Estrous cycle variation of TRPV1-mediated cross-organ sensitization between uterus and NMDA-dependent pelvic-urethra reflex activity

Peng, Hsien Yu; Huang, Po-Chiun; Liao, Jiuan Miaw; Tung, Kwong‐Chung; Lee, Shin-Da; Cheng, Chen Li; Shyu, Jyh Cherng; Lai, Chih-Sheng; Chen, Gin Den; Lin, Tzer Bin

doi:10.1152/ajpendo.90289.2008

Cited by 40 publications

(26 citation statements)

References 81 publications

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“…Stimulation of TRPV1 in rat C fibres is dependent on the oestrous cycle favouring oestradiol (Peng et al 2008), and oestradiol may contribute to pain through TRPV1 regulation in the hippocampus (Wu et al 2010). It exerts classical (slow, genomic) effects on Trpv transcription (Hoenderop et al 2005) and can also directly or indirectly stimulate the TRPV1 receptor (Kumar et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium

Pohóczky

Kun

Szalontai

et al. 2015

Journal of Molecular Endocrinology

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Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly in sensory nerves are activated by inflammatory stimuli and mediate inflammation and pain. Although they have been shown in the human endometrium, their regulation and function are unknown. Therefore, we investigated their estrogen-and progesterone-dependent alterations in the rat endometrium in comparison with the estrogenregulated inflammatory cytokine macrophage migration inhibitory factor (MIF). Four-week-old (sexually immature) and four-month-old (sexually mature) female rats were treated with the non-selective estrogen receptor (ER) agonist diethylstilboestrol (DES), progesterone and their combination, or ovariectomized. RT-PCR and immunohistochemistry were performed to determine mRNA and protein expression levels respectively. Channel function was investigated with ratiometric [Ca 2C ] i measurement in cultured primary rat endometrial cells. Both TRP receptors and MIF were detected in the endometrium at mRNA and protein levels, and their localizations were similar. Immunostaining was observed in the immature epithelium, while stromal, glandular and epithelial positivity were observed in adults. Functionally active TRP receptor proteins were shown in endometrial cells by activation-induced calcium influx. In adults, Trpa1 and Trpv1 mRNA levels were significantly up-regulated after DES treatment. TRPA1 increased after every treatment, but TRPV1 remained unchanged following the combined treatment and ovariectomy. In immature rats, DES treatment resulted in increased mRNA expression of both channels and elevated TRPV1 immunopositivity. MIF expression changed in parallel with TRPA1/TRPV1 in most cases. DES up-regulated Trpa1, Trpv1 and Mif mRNA levels in endometrial cell cultures, but 17b-oestradiol having ERa-selective potency increased only the expression of Trpv1. We provide the first evidence for TRPA1/TRPV1 expression and their estrogen-induced up-regulation in the rat endometrium in correlation with the MIF. Journal of Molecular EndocrinologyResearch K POHÓ CZKY and others TRPV1 and TRPA1 in the rat endometrium 56:2 135-149

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Section: Discussionmentioning

confidence: 99%

Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium

Pohóczky

Kun

Szalontai

et al. 2015

Journal of Molecular Endocrinology

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“…At the lumbosacral spinal cord, our laboratory has recently demonstrated a novel form of pain-related central sensitization, cross-organ sensitization, in which instillation of mustard oil (MO) into the descending colon could sensitize the reflex activity of the urethra (21,22). Pharmacological investigations indicated spinal NR2B subunit phosphorylation is crucial in the induction of cross-organ sensitization (19,20,23).…”

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confidence: 99%

Endogenous ephrinB2 mediates colon-urethra cross-organ sensitization via Src kinase-dependent tyrosine phosphorylation of NR2B

Peng

Chen²,

Lai

et al. 2010

American Journal of Physiology-Renal Physiology

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Endogenous ephrinB2 mediates colon-urethra cross-organ sensitization via Src kinase-dependent tyrosine phosphorylation of NR2B. Am J Physiol Renal Physiol 298: F109 -F117, 2010. First published October 28, 2009 doi:10.1152/ajprenal.00287.2009.-Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in spinal pain-related neural plasticity has been identified. To test whether Src-family non-receptor tyrosine kinase-dependent glutamatergic Nmethyl-D-aspartate receptor (NMDAR) NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate crossorgan sensitization between the colon and the urethra, external urethra sphincter electromyogram activity evoked by pelvic nerve stimulation and protein expression in the lumbosacral (L6 -S2) dorsal horn were studied before and after intracolonic mustard oil (MO) instillation. We found MO instillation produced colon-urethra reflex sensitization along with an upregulation of endogenous ephrinB2 expression as well as phosphorylation of EphB1/2, Src-family kinase, and NR2B tyrosine residues. Intrathecal immunoglobulin fusion protein of EphB1 and EphB2 as well as PP2 reversed the reflex sensitization and NR2B phosphorylation caused by MO. All these results suggest that EphBR-ephrinB interactions, which provoke Src-family kinase-dependent NMDAR NR2B phosphorylation at the lumbosacral spinal cord level, are involved in cross-organ sensitization, contributing to the development of viscero-visceral referred pain between the bowel and the urethra. pelvic pain syndrome; urethra; irritable bowel syndrome; colon; NMDA ALTHOUGH THE ETIOLOGY IS NOT fully understood, patients with irritable bowel syndrome (IBS) have a higher prevalence of lower urinary tract dysfunction with pelvic pain compared with control groups (15). In addition, pelvic visceral pain might not only arise from an inflamed/injured organ itself but might also be referred from other diseased viscera, and thus results in viscero-visceral referred pain (6). Despite the fact that bowelto-urethra cross-organ sensitization has been demonstrated previously (25), little information is available to explain the underlying mechanism because it could involve complicated interactions in afferent inputs arising from different viscera, known as central sensitization (33).It is established that spinal glutamatergic N-methyl-D-aspartate receptor (NMDAR)-dependent neurotransmission underlies pain-related central sensitization (10, 11). The NMDAR NR2B subunit, as a major unit controlling NMDAR activity via phosphorylation mechanisms, was found to play a pivot role in the NMDA-dependent form of neural plasticity at the spinal cord level (10,11,17,19,20). Chronic inflammatory pain caused by Freund's adjuvant injections was shown to be associated with increases in spinal NR2B subunit phosphorylation (10). Moreover, Slack and colleagues (28) revealed that intrathecal administration of Src-family kinase inhibitors prevented hyperalgesia-related NR2B subunit phosphorylation in the spinal dorsa...

