Role of 5-HT receptors in neuropathic pain: potential therapeutic implications

Liu, Qian Qian; Yao, Xiao Xiao; Gao, Shuo Hui; Li, Rui; Li, Bing Jin; Yang, Wei; Cui, Ran

doi:10.1016/j.phrs.2020.104949

Cited by 75 publications

(60 citation statements)

References 122 publications

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“…Serotonin affects the proliferation of PASMCs through serotonin receptors or SERT [9]. The underlying mechanism of serotonin receptors or SERT is not the same.…”

Section: Discussionmentioning

confidence: 98%

“…A recent study suggests that abnormal proliferation of PASMCs is the key pathological basis for pulmonary vascular remodeling in PAH [6]. Their proliferation is promoted by vasoactive substances, such as serotonin (5-hydroxytryptamine; 5-HT) [7], which is a neurotransmitter involved in many physiological processes [8,9]. Understanding the molecular mechanism of serotonin-induced abnormal PASMC proliferation and identifying effective therapeutic targets are key goals in PAH research.…”

Section: Introductionmentioning

confidence: 99%

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Upregulation of miR-361-3p suppresses serotonin-induced proliferation in human pulmonary artery smooth muscle cells by targeting SERT

et al. 2020

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Background Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a key mechanism in pulmonary arterial hypertension (PAH). Serotonin (5-hydroxytryptamine, 5-HT) can induce abnormal proliferation of PASMCs. The role of miR-361-3p in serotonin-induced abnormal PASMCs proliferation remains unclear. Methods The miR-361-3p level was analyzed in plasma from PAH patients and normal controls and in human PASMCs (hPASMCs) using RT-PCR. The hPASMCs were transfected with an miR-361-3p mimic and then treated with serotonin. Untransfected hPASMCs were used as the control. Cell proliferation was evaluated using an MTS assay and 5-ethynyl-2′-deoxyuridine (EdU) staining. The cell cycle stages were evaluated using flow cytometry. The association between miR-361-3p and serotonin transporter (SERT) was determined using a luciferase reporter assay and anti-AGO2 RNA immunoprecipitation assay. The protein expression was evaluated via western blotting. Results The miR-361-3p level was lower in plasma from PAH patients than in plasma from the any of the normal control subjects. The mean pulmonary arterial pressure, pulmonary vascular resistance and pulmonary vascular resistance index were higher in PAH patients whose miR-361-3p level was lower than the median value for patients than in those whose miR-361-3p level was higher than the median. Serotonin treatment reduced miR-361-3p expression in the hPASMCs. MiR-361-3p overexpression suppressed cell proliferation, promoted apoptosis, induced G1 arrest, and decreased the phosphorylation level of ERK1/2 in serotonin-treated hPASMCs. SERT was identified as an miR-361-3p target. Its overexpression alleviated the effect of miR-361-3p overexpression on serotonin-induced hPASMC proliferation and upregulation of phosphorylated ERK1/2. Conclusions The miR-361-3p level is lower in the plasma of PAH patients. Upregulation of miR-361-3p suppresses serotonin-induced proliferation of hPASMCs by targeting SERT. Our results suggest that miR-361-3p is a potential therapeutic target in PAH.

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“…Serotonin affects the proliferation of PASMCs through serotonin receptors or SERT [9]. The underlying mechanism of serotonin receptors or SERT is not the same.…”

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Upregulation of miR-361-3p suppresses serotonin-induced proliferation in human pulmonary artery smooth muscle cells by targeting SERT

et al. 2020

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“…5-HT3 receptors are also expressed on inhibitory GABAergic interneurons. 37,41 Previous studies have reported key roles of the 5-HT2A and 5-HT3 receptors in descending pain facilitation in a lot of pain states. These data identified modality and intensity selective facilitatory roles of spinal 5-HT2A and 5-HT3 receptors on sensory neuronal processing within the pain ascending transmission pathway.…”

mentioning

confidence: 99%

“…Some studies have shown that RVM 5-HTcontaining neurons played a role in descending pain facilitation, while other studies have reported that they participated in descending pain inhibition. 37,41 Wei et al reported that descending 5-HT released from the RVM played a critical role in descending pain facilitation, rather than inhibition, during hyperalgesia and allodynia maintenance after peripheral inflammation and nerve injury via RNAi of Tph in the RVM. 13 Wei et al's results suggest that spinal projection of 5-HT from the RVM is necessary to maintain persistent pain states.…”

