Peripheral 5-HT3 mediates mirror-image pain by a cross-talk with acid-sensing ion channel 3

Su, Yeu Shiuan; Mei, Hao Ruei; Wang, Chun Hung; Sun, Wei Hsin

doi:10.1016/j.neuropharm.2017.11.044

Cited by 12 publications

(7 citation statements)

References 51 publications

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“…Staining of SGCs was as previously described [24]. Briefly, at 0, 1, 4, 8, and 12 weeks after CFA injection, DRG isolated from vehicle-or compound-treated mice were frozen in freezing solution and cut at 12 μm by using a cryostat (Leica microsystem 3510S, Bensheim, Germany).…”

Section: Immunohistochemistry and Immunostainingmentioning

confidence: 99%

“…To detect TDAG8-mediated signaling, calcium imaging was performed as described [24]. Briefly, human embryonic kidney, adenovirus type 5-transformed 293 cells (HEK293T, obtained from the Bioresource Collection and Research Center of Food Industry Research and Development Institute, Taiwan) were cultured on coverslips and transfected with 1.2 μg pIRES-GFP-TDAG8.…”

Section: Calcium Imagingmentioning

confidence: 99%

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TDAG8 deficiency reduces satellite glial number and pro-inflammatory macrophage number to relieve rheumatoid arthritis disease severity and chronic pain

Dai

Hsieh

Chen

et al. 2020

J Neuroinflammation

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Background: The autoimmune disease rheumatoid arthritis (RA) affects approximately 1% of the global population. RA is characterized with chronic joint inflammation and often associated with chronic pain. The imbalance of proinflammatory and anti-inflammatory macrophages is a feature of RA progression. Glial cells affecting neuronal sensitivity at both peripheral and central levels may also be important for RA progression and associated pain. Genetic variants in the T cell death-associated gene 8 (TDAG8) locus are found to associate with spondyloarthritis. TDAG8 was also found involved in RA disease progression and associated hyperalgesia in the RA mouse model. However, its modulation in RA remains unclear. Methods: To address this question, we intra-articularly injected complete Freund's adjuvant (CFA) into TDAG8 +/+ , TDAG8 −/− or wild-type mice, followed by pain behavioral tests. Joints and dorsal root ganglia were taken, sectioned, and stained with antibodies to observe the number of immune cells, macrophages, and satellite glial cells (SGCs). For compound treatments, compounds were intraperitoneally or orally administered weekly for 9 consecutive weeks after CFA injection. Results: We demonstrated that TDAG8 deletion slightly reduced RA pain in the early phase but dramatically attenuated RA progression and pain in the chronic phase (> 7 weeks). TDAG8 deletion inhibited an increase in SGC number and inhibition of SGC function attenuated chronic phase of RA pain, so TDAG8 could regulate SGC number to control chronic pain. TDAG8 deletion also reduced M1 pro-inflammatory macrophage number at 12 weeks, contributing to the attenuation of chronic RA pain. Such results were further confirmed by using salicylanilide derivatives, CCL-2d or LCC-09, to suppress TDAG8 expression and function. Conclusions: This study demonstrates that TDAG8 deletion reduced SGC and M1 macrophage number to relieve RA disease severity and associated chronic pain. M1 macrophages are critical for the development and maintenance of RA disease and pain, but glial activation is also required for the chronic phase of RA pain.

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Section: Immunohistochemistry and Immunostainingmentioning

confidence: 99%

Section: Calcium Imagingmentioning

confidence: 99%

TDAG8 deficiency reduces satellite glial number and pro-inflammatory macrophage number to relieve rheumatoid arthritis disease severity and chronic pain

Dai

Hsieh

Chen

et al. 2020

J Neuroinflammation

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“…In chemo-sensing, Asic3 −/− mice lost the acid-induced sustained current in DRG neurons that express ASIC-like currents, whereas in wild-type mice, ~ 20% of DRG neurons expressed ASIC3-like currents containing the sustained component [ 57 ]. Accordingly, Asic3 −/− mice show largely reduced acid-induced pain behaviors [ 58 , 59 ] and impaired triggering of acid-induced nociceptor priming [ 60 ]. In a mouse model of fibromyalgia, Asic3 −/− mice failed to develop chronic widespread muscle pain induced by repeated intramuscular injections of acid saline [ 60 – 62 ].…”

