Characterization of EP‐receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E<sub>2</sub> to mice

Minami, Toshiaki; Nishihara, Isao; Uda, Rumiko; Ito, Seiji; Hyodo, Masayoshi; Hayaishi, Osamu

doi:10.1111/j.1476-5381.1994.tb13139.x

Cited by 101 publications

(62 citation statements)

References 23 publications

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“…EP 1 is coupled to intracellular Ca 2ϩ mobilization, EP 2 and EP 4 are coupled to stimulation of adenylate cyclase via G s protein, and EP 3 is coupled to inhibition of adenylate cyclase via G i protein. Studies performed either in mutant mice lacking the individual PG receptors (Murata et al, 1997;Minami et al, 2001;Stock et al, 2001) or with synthetic EP receptor agonist/antagonist (Minami et al, 1994;Nakayama et al, 2002) have not yet provided a coherent picture of which EP receptors are responsible for inflammatory pain. Recently it has been reported that EP 4 knockdown with intrathecally delivered short hairpin RNA attenuates inflammation-induced thermal and mechanical behavioral hypersensitivity (Lin et al, 2006), suggesting that EP 4 is a potential target for the pharmacological treatment of inflammatory pain.…”

mentioning

confidence: 99%

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP₄Receptor Antagonist with Antihyperalgesic Properties

Nakao¹,

Murase²,

Ohshiro³

et al. 2007

J Pharmacol Exp Ther

106

109

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The prostaglandin (PG) EP 4 receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP 4 receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP 4 or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP 4 receptor antagonist, N- [({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors are mainstays of the pharmacopoeia for the treatment of signs and symptoms of osteoarthritis and inflammatory pain of various etiologies. Their mechanism of action is to decrease prostaglandin (PG) synthesis by inhibiting COX activities. Two isoforms of COX, COX-1 and COX-2, have been identified. COX-1 is constitutively expressed throughout the body, and it is thought to play an essential role in normal gastrointestinal and renal function, whereas COX-2 is induced in the presence of inflammation. NSAIDs inhibit both isoforms and inhibition of COX-1 is thought to cause the adverse gastrointestinal effects such as gastric erosion, ulceration, and hemorrhage, whereas inhibition of COX-2 is associated with the therapeutic effects of NSAIDs. Thus, inhibition of PG synthesis by NSAIDs has demonstrated clear efficacy in the reduction of K.N. and A.M. contributed equally to this work. Article, publication date, and citation information can be found at

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mentioning

confidence: 99%

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP₄Receptor Antagonist with Antihyperalgesic Properties

Nakao¹,

Murase²,

Ohshiro³

et al. 2007

J Pharmacol Exp Ther

106

109

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“…EP2 and EP4 are coupled to G s , some splice variants of EP3 are coupled to G s , and some are coupled to G i , whereas EP1 is coupled to G q /G11. Studies performed either in mutant mice lacking the individual PG receptors (Murata et al, 1997;Minami et al, 2001;Stock et al, 2001) or with EP receptorspecific ligands (Minami et al, 1994) have not yet provided a coherent picture of which EP receptor(s) are responsible for inflammatory pain. This is partly due to the fact that PGE 2 facilitates nociception at multiple levels in the neuraxis and that multiple receptors are involved.…”

mentioning

confidence: 99%

Prostaglandin E₂ Receptor EP4 Contributes to Inflammatory Pain Hypersensitivity

Lin

Amaya

Barrett

et al. 2006

J Pharmacol Exp Ther

231

179

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Prostaglandin E 2 (PGE 2 ) is both an inflammatory mediator released at the site of tissue inflammation and a neuromodulator that alters neuronal excitability and synaptic processing. The effects of PGE 2 are mediated by four G-protein-coupled EP receptors (EP1-EP4). Here we show that the EP4 receptor subtype is expressed by a subset of primary sensory dorsal root ganglion (DRG) neurons, and that its levels, but not that of the other EP1-3 subtypes, increase in the DRG after complete Freund' adjuvant-induced peripheral inflammation. Administration of both an EP4 antagonist [AH23848, (4Z)-7-[(rel-1S,2S,5R)-5-((1,1Ј-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid] and EP4 knockdown with intrathecally delivered short hairpin RNA attenuates inflammation-induced thermal and mechanical behavioral hypersensitivity, without changing basal pain sensitivity. AH23848 also reduces the PGE 2 -mediated sensitization of capsaicin-evoked currents in DRG neurons in vitro. These data suggest that EP4 is a potential target for the pharmacological treatment of inflammatory pain.

