ONO-8130, a selective prostanoid EP1 receptor antagonist, relieves bladder pain in mice with cyclophosphamide-induced cystitis

Miki, Takahiro; Matsunami, Masatoshi; Nakamura, Shin; Okada, Hiroki; Matsuya, Hidekazu; Kawabata, Atsufumi

doi:10.1016/j.pain.2011.02.019

Cited by 51 publications

(55 citation statements)

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“…There is a report that intravenous administration of EP1 antagonist relieved bladder pain in cystitis model rats. 7 However, there have been few studies that investigated the pathophysiological role of PGE2 in patients with IC/BPS. To our knowledge, no single study has ever investigated the involvement of PGE2 and EP receptors in different subtypes of IC/BPS.…”

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confidence: 99%

“…11,12 Systemic administration of EP1 antagonist attenuates esophageal hyperalgesia in human and bladder pain in cystitis model mice. 7,13 Regarding EP1 receptor and bladder function, it is suggested that intravesical PGE2 promotes micturition reflex by stimulating C-fiber afferent nerves via EP1 receptor. 14,15 These previous studies and the present study indicate that the action of PGE2 via EP1 receptor has an important role in the development of bladder pain and urinary frequency in ulcer-type IC/BPS.…”

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Evaluation of Prostaglandin E2 and E-Series Prostaglandin Receptor in Patients with Interstitial Cystitis

et al. 2015

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Runninghead: Involvement of prostaglandin E2 in interstitial cystitisKey words: bladder pain syndrome, interstitial cystitis, prostaglandin E2 ABSTRACT (250 words)Purpose: To examine the precise role of prostaglandin E2 (PGE2) and E-series prostaglandin (EP) receptor in the pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS). Materials and Methods:Twenty female patients with IC/BPS (11 ulcer-type and 9 non ulcer-type), 9 female controls with other urological diseases who needed cystoscopic procedure, and 10 normal female volunteers were enrolled. O'Leary-Sant Score (OSS) for symptoms and problems and voluntary urine for PGE2 analysis were obtained from all objectives. Under anesthesia, the bladder was distended by saline in a stepwise fashion (from 100 ml to maximum capacity) in patients with IC/BPS, and the infused saline was retrieved each time for PGE2 analysis. We also measured PGE2 and expression of EP receptors mRNA in bladder biopsy tissue in patients with IC/BPS.Results: Symptoms and problems index in patients with ulcer-type was significantly higher than those with non ulcer-type. Urinary PGE2 in patients with ulcer-type was significantly higher than those with non ulcer-type and normal volunteers. PGE2 level in retrieved saline in patients with ulcer-type increased depending on infusion volume, but not in those with non ulcer-type. PGE2 content in bladder biopsy tissue was significantly higher in patients with ulcer-type than controls. In patients with ulcer-type, expression of EP1 and EP2 mRNA was significantly higher than controls. Conclusions:Overproduction of PGE2 in the bladder seems to play a pathophysiological role in patients with ulcer-type IC/BPS via EP1 and EP2 receptors. Localized blockade of the action of PGE2 may lead to relieving symptoms in patients with ulcer-type IC/BPS. TEXTInterstitial cystitis/bladder pain syndrome (IC/BPS), non-specific inflammatory disease of the bladder, presents with a constellation of symptoms including urinary frequency, urgency and bladder pain. IC/BPS has 2 distinct subtypes based on cystoscopic evaluation. One is ulcer-type and another is non ulcer-type. In patients with IC/BPS and controls, samples were taken by cystoscopic procedure under general or spinal anesthesia. In patients with IC/BPS, the bladder was distended in a stepwise fashion with a drip infusion of saline. Saline bottles were placed at 80cm height from the symphysis pubis. First, cystoscope was inserted and the bladder was emptied. Then 100ml of saline was infused into the bladder as first step and maintained for 5 minutes. All of the infused saline was retrieved and sampled. Next, 200ml of saline was infused, maintained for 5 minutes, retrieved and sampled as second step. Third step and final step were similarly performed after 300ml saline infusion and maximum bladder capacity. Maximum bladder capacity was defined as bladder capacity at the time when saline infusion stopped after reaching 80cmH2O. In control patients, infused saline only at first step (100ml infusi...

