Effect of TRPV4-p38 MAPK Pathway on Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion

Qu, Yu-Juan; Zhang, Xiao; Fan, Zhenzhen; Huai, Juan; Teng, Yong-Bo; Yang, Zhiwei; Yue, Shouwei

doi:10.1155/2016/6978923

Cited by 43 publications

(35 citation statements)

References 37 publications

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“…After various stress stimuli, p38 is phosphorylated in association with sequential activation of MAPK kinase kinase and MAPK kinase 6 cascades [9]. This pp38 is involved in producing various downstream intracellular molecules in DRG neurons [21]. The present fi ndings showed a signifi cant increase in the number of pp38-IR cells in the TG in dry-tongue rats and considerable suppression of the number of pp38-IR cells after continuous intraganglionic administration of p38 MAPK inhibitor in these animals.…”

Section: Discussionsupporting

confidence: 53%

Involvement of TRPV4 ionotropic channel in tongue mechanical hypersensitivity in dry-tongue rats

et al. 2020

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Although xerostomia can cause persistent oral pain, the mechanisms underlying such pain are not well understood. To evaluate whether a phosphorylated p38 (pp38)-TRPV4 mechanism in trigeminal ganglion (TG) neurons has a role in mechanical hyperalgesia of dry tongue, a rat model of dry tongue was used to study the nocifensive reflex and pp38 and TRPV4 expression in TG neurons. The head-withdrawal reflex threshold for mechanical stimulation of the tongue was significantly lower in dry-tongue rats than in sham rats. The numbers of TRPV4-and pp38immunoreactive cells in the TG were significantly higher in dry-tongue rats than in sham rats. Many TRPV4-IR cells were also pp38-immunoreactive. The number of TRPV1-IR cells was unchanged in the TG after induction of tongue dryness. Local injection of a TRPV4 blocker attenuated tongue mechanical hypersensitivity in dry-tongue rats. Intraganglionic injection of a selective p38 MAP kinase inhibitor eliminated tongue hypersensitivity in dry-tongue rats and suppressed TRPV4 expression in TG neurons. The present findings suggest that TRPV4 activation via p38 phosphorylation in TG neurons is involved in mechanical hypersensitivity associated with dry tongue. These mechanisms may have a role in pain associated with xerostomia. Dry-tongue rat modelRats were anesthetized in a plastic chamber with 2% isoflurane (Mylan, Canonsburg, PA, USA) in normal room air. The tongue was gently extended out of the mouth and left exposed to room air for 2 h daily for 7 days (dry-tongue rats). Sham rats were anesthetized in the same manner, but dry tongue was not induced.

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Section: Discussionsupporting

confidence: 53%

Involvement of TRPV4 ionotropic channel in tongue mechanical hypersensitivity in dry-tongue rats

et al. 2020

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“…It has been identified that an ERK1/2 inhibitor decreased the expression of Piezo1 in neonatal rat ventricular myocytes, whereas this effect was not observed when p38 and JNK inhibitors were applied (21). Additionally, the p38 inhibitor SB203580 enhanced the expression of TrPV4 in the dorsal root ganglion (22). collectively, these observations suggest that MaPKs may participate in signal transduction pathways downstream of MScs under conditions of mechanical loading.…”

Section: The Roles Of Mechanosensitive Ion Channels and Associated Domentioning

confidence: 65%

The roles of mechanosensitive ion channels and associated downstream MAPK signaling pathways in PDLC mechanotransduction

et al. 2020

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The present study aimed to investigate whether the cytoskeleton, the Piezo1 ion channel and the transient receptor potential cation channel subfamily V member 4 (TrPV4) ion channel are equally functional in the mechanotransduction of periodontal ligament cells (Pdlcs) and to reveal the interplay of these mechanically sensitive ion channels (MScs). Human Pdlcs (hPdlcs) were pretreated with cytochalasin d (the inhibitor of actin polymerization), GsMTx4 (the antagonist of Piezo1) and GSK205 (the antagonist of TrPV4), and then subjected to periodic mechanical loading. The expression levels of macrophage colony stimulating factor (M-cSF), receptor activator of nF-κB ligand (ranKl) and cyclooxygenase-2 (coX2) in hPdlcs were detected via western blotting. osteoblast mineralization induction capacity of the hPdlcs was also studied and the mitogen-activated protein kinase (MAPK) expression profile was determined via protein microarray. The expression of Piezo1 and TRPV4 in the PDLCs was significantly increased at 8 h after loading. These differences in expression were accompanied by increased expression of M-cSF, ranKl and coX2. compared with the control group, key Pdlc biomarkers were suppressed after mechanical loading following treatment with the inhibitors of Piezo1 (GsMTx4) and TrPV4 (GSK205). The phosphorylated-MAPK protein array showed differential biomarker profiles among all groups. The present study suggested that both MScs and the cytoskeleton participated as mechanical sensors, and did so independently in hPdlc mechanotransduction. Furthermore, the Piezo1 ion channel may transmit mechanical signals via the erK signaling pathway; however, the TrPV4 channel may function via alternative signaling pathways.

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“…Changes in the level of nitrite are positively associated with the changes in thermal hyperalgesia. Identified signaling pathways involved in the CCD neuropathic pain model include NF-kappa-B, which mediates the TRPV4-NO pathway [288] and the p38 pathway [289].…”

Section: Trpv4 In Transduction Of Mechanically-evokedmentioning

confidence: 99%

Regulation of Pain and Itch by TRP Channels

et al. 2017

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Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and finally members of the melastatin group (TRPM2, TRPM3, and TRPM8). Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory compounds targeting specific pain/itch-TRPs so that physiological protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1-modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accomplished via simple dosing strategies, and also by incorporating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.

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Effect of TRPV4-p38 MAPK Pathway on Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion

Cited by 43 publications

References 37 publications

Involvement of TRPV4 ionotropic channel in tongue mechanical hypersensitivity in dry-tongue rats

Involvement of TRPV4 ionotropic channel in tongue mechanical hypersensitivity in dry-tongue rats

The roles of mechanosensitive ion channels and associated downstream MAPK signaling pathways in PDLC mechanotransduction

Regulation of Pain and Itch by TRP Channels

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