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  • In conclusion the data suggest that doses of COX inhibitors

    2019-08-13

    In conclusion, the data suggest that doses of COX-2 inhibitors and EP1 receptor antagonists which have previously been reported to exert disease modulating or antiepileptic drug potentiating effects do not negatively affect seizure control in temporal lobe epilepsy. The contrasting impact of the EP1 receptor antagonist and agonist on seizure duration suggests that EP1 receptors can affect endogenous mechanisms involved in termination of seizure activity. As a matter of course, translational development of COX-2 inhibitor or EP1 antagonist add-on approaches will require further tolerability considerations taking gastrointestinal effects, renal effects, and the increased risk for cardio- and cerebrovascular events into account (Laufer, 2004).
    Acknowledgements We thank Marion Fisch and Carmen Meyer for technical assistance. The study was supported by a grant from the Deutsche ForschungsgemeinschaftPo 681/4-1 (Bonn, Germany).
    Introduction Prostaglandins contribute to the sensitization of peripheral and central nociceptive neurons during peripheral inflammation. Prostaglandin E2 (PGE2), in particular, is considered a dominant pronociceptive prostanoid. PGE2 receptors are classified into 4 general subtypes (EP1, EP2, EP3, and EP4) that are products of different genes and located unevenly in different tissues. All 4 subtypes of PGE2 receptors belong to a large superfamily of G protein-coupled receptors, but are coupled to distinct G proteins. Activation of EP1 receptors causes activation of phospholipase C via Gq/11 protein, resulting in Ca2+ mobilization and activation of protein kinase C. On the other hand, EP2 and EP4 receptors are coupled to Gs protein, and EP3 receptors are coupled mainly to Gi protein [40]. Among the 4 subtypes of PGE2 receptors, EP1 receptors appear to play a major role in processing of pain [40]. EP1-deficient mice exhibit reduced nociception in the acetic PF2341066 writhing test [32], and intrathecal administration of an EP1 receptor antagonist reduces carrageenan-induced hyperalgesia [26]. There is also clinical evidence that oral administration of an EP1 antagonist attenuates acid-induced esophageal hyperalgesia in humans [29]. In the urinary bladder, PGs are synthesized in the smooth muscle and urothelium [4], and elevation of PGE2 generation occurs in response to physiological stimuli such as distention of bladder [28], [39], and also during cystitis [15]. Increases in urinary PGE2 levels have been shown in patients with chronic cystitis [38]. EP1 receptors are expressed in not only the primary afferents [26], but also the urothelium [35]. An EP1 receptor antagonist, ONO-8711, inhibits bladder afferent nerve activity during bladder inflammation in rats [16], and an EP1 receptor agonist, ONO-DI-004, facilitates the micturition reflex in mice [35]. Hence, it is likely that the PGE2/EP1 pathway in the primary afferents contributes to processing of bladder pain. It is well known that systemic administration of cyclophosphamide produces cystitis in humans and also rodents. In the mice with cyclophosphamide-induced cystitis, bladder pain is characterized by an increased response to mechanical stimulation in the lower abdomen and bladder pain-like nociceptive behavior [20], [27]. It has been proposed that the cyclophosphamide-induced cystitis in rodents is useful as a model for interstitial cystitis [37]. In the present study, we thus examined effects of ONO-8130, a highly selective EP1 antagonist, on bladder pain in the mice with cyclophosphamide-induced cystitis. Further, we asked if intravesical administration of PGE2 causes phosphorylation of extracellular signal-regulated kinase (ERK) in the spinal cord, an indicator for activation of spinal nociceptive neurons, and examined possible involvement of EP1 in the evoked responses.
    Methods
    Results
    Discussion The present findings that oral preadministration of ONO-8130, a selective prostanoid EP1 receptor antagonist, prevented the cyclophosphamide-induced bladder pain, but had only slight or no effect on the increased bladder weight and vascular permeability, suggest that EP1 receptors play a major role in the development of cystitis-related pain, but not inflammation. Our data showing the reversal of the established bladder pain by ONO-8130 emphasize its therapeutic usefulness for treatment of bladder pain accompanying interstitial cystitis and/or other bladder diseases. Further, our results from immunohistochemical determination of spinal ERK phosphorylation provide direct evidence for the pronociceptive role of the PGE2/EP1 receptor system in the mouse bladder.