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Evaluation of Prostaglandin E2 and E-Series Prostaglandin Receptor in Patients with Interstitial Cystitis

et al. 2015

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“…53,54) We have shown that ONO-8130, a selective EP 1 receptor antagonist, reverses bladder pain-like behavior and referred hyperalgesia in mice with cyclophosphamide-induced cystitis, and prevents prompt phosphorylation of ERK in the spinal dorsal horn following intravesical administration of PGE 2 . 55) There is also evidence for involvement of peripheral EP 3 receptors in the regulation of bladder micturition and bladder nociception. 56) Thus, selective antagonists of EP 1 receptors and, perhaps, EP 3 receptors may be useful for treatment of visceral pain including esophageal and/or bladder pain.…”

Section: Application Of Pge 2 Receptor Antago-nists To Treatment Of Vmentioning

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Prostaglandin E2 and Pain-An Update

Kawabata

2011

Biological & Pharmaceutical Bulletin

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Prostaglandin E 2 (PGE 2 ), a cyclooxygenase (COX) product, is the best known lipid mediator that contributes to inflammatory pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), inhibitors of COX-1 and/or COX-2, suppress inflammatory pain by reducing generation of prostanoids, mainly PGE 2 , while they exhibit gastrointestinal, renal and cardiovascular toxicities. Selective inhibitors of microsomal PGE synthase-1 and subtypeselective antagonists of PGE 2 receptors, particularly EP 1 and EP 4 , may be useful as analgesics with minimized side-effects. Protein kinase C (PKC) and PKA downstream of EP 1 and EP 4 , respectively, sensitize/activate multiple molecules including transient receptor potential vanilloid-1 (TRPV1) channels, purinergic P2X3 receptors, and voltage-gated calcium or sodium channels in nociceptors, leading to hyperalgesia. PGE 2 is also implicated in neuropathic and visceral pain and in migraine. Thus, PGE 2 has a great impact on pain signals, and pharmacological intervention in upstream and downstream signals of PGE 2 may serve as novel therapeutic strategies for the treatment of intractable pain.

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“…Thus pain hypersensitivity is attenuated in EP1-deficient mice (25) and after systemic or intrathecal administration of EP1 receptor antagonists (16,19). In the rodent viscera, EP1 receptor antagonists inhibit bladder afferent nerve activity during bladder inflammation and attenuate cystitis-related bladder pain (10,14). Furthermore, there is preclinical evidence that prior systemic treatment with an EP1 receptor antagonist attenuates acid-induced primary and secondary esophageal hyperalgesia in humans (24).…”

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Prostaglandin E₂ mediates acid-induced heartburn in healthy volunteers

Kondo

Oshima

Tomita

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Prostaglandin E(2) (PGE(2)) plays a major role in pain processing and hypersensitivity. This study investigated whether PGE(2) levels are increased in the esophageal mucosa after acid infusion and whether increases in PGE(2) are associated with heartburn. Furthermore, expression of the PGE(2) receptor EP1 was investigated in human esophageal mucosa. Fourteen healthy male volunteers were randomized to 30-min lower esophageal acid (1% HCl) or saline perfusion. Before and after acid perfusion, endoscopic biopsies were taken from the distal esophagus. PGE(2) concentration (pg/mg protein) and EP1 mRNA and protein in biopsy samples were measured by ELISA, RT-PCR, and Western blotting. Symptom status of heartburn was evaluated with a validated categorical rating scale with a higher values corresponding to increasing intensity. PGE(2) levels in the esophageal mucosa significantly increased after acid infusion (before vs. after acid infusion: 23.2 ± 8.6 vs. 68.6 ± 18.3, P < 0.05), but not after saline infusion (before vs. after saline infusion: 9.3 ± 2.5 vs. 9.0 ± 3.2, NS). Time to first sensation (min) after acid infusion was less than after saline (saline vs. acid infusion: 22.1 ± 4.1 vs. 5.4 ± 1.5, P < 0.05). Intensity of heartburn in the acid-infusion group was also significantly greater compared with saline (saline vs. acid infusion: 54.3 ± 13.1 vs. 178.5 ± 22.8, P < 0.01). Changes in PGE(2) levels in the esophagus correlated with symptom intensity score (r = 0.80, P = 0.029). EP1 mRNA and protein expression were observed in the normal human esophageal mucosa. Esophageal PGE(2) expression is associated with mucosal acid exposure and heartburn.

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ONO-8130, a selective prostanoid EP1 receptor antagonist, relieves bladder pain in mice with cyclophosphamide-induced cystitis

Cited by 51 publications

References 37 publications

Evaluation of Prostaglandin E2 and E-Series Prostaglandin Receptor in Patients with Interstitial Cystitis

Evaluation of Prostaglandin E2 and E-Series Prostaglandin Receptor in Patients with Interstitial Cystitis

Prostaglandin E2 and Pain-An Update

Prostaglandin E₂ mediates acid-induced heartburn in healthy volunteers

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ONO-8130, a selective prostanoid EP1 receptor antagonist, relieves bladder pain in mice with cyclophosphamide-induced cystitis

Cited by 51 publications

References 37 publications

Evaluation of Prostaglandin E2 and E-Series Prostaglandin Receptor in Patients with Interstitial Cystitis

Evaluation of Prostaglandin E2 and E-Series Prostaglandin Receptor in Patients with Interstitial Cystitis

Prostaglandin E2 and Pain-An Update

Prostaglandin E2 mediates acid-induced heartburn in healthy volunteers

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Product

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Prostaglandin E₂ mediates acid-induced heartburn in healthy volunteers