The 5-HT 4 receptor-mediated inhibition of visceral nociceptive neurons in the rat caudal ventrolateral medulla

Lyubashina, O. A.; Sivachenko, Ivan B.

doi:10.1016/j.neuroscience.2017.07.039

Cited by 16 publications

(6 citation statements)

References 90 publications

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“…20 Moreover, minesapride inhibits visceral hypersensitivity in rats. 20 Another 5-HT4 agonist tegaserod also inhibits visceral hypersensitivity in rats 30 and humans 31 via inhibition of nociceptive flexor reflex (RIII reflex). It is not surprising that minesapride acts as a visceral analgesic in humans.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of 5-HT4 Receptor Agonist Minesapride for Irritable Bowel Syndrome with Constipation in a Randomized Controlled Trial

Fukudo

Nakamura

Hamatani

et al. 2021

Clinical Gastroenterology and Hepatology

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BACKGROUND & AIMS:Treatment options for irritable bowel syndrome with constipation (IBS-C) are limited-new prokinetic drugs are needed. We evaluated the efficacy and safety of minesapride (DSP-6952), a partial agonist with high affinity for 5-HT4 receptors, in patients with IBS-C in Japan. METHODS:We performed a double-blind phase 2 study of 171 patients with Rome III-defined IBS-C at 33 centers in Japan, from December 2012 through August 2013. Patients were randomly assigned to groups given minesapride (1, 4, 12, or 40 mg) or placebo once daily for 4 weeks. The primary outcome was efficacy, defined as improvement in the weekly frequency of complete spontaneous bowel movements (CSBMs), abdominal symptoms, and IBS-C symptoms (according to the Japanese version of the IBS severity index score). For evaluation of safety, adverse events (AEs) were recorded. RESULTS:The least squares mean change from baseline in the weekly frequency of CSBMs was greater in all minesapride groups than in the placebo group at week 4 (40 mg vs placebo, P [ .040). The abdominal symptoms score improved in minesapride 40 mg group. The overall IBS severity index score decreased from baseline to week 4 in all treatment groups-especially in the 12 mg and 40 mg groups (P [ .048 and <.001 vs placebo, respectively). The proportions of patients with treatment-emergent AEs in the pooled minesapride and placebo groups were 55.0% and 60.0%, respectively. The most common treatment-emergent AE was diarrhea (in 42.9% and 37.1% of patients in the pooled minesapride and placebo groups, respectively). CONCLUSIONS:In a phase 2 trial of patients with IBS-C in Japan, minesapride increased stool frequency (measured by CSBMs), reduced abdominal and overall IBS-C symptoms, and was well tolerated. Japan Pharmaceutical Information Center trial no: JapicCTI-122041.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of 5-HT4 Receptor Agonist Minesapride for Irritable Bowel Syndrome with Constipation in a Randomized Controlled Trial

Fukudo

Nakamura

Hamatani

et al. 2021

Clinical Gastroenterology and Hepatology

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“…It has been found that tegaserod could reduce the rectal sensitivity to distension significantly in IBS patients [132] and the responses to nociceptive stimulation of intestine in animal models of visceral pain [133]. The analgesic effects of 5HT 4 receptor agonists may relate to their action at a supraspinal level [20,133]. Specifically, intravenous administration of 5-HT 4 receptor agonists produced dose-dependent suppression of the visceromotor response (an objective measure of visceral sensation) and the activity of caudal ventrolateral medullary (CVLM) neurons, which could be blocked by intracerebroventricular pretreatment with 5-HT 4 receptor antagonist [20], indicating the preferential involvement of supraspinal 5-HT 4 receptors.…”

Section: -Ht 3 Receptorsmentioning

confidence: 99%

“…The analgesic effects of 5HT 4 receptor agonists may relate to their action at a supraspinal level [20,133]. Specifically, intravenous administration of 5-HT 4 receptor agonists produced dose-dependent suppression of the visceromotor response (an objective measure of visceral sensation) and the activity of caudal ventrolateral medullary (CVLM) neurons, which could be blocked by intracerebroventricular pretreatment with 5-HT 4 receptor antagonist [20], indicating the preferential involvement of supraspinal 5-HT 4 receptors. Microinjection of tegaserod into the RVM, but not the spinal cord, attenuated the visceromotor response and reduced the spontaneous firing of lumbosacral neurons.…”