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“…The synergistic action of N/OFQ and NST is really surprising; because studies reported on their opposite effects in several biological functions [3][4][5][6][7][8]22,23]. However these studies were carried out in the Central Nervous System (CNS) and gave no information about the peripheral interaction of these two neuropeptides.…”

Section: Amentioning

confidence: 98%

“…NST was thought to be a functional antagonist of N/OFQ on the basis of their effects in the central nervous system [3][4][5][6][7][8]. Although N/OFQ has no affinity to opiate receptors; interaction was reported between the N/OFQ and dynorphin in neuropathic pain [9].…”

Section: Introductionmentioning

confidence: 99%

Uterus-Relaxing Effects of Nociceptin and Nocistatin: Studies on Preterm and Term-Pregnant Human Myometrium In vitro

BH¹

2013

Reprod Sys Sexual Disorders

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The endogenous neuropeptides nociceptin/orphanin FQ and nocistatin translated from the prepronociceptin gene exert a relaxant effect on the rat uterus. Previous studies have reported their role in pain transmission in the central nervous system both in rodents and in humans, but to date only limited information is available on their effects in the periphery, and there are no data on their presence in the human uterus.The expression of prepronociceptin mRNA in the human uterus was confirmed by an RT-PCR technique. In vitro contractility studies of the action of nociceptin and nocistatin on human uterine tissues were performed in an isolated organ system. Human myometrial strips from cesarean sections at full-term pregnancy and at preterm labor were stimulated with oxytocin, and the relaxant effects of nociceptin and nocistatin were studied.The level of prepronociceptin mRNA was significantly decreased in full-term pregnant uterus samples as compared with preterm pregnancy samples. Nociceptin and nocistatin significantly and dose-dependently inhibited the oxytocinevoked contractions in the human uterus. In the presence of nocistatin, the uterus-relaxant effect of nociceptin was enhanced. In contrast, nociceptin did not alter the uterus-relaxant effect of nocistatin.We conclude that locally generated nociceptin and nocistatin both exert a relaxant effect on the human uterus, and nocistatin can potentiate the relaxant effect of nociceptin, though for this to occur nocistatin administration must precede the administration of nociceptin.

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Characterization of EP‐receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E₂ to mice

Cited by 101 publications

References 23 publications

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP₄Receptor Antagonist with Antihyperalgesic Properties

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP₄Receptor Antagonist with Antihyperalgesic Properties

Prostaglandin E₂ Receptor EP4 Contributes to Inflammatory Pain Hypersensitivity

Uterus-Relaxing Effects of Nociceptin and Nocistatin: Studies on Preterm and Term-Pregnant Human Myometrium In vitro

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Characterization of EP‐receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E2 to mice

Cited by 101 publications

References 23 publications

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP4Receptor Antagonist with Antihyperalgesic Properties

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP4Receptor Antagonist with Antihyperalgesic Properties

Prostaglandin E2 Receptor EP4 Contributes to Inflammatory Pain Hypersensitivity

Uterus-Relaxing Effects of Nociceptin and Nocistatin: Studies on Preterm and Term-Pregnant Human Myometrium In vitro

Contact Info

Product

Resources

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Characterization of EP‐receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E₂ to mice

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP₄Receptor Antagonist with Antihyperalgesic Properties

CJ-023,423, a Novel, Potent and Selective Prostaglandin EP₄Receptor Antagonist with Antihyperalgesic Properties

Prostaglandin E₂ Receptor EP4 Contributes to Inflammatory Pain Hypersensitivity