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“…At the lumbosacral spinal cord, our laboratory has recently demonstrated a novel form of neural plasticity, the spinal reflex potentiation (SRP) (48 -50, 72), in which the reflex activity of the urethra could be sensitized by the activation of capsaicinsensitive (75), mustard oil-sensitive (73), and transient receptor potential vanilloid subfamily member 1 (TRPV1)-sensitive (74) afferent fibers. Pharmacological investigations on SRP have demonstrated that, similar to other forms of neural plasticity, glutamatergic NMDA-dependent (11-14, 46, 47) ERK activation that subsequently phosphorylates the NMDA NR2B subunit (70 -73), a subunit that is presumed to be essential for Ca 2ϩ gating, to define the role of the NMDA receptor for dynamic synaptic plasticity (52,69), underlies the induction of SRP.…”

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confidence: 99%

Estrogen-dependent facilitation on spinal reflex potentiation involves the Cdk5/ERK1/2/NR2B cascade in anesthetized rats

Peng

Chen

Tung

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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TB. Estrogen-dependent facilitation on spinal reflex potentiation involves the Cdk5/ERK1/2/NR2B cascade in anesthetized rats. Am J Physiol Endocrinol Metab 297: E416 -E426, 2009. First published June 16, 2009 doi:10.1152/ajpendo.00129.2009.-Cyclin-dependent kinase-5 (Cdk5), a proline-directed serine/threonine kinase, may alter pain-related neuronal plasticity by regulating extracellular signal-related kinase-1/2 (ERK1/2) activation. This study investigated whether Cdk5-dependent ERK activation underlies the estrogen-elicited facilitation on the repetitive stimulation-induced spinal reflex potentiaton (SRP) that is presumed to be involved in postinflammatory/neuropathic hyperalgesia and allodynia. Reflex activity of the external urethra sphincter electromyogram evoked by pelvic afferent nerve test stimulation (TS; 1 stimulation/30 s for 10 min) and repetitive stimulation (RS; 1 stimulation/1 s for 10 min) was recorded in anesthetized rats. TS evoked a baseline reflex activity, whereas RS produced SRP. Intrathecal (it) ␤-estradiol facilitated the repetitive stimulation-induced SRP that was reversed by pretreatment with the estrogen receptor anatogonist ICI 182,780 (10 nM, 10 l it), Cdk5 inhibitor roscovitine (100 nM, 10 l it), ERK inhibitor (U-0126; 100 M, 10 l it) and N-methyl-D-aspartate (NMDA) NR2B subunit antagonist (Co-101244; 100 nM, 10 l it). Moreover, ER␣ (propylpyrazoletriol; 100 nM, 10 l it) and ER␤ (diarylpropionitrile; 100 M, 10 l it) agonists both facilitated the SRP, similar to results with a ␤-estradiol injection. In association with the facilitated RS-induced SRP, an intrathecal ␤-estradiol injection elicited ERK1/2 and NR2B subunit phosphorylation that were both reversed by intrathecal roscovitine and U-0126. These results indicated that the Cdk/ERK cascade, which is activated by ER␣ and ER␤, may subsequently phosphorylate the NR2B subunit to develop NMDA-dependent postinflammatory hyperalgesia and allodynia to maintain the protective mechanisms of the body. estradiol; cyclin-dependent kinase-5; NR2B; extracellular signal-related kinase; pelvic pain; spinal reflex potentiaton; hyperalgesia PAIN IS A PROTECTIVE MECHANISM required for the survival and the maintenance of the integrity of organism. However, sustained or chronic pain can result in secondary symptoms, such as anxiety and depression, that reduce life quality (30). Convincing evidence demonstrates that postinflammatory hyperalgesia and tactile allodynia are associated with the development of activity-dependent hyperexcitability in the spinal cord (19,91,92), a process that shares common characteristics with glutamatergic N-methyl-D-aspartate (NMDA)-dependent neural plasticity in other brain areas (2, 27, 53, 76). Although specific molecules regulating nociception have been intensively investigated, the underlying molecular mechanisms remain undefined. So far, studies using genetic modification, antisense knockdown, and gene expression assays have identified several genes, whose expression levels are affected during pain sensation and/or ...

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Estrous cycle variation of TRPV1-mediated cross-organ sensitization between uterus and NMDA-dependent pelvic-urethra reflex activity

Cited by 40 publications

References 81 publications

Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium

Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium

Endogenous ephrinB2 mediates colon-urethra cross-organ sensitization via Src kinase-dependent tyrosine phosphorylation of NR2B

Estrogen-dependent facilitation on spinal reflex potentiation involves the Cdk5/ERK1/2/NR2B cascade in anesthetized rats

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