mice). Herein, we report that I Na was inhibited by acute application of GSK1016790A or 4α-PDD. In the presence of TRPV4 agonists, the voltage-dependent inactivation curve shifted to the hyperpolarization, whereas the voltage-dependent activation curve remained unchanged. The TRPV4 agonist-induced inhibition of I Na was blocked by the TRPV4 antagonist or tetrodotoxin. Moreover, blocking protein kinase A (PKA) markedly attenuated the GSK1016790A-induced inhibition of I Na, whereas antagonism of protein kinase C or p38 mitogen-activated protein kinase did not change GSK1016790A action. Finally, the protein levels of Nav1.1, Nav1.2, and Nav1.6 in the hippocampus increased in GSK-injected mice, whereas those of Nav1.3 and Navβ1 remained nearly unchanged. We conclude that I Na is inhibited by the acute activation of TRPV4 through PKA signaling pathway in hippocampal pyramidal neurons, but protein expression of α-subunit of VGSCs is increased by sustained TRPV4 activation, which may compensate for the acute inhibition of I Na and provide a possibility for hyper-excitability upon sustained TRPV4 activation.

show abstract

Section: Discussionmentioning

confidence: 95%

Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

et al. 2014

View full text Add to dashboard Cite

show abstract

“…A recent study has shown the importance of a trio of TRP receptors (TRPM3, TRPV1, and TRPA1) that are functionally redundant TRP channels, representing a fault‐tolerant mechanism to avoid burn injury . Little is known about these receptors in FM, but preclinical and clinical studies have shown that certain TRPV haplotypes contribute to the symptoms of FM . QST findings in FM reveal an alarm system to thermal insults that is amplified and prioritized compared to discriminative information.…”

Section: Discussionmentioning

confidence: 99%

Electrochemical Skin Conductance and Quantitative Sensory Testing on Fibromyalgia

et al. 2019

View full text Add to dashboard Cite

Background An impairment of the peripheral nervous system has been suggested in fibromyalgia (FM). Noninvasive distal electrochemical skin conductance (ESC) has been studied little so far when combined with quantitative sensory testing (QST) in patients with FM. Methods This study (clinicaltrials.gov NCT03347669) included 50 female patients with FM and 50 matched healthy volunteers (HVs). ESC (measured in microsiemens [µS] with Sudoscan), as well as psychological, quality of life, sleep, and social characteristics, were assessed in both groups. In a subgroup of 24 patients with FM and 24 HVs, QST of cold and warm detection and pain thresholds and diffuse noxious inhibitory controls (DNICs) were explored. Statistical analysis was performed for a 2‐sided type I error at 5%. Results Between patients with FM and HVs, ESC values differed (71.4 ± 11.2 µS vs. 74.4 ± 10.3 µS, respectively; P = 0.003), especially on the dominant hand (P = 0.03), where more patients with FM had ESC values < 66 µS than did HVs (P = 0.046). No difference was observed on feet. In patients with FM, all collected characteristics were impaired (P < 0.001), DNICs were less functional, detection thresholds occurred later, and pain thresholds occurred earlier. No correlation was observed between ESC and DNICs or with any parameter. Conclusion This study shows that the sudomotor function is significantly impaired in patients with FM, especially on the dominant hand. This occurs in parallel with adjustments of detection and pain thresholds in the context of deficient spinal pain modulation. ESC values combined with QST values are relevant in the context of patients with FM and need to be explored further in this nociception‐autonomic system intertwining.

show abstract

“…ASIC3−/− mice do not develop hyperalgesia after repeated acid injections into muscle, inflammation of muscle, or inflammation of joint [27–29, 44–47]. Further, prior studies also show that blockade of ASICs locally in muscle both prevents and reverses muscle hyperalgesia associated with either repeated acid injections into muscle or muscle inflammation [29, 47, 48]. The current study is consistent with these prior studies and shows that fatigue-enhanced hyperalgesia does not occur in ASIC3−/− mice or after pharmacological blockade of ASIC3 in muscle.…”

Section: Discussionmentioning

confidence: 99%

ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia

et al. 2015

View full text Add to dashboard Cite

An acute bout of exercise can exacerbate pain, hindering participation in regular exercise and daily activities. The mechanisms underlying pain in response to acute exercise are poorly understood. We hypothesized that proton accumulation during muscle fatigue activates ASIC3 on muscle nociceptors to produce hyperalgesia. We investigated the role of ASIC3 using genetic and pharmacological approaches in a model of fatigue-enhanced hyperalgesia. This model uses two injections of pH 5.0 saline into muscle in combination with an electrically-induced fatigue of the same muscle just prior to the second injection of acid to induce mechanical hyperalgesia. We show a significant decrease in muscle force and decrease in muscle pH after 6 minutes of electrical stimulation. Genetic deletion of ASIC3 using knockout mice and pharmacological blockade of ASIC3 with APETx2 in muscle prevents the fatigue-enhanced hyperalgesia. However, ASIC3−/− mice and APETx2 have no effect on the fatigue response. Genetic deletion of ASIC3 in primary afferents innervating muscle using an HSV-1 expressing miRNA to ASIC3 surprisingly had no effect on the development of the hyperalgesia. Muscle fatigue increased the number of macrophages in muscle, and removal of macrophages from muscle with clodronate liposomes prevented the development of fatigue-enhanced hyperalgesia. Thus, these data suggest that fatigue reduces pH in muscle that subsequently activates ASIC3 on macrophages to enhance hyperalgesia to muscle insult.

show abstract

Roles of ASIC3, TRPV1, and Na_V1.8 in the Transition from Acute to Chronic Pain in a Mouse Model of Fibromyalgia

Cited by 58 publications

References 57 publications

Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

Electrochemical Skin Conductance and Quantitative Sensory Testing on Fibromyalgia

ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia

Contact Info

Product

Resources

About

Roles of ASIC3, TRPV1, and NaV1.8 in the Transition from Acute to Chronic Pain in a Mouse Model of Fibromyalgia

Cited by 58 publications

References 57 publications

Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

Electrochemical Skin Conductance and Quantitative Sensory Testing on Fibromyalgia

ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia

Contact Info

Product

Resources

About

Roles of ASIC3, TRPV1, and Na_V1.8 in the Transition from Acute to Chronic Pain in a Mouse Model of Fibromyalgia