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confidence: 99%

<p>Selective Ablation of Descending Serotonin from the Rostral Ventromedial Medulla Unmasks Its Pro-Nociceptive Role in Chemotherapy-Induced Painful Neuropathy</p>

Liu¹,

Wang²,

Ai³

et al. 2020

JPR

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Purpose: Chemotherapy-induced painful neuropathy (CIPN) is a severe adverse effect of many anti-neoplastic drugs that is difficult to manage. Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter in the rostral ventromedial medulla (RVM), which modulates descending spinal nociceptive transmission. However, the influence of the descending 5-HT from the RVM on CIPN is poorly understood. We investigated the role of 5-HT released from descending RVM neurons in a paclitaxel-induced CIPN rat model. Methods: CIPN rat model was produced by intraperitoneally injecting of paclitaxel. Pain behavioral assessments included mechanical allodynia and heat hyperalgesia. 5-HT content was analyzed by high-performance liquid chromatography (HPLC). Western blot and immunohistochemistry were used to determine tryptophan hydroxylase (Tph) and c-Fos expression. The inhibitors p-chlorophenylalanine (PCPA) and SB203580 were administrated by stereotaxical RVM microinjection. Ondansetron was injected through intrathecal catheterization. Results: The results demonstrated that Tph, the rate-limiting enzyme in 5-HT synthesis, was significantly upregulated in the RVM, and that spinal 5-HT release was increased in CIPN rats. Intra-RVM microinjection of Tph inhibitor PCPA significantly attenuated mechanical and thermal pain behavior through Tph downregulation and decreased spinal 5-HT. Intra-RVM administration of p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 alleviated paclitaxel-induced pain in a similar manner to PCPA. Intrathecal injection of ondansetron, a 5-HT3 receptor antagonist, partially reversed paclitaxel-induced pain, indicating that 5-HT3 receptors were involved in descending serotoninergic modulation of spinal pain processing. Conclusion: The results suggest that activation of the p38 MAPK pathway in the RVM leads to increased RVM Tph expression and descending serotoninergic projection to the spinal dorsal horn and contributes to the persistence of CIPN via spinal 5-HT3 receptors.

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“…The 5-HT 2B R has been implicated in migraine and neuropathic pain, which are two common forms of pain disorders in humans [75][76][77]. Migraine is a common primary headache disorder characterized by moderate to severe recurrent headaches.…”

Section: Regulation Of Pain Disordersmentioning

confidence: 99%

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

et al. 2021

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Since the first characterization of the 5-hydroxytryptamine 2B receptor (5-HT2BR) in 1992, significant progress has been made in 5-HT2BR research. Herein, we summarize the biological function, structure, and small-molecule pharmaceutical ligands of the 5-HT2BR. Emerging evidence has suggested that the 5-HT2BR is implicated in the regulation of the cardiovascular system, fibrosis disorders, cancer, the gastrointestinal (GI) tract, and the nervous system. Eight crystal complex structures of the 5-HT2BR bound with different ligands provided great insights into ligand recognition, activation mechanism, and biased signaling. Numerous 5-HT2BR antagonists have been discovered and developed, and several of them have advanced to clinical trials. It is expected that the novel 5-HT2BR antagonists with high potency and selectivity will lead to the development of first-in-class drugs in various therapeutic areas.

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Role of 5-HT receptors in neuropathic pain: potential therapeutic implications

Cited by 75 publications

References 122 publications

Upregulation of miR-361-3p suppresses serotonin-induced proliferation in human pulmonary artery smooth muscle cells by targeting SERT

Upregulation of miR-361-3p suppresses serotonin-induced proliferation in human pulmonary artery smooth muscle cells by targeting SERT

<p>Selective Ablation of Descending Serotonin from the Rostral Ventromedial Medulla Unmasks Its Pro-Nociceptive Role in Chemotherapy-Induced Painful Neuropathy</p>

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

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