Section: Introductionmentioning

confidence: 99%

Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing

2018

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BackgroundAcid-sensing ion channels (ASICs) are a group of amiloride-sensitive ligand-gated ion channels belonging to the family of degenerin/epithelial sodium channels. ASICs are predominantly expressed in both the peripheral and central nervous system and have been characterized as potent proton sensors to detect extracellular acidification in the periphery and brain.Main bodyHere we review the recent studies focusing on the physiological roles of ASICs in the nervous system. As the major acid-sensing membrane proteins in the nervous system, ASICs detect tissue acidosis occurring at tissue injury, inflammation, ischemia, stroke, and tumors as well as fatiguing muscle to activate pain-sensing nerves in the periphery and transmit pain signals to the brain. Arachidonic acid and lysophosphocholine have been identified as endogenous non-proton ligands activating ASICs in a neutral pH environment. On the other hand, ASICs are found involved in the tether model mechanotransduction, in which the extracellular matrix and cytoplasmic cytoskeletons act like a gating-spring to tether the mechanically activated ion channels and thus transmit the stimulus force to the channels. Accordingly, accumulating evidence has shown ASICs play important roles in mechanotransduction of proprioceptors, mechanoreceptors and nociceptors to monitor the homoeostatic status of muscle contraction, blood volume, and blood pressure as well as pain stimuli.ConclusionTogether, ASICs are dual-function proteins for both chemosensation and mechanosensation involved in monitoring physiological homoeostasis and pathological signals.

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“…However, since the exact function of the different voltage-gated sodium channels is unknown, as well as the mechanisms behind paresthesia after lidocaine injection, these could be possible areas for future research. In addition, there are indications that 5-HT 3 antagonists also block other ion channels, such as potassium, calcium, and acid-sensing ion channels (48,49), so the local anesthetic effect may not be limited to 5-HT 3 receptor and sodium channel blocking.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Granisetron on Sensory Detection and Pain Thresholds in Facial Skin of Healthy Young Males

et al. 2020

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Background: The specific serotonin type 3 (5-HT 3 )-receptor antagonist granisetron effectively reduces clinical as well as experimental muscle pain and hyperalgesia and with a duration that exceeds that of lidocaine. Hence, it may be an alternative to lidocaine as a local anesthetic. There are also some indications that granisetron in addition to 5-HT 3 receptors blocks sodium channels. Thus, the local anesthetic effect by granisetron may resemble that of lidocaine, but this has not been tested. The aim of this study was therefore to compare the effect granisetron has on facial skin sensitivity to the effect of lidocaine and isotonic saline.Methods: This was a randomized, controlled, and double-blind study, in which 1 ml of either granisetron (test-substance), lidocaine (positive control), or isotonic saline (negative control) was injected into the skin over the masseter muscle at three different occasions in 18 healthy males (27.2 ± 5.8 years old). Skin detection thresholds and pain thresholds for thermal stimuli as well as mechanical detection thresholds and sensitivity to a painful mechanical (pinprick) stimulus were assessed before (baseline) and 5, 20, 40, and 60 min after injection. The quality and area of subjective sensory change over the cheek were assessed 20 min after injection.Results: All substances increased the mechanical detection threshold (granisetron: p = 0.011; lidocaine: p = 0.016; saline: p = 0.031). Both granisetron and lidocaine, but not isotonic saline, increased the heat detection thresholds (p < 0.001 and p < 0.02, respectively), but not the cold detection thresholds. Granisetron and lidocaine also reduced pinprick pain (p = 0.001 for each comparison). There were no significant differences between granisetron and lidocaine for any of these variables. There was no effect on thermal pain thresholds for any substance. Conclusion:The similar analgesic patterns on mechanical sensory and pain thresholds as well as thermal sensory thresholds over the facial skin by subcutaneous injection of granisetron and lidocaine shown in this study and the absence of paresthesia, in combination with the reduced pain intensity and pressure pain sensitivity shown in previous studies, indicate that granisetron might be a novel candidate as a local anesthetic.

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Peripheral 5-HT3 mediates mirror-image pain by a cross-talk with acid-sensing ion channel 3

Cited by 12 publications

References 51 publications

TDAG8 deficiency reduces satellite glial number and pro-inflammatory macrophage number to relieve rheumatoid arthritis disease severity and chronic pain

TDAG8 deficiency reduces satellite glial number and pro-inflammatory macrophage number to relieve rheumatoid arthritis disease severity and chronic pain

Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing

The Effect of Granisetron on Sensory Detection and Pain Thresholds in Facial Skin of Healthy Young Males

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