Section: -Ht 3 Receptorsmentioning

confidence: 99%

“…The descending pain system plays an important role in different pain conditions, and it is well recognized that descending control can be either facilitatory or inhibitory even though it cannot be fully dissociated anatomically [15]. The descending pain facilitatory system consists of the anterior cingulate cortex (ACC), the rostral ventromedial medulla (RVM), and the dorsal reticular nucleus of the medulla [16][17][18], while the descending inhibitory system includes the periaqueductal gray (PAG), RVM, and caudal lateral ventrolateral medulla (VLM) [19,20]. The descending control modulates pain circuitry at multiple levels, and numerous findings have identified that the imbalance of descending pain modulation favoring pain facilitation contributes to the promotion and maintenance of chronic pain [21].…”

Section: Introductionmentioning

confidence: 99%

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The Role of Descending Pain Modulation in Chronic Primary Pain: Potential Application of Drugs Targeting Serotonergic System

et al. 2019

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Chronic primary pain (CPP) is a group of diseases with long-term pain and functional disorders but without structural or specific tissue pathologies. CPP is becoming a serious health problem in clinical practice due to the unknown cause of intractable pain and high cost of health care yet has not been satisfactorily addressed. During the past decades, a significant role for the descending pain modulation and alterations due to specific diseases of CPP has been emphasized. It has been widely established that central sensitization and alterations in neuroplasticity induced by the enhancement of descending pain facilitation and/or the impairment of descending pain inhibition can explain many chronic pain states including CPP. The descending serotonergic neurons in the raphe nuclei target receptors along the descending pain circuits and exert either pro- or antinociceptive effects in different pain conditions. In this review, we summarize the possible underlying descending pain regulation mechanisms in CPP and the role of serotonin, thus providing evidence for potential application of analgesic medications based on the serotonergic system in CPP patients.

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“…The potential role of 5-HT4 receptors in mediating pain has not yet been perceived. However, 5-HT4 receptors possibly decrease pain [46], and 5-HT4 agonists cause antinociception through cholinergic strategies [47].…”

Section: Discussionmentioning

confidence: 99%

Possible Involvement of Serotonergic Mechanism(s) in the Antinociceptive Effects of kaempferol

Jabbari

Bananej

Zarei

et al. 2020

ajnpp

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Background and Objectives: A flavonoid kaempferol (KM) exerts an anti-inflammatory effect and is reportedly capable of preventing metabolic diseases. Nonetheless, a limited number of studies have been carried out on the antinociceptive effects of kaempferol. Objectives: The present study aimed to investigate the involvement of serotonin receptors in the antinociceptive-like activity of KM in male Wistar rats using the tail-flick test. Materials and Methods: The compounds (i.e., KM, morphine, and diclofenac) were intracerebroventricularly administered to rats for the examination of central effects on the thermal pain using the tail-flick test. For the evaluation of the involvement of serotonin receptors in the possible antinociceptive effects of kaempferol, several antagonists (i.e., tropisetron, ketanserin, GR113808, WAY 100635, and penbutolol) were used. Additionally, locomotor activity and motor responses were investigated by the rotarod test after KM treatment. Results: The intracerebroventricular microinjections of KM showed antinociceptive effects using the tail-flick test. The pretreatment with tropisetron as a 5-HT3 receptor antagonist at 1 and 10 mg completely reversed the KM-related antinociception. Furthermore, ketanserin (5-HT2A receptor antagonist) and GR113808 (5-HT4 receptor antagonist) both at 10 mg reduced KM-related antinociception; however, 5-HT1A receptor antagonist WAY 100635 and 5-HT1B antagonist penbutolol did not decrease KM-related antinociception. All KM doses were not observed with a significant effect on locomotor activity or motor reactions. Conclusion: The results of the current study suggested that serotonergic receptors (i.e., 5-HT2A, 5-HT3, and 5-HT4) are effective in the KM antinociceptive activity in male rats.

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The 5-HT 4 receptor-mediated inhibition of visceral nociceptive neurons in the rat caudal ventrolateral medulla

Cited by 16 publications

References 90 publications

Efficacy and Safety of 5-HT4 Receptor Agonist Minesapride for Irritable Bowel Syndrome with Constipation in a Randomized Controlled Trial

Efficacy and Safety of 5-HT4 Receptor Agonist Minesapride for Irritable Bowel Syndrome with Constipation in a Randomized Controlled Trial

The Role of Descending Pain Modulation in Chronic Primary Pain: Potential Application of Drugs Targeting Serotonergic System

Possible Involvement of Serotonergic Mechanism(s) in the Antinociceptive Effects of kaempferol

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