Blocking PAR2 alleviates bladder pain and hyperactivity via TRPA1 signal

Chen, Daihui; Liu, Nian; Li, Mao; Liang, Simin

doi:10.1515/tnsci-2016-0020

Cited by 8 publications

(6 citation statements)

References 26 publications

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“…This suggests that peripheral inflammation leads to the endogenous activation of spinal PAR2 receptors that contribute to the spinal mechanisms, leading to increased sensitivity. The involvement of spinal PAR2 activation was demonstrated before in other pathological pain conditions like bone cancer, oxaliplatininduced neuropathic pain, bladder pain and chronic arthritis [57][58][59][60][61]. We suggest that carrageenan-induced peripheral inflammation triggers an increased activity in primary afferent fibers ending in the dorsal horn and modulates nociceptive signaling among others via the activation of spinal presynaptic PAR2.…”

Section: Activation Of Spinal Par2 After Peripheral Inflammationsupporting

confidence: 55%

Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats

Mrózková

Spicarova

Paleček

2021

IJMS

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The mechanisms of inflammatory pain need to be identified in order to find new superior treatments. Protease-activated receptors 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) are highly co-expressed in dorsal root ganglion neurons and implicated in pain development. Here, we examined the role of spinal PAR2 in hyperalgesia and the modulation of synaptic transmission in carrageenan-induced peripheral inflammation, using intrathecal (i.t.) treatment in the behavioral experiments and recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs and eEPSCs) in spinal cord slices. Intrathecal PAR2-activating peptide (AP) administration aggravated the carrageenan-induced thermal hyperalgesia, and this was prevented by a TRPV1 antagonist (SB 366791) and staurosporine i.t. pretreatment. Additionally, the frequency of the mEPSC and sEPSC and the amplitude of the eEPSC recorded from the superficial dorsal horn neurons were enhanced after acute PAR2 AP application, while prevented with SB 366791 or staurosporine pretreatment. PAR2 antagonist application reduced the thermal hyperalgesia and decreased the frequency of mEPSC and sEPSC and the amplitude of eEPSC. Our findings highlight the contribution of spinal PAR2 activation to carrageenan-induced hyperalgesia and the importance of dorsal horn PAR2 and TRPV1 receptor interactions in the modulation of nociceptive synaptic transmission.

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Section: Activation Of Spinal Par2 After Peripheral Inflammationsupporting

confidence: 55%

Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats

Mrózková

Spicarova

Paleček

2021

IJMS

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“…Additionally, in the rat model, PAR2 expression is enhanced. The blockade of PAR2 reduces the TRPA1 signaling pathway and attenuates OAB symptoms (149). Similarly, another compound produced in inflammatory states, nitro-oleic acid (OA-NO 2 ), enhances the contractile activity of rat bladder strips by TRPA1 activation in afferent nerves (45).…”

Section: H Trpa1 In the Urogenital Systemmentioning

confidence: 99%

Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

Talavera

Startek

Alvarez‐Collazo

et al. 2020

Physiological Reviews

288

274

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The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.

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“…It has also been shown to localize to the urothelial and interstitial cells of the urethra, and that TRPA1 agonists can modify the tone of human urethral preparations, suggesting a role in signaling in the human urinary outflow region (19). In a rat model of IC, inhibition of the TRPA1 decreased bladder hyperactivity and pain (20). It has also been shown to be differentially expressed in bladder tissue of those with IC (21).…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammatory gene expression analysis reveals potential novel mediators and treatment targets in interstitial cystitis with Hunner lesions

Werneburg¹,

Keslar²,

Gotwald³

et al. 2021

Transl Androl Urol

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Background: We sought to study differential neuroinflammatory gene expression in men with interstitial cystitis (IC) with Hunner lesions compared with asymptomatic controls using NanoString, which uses barcoded probes to measure hundreds of genes. IC is a heterogenous condition lacking reliable biomarkers, and a subset of patients exhibits Hunner lesions, implicating the bladder as an inflammatory pain generator.Methods: Blood, urine, and bladder biopsies were collected from 6 men with IC and Hunner lesions. 7 asymptomatic controls had blood and urine collected and 2 benign bladder biopsies were obtained from our tissue bank. RNA was isolated and analyzed with NanoString Human Neuroinflammation panel. Gene expression was considered significant if there was a >1.5-fold change and adjusted P value <0.05 compared with controls.Results: Mean patient age was 61.5 years with 8 years median symptom duration. In bladder tissue, while many cytokine and chemokine genes had higher expression as expected (e.g., TNF , CXCL10), other significant genes included TRPA1 (1098-fold increased, expressed in pain sensing neurons) and TNFRSF17 (735-fold, B-cell related). In urine, there was 114-fold increase in S1PR4, which mediates pain via TRPdependent pathways. A patient on cyclosporine had lower inflammatory gene expression levels relative to other IC patients, but no difference in TRPA1.Conclusions: Men with IC and Hunner lesions have a diverse set of neuroinflammatory genes with differential expression compared to controls. We identified genes linked to neuropathic pain through the TRP pathway and this expression was not reduced by cyclosporine. These findings open a new direction for biomarker and therapeutic discovery.

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Blocking PAR2 alleviates bladder pain and hyperactivity via TRPA1 signal

Cited by 8 publications

References 26 publications

Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats

Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats

Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

Neuroinflammatory gene expression analysis reveals potential novel mediators and treatment targets in interstitial cystitis with Hunner lesions

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