Molecular Pain最新文献

{"title":"Epitranscriptomic profiling of N4-acetylcytidine-related RNA acetylation in the spinal dorsal horn of rat with cancer-induced bone pain.","authors":"Longsheng Xu,&nbsp;Shang Zheng,&nbsp;Beibei Liu,&nbsp;Chengfei Xu,&nbsp;Lei Yang,&nbsp;Qinghe Zhou,&nbsp;Ming Yao,&nbsp;Xiang-Yao Li","doi":"10.1177/17448069231178487","DOIUrl":"https://doi.org/10.1177/17448069231178487","url":null,"abstract":"<p><p>Recently, epigenetics involved in the regulation of gene expression has become a research hotspot. This study evaluated N4-acetylcytidine (ac4c) RNA acetylation in the spinal dorsal horn (SDH) of rats with cancer-induced bone pain (CIBP). The ac4C-specific RIP sequencing and NAT10-specific RIP sequencing were performed to identify the differences in ac4C acetylation and gene expression in the SDH between CIBP and sham groups, the relationship with the acetylation-modifying enzyme NAT10, and association analysis was performed. By interfering with the NAT10 expression, the relationship between some up-regulated genes and ac4C acetylation in CIBP was verified. In this study, we demonstrated that bone cancer increases the levels of NAT10 and the overall acetylation, inducing differential ac4C patterns in the SDH of rats. Through verification experiments, it was found that ac4C acetylation of some genes is regulated by NAT10, and differential ac4C patterns in RNA determine the expression of this RNA. We exposed that some CIBP-related gene expression was altered in the SDH of rats, which was regulated by differentially expressed ac4C acetylation.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2b/07/10.1177_17448069231178487.PMC10204061.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9517442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzydamine plays a role in limiting inflammatory pain induced by neuronal sensitization.","authors":"Magdalena Nikolaeva-Koleva,&nbsp;Ana Espinosa,&nbsp;Matteo Vergassola,&nbsp;Lorenzo Polenzani,&nbsp;Giorgina Mangano,&nbsp;Lorella Ragni,&nbsp;Sara Zucchi,&nbsp;Antonio Ferrer Montiel,&nbsp;Isabel Devesa","doi":"10.1177/17448069231204191","DOIUrl":"10.1177/17448069231204191","url":null,"abstract":"<p><p>Benzydamine is an active pharmaceutical compound used in the oral care pharmaceutical preparation as NSAID. Beside from its anti-inflammatory action, benzydamine local application effectively reliefs pain showing analgesic and anaesthetic properties. Benzydamine mechanism of action has been characterized on inflammatory cell types and mediators highlighting its capacity to inhibit pro-inflammatory mediators' synthesis and release. On the other hand, the role of benzydamine as neuronal excitability modulator has not yet fully explored. Thus, we studied benzydamine's effect over primary cultured DRG nociceptors excitability and after acute and chronic inflammatory sensitization, as a model to evaluate relative nociceptive response. Benzydamine demonstrated to effectively inhibit neuronal basal excitability reducing its firing frequency and increasing rheobase and afterhyperpolarization amplitude. Its effect was time and dose-dependent. At higher doses, benzydamine induced changes in action potential wavelength, decreasing its height and slightly increasing its duration. Moreover, the compound reduced neuronal acute and chronic inflammatory sensitization. It inhibited neuronal excitability mediated either by an inflammatory cocktail, acidic pH or high external KCl. Notably, higher potency was evidenced under inflammatory sensitized conditions. This effect could be explained either by modulation of inflammatory and/or neuronal sensitizing signalling cascades or by direct modulation of proalgesic and action potential firing initiating ion channels. Apparently, the compound inhibited Na_v1.8 channel but had no effect over K_v7.2, K_v7.3, TRPV1 and TRPA1. In conclusion, the obtained results strengthen the analgesic and anti-inflammatory effect of benzydamine, highlighting its mode of action on local pain and inflammatory signalling.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/93/55/10.1177_17448069231204191.PMC10583526.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10609496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T-cells and IL-5 mediate pain outcomes in a preclinical model of chronic muscle pain.","authors":"Melissa E Lenert,&nbsp;Thomas A Szabo-Pardi,&nbsp;Michael D D Burton","doi":"10.1177/17448069221110691","DOIUrl":"https://doi.org/10.1177/17448069221110691","url":null,"abstract":"<p><p>Fibromyalgia (FM) is a chronic musculoskeletal pain disorder primarily diagnosed in women. Historically, clinical literature focusing on cytokines and immune cells has been inconsistent. However, recent key studies show several layers of immune system dysfunction in FM. Preclinically, studies of the immune system have focused on monocytes with little focus on other immune cells. Importantly, T-cells are implicated in the development and resolution of chronic pain states, particularly in females. Our previous work showed that monocytes from women with FM produced more interleukin 5 (IL-5) and systemic treatment of IL-5 reversed mechanical hypersensitivity in a preclinical model of FM. Typically, IL-5 is produced by T_H2-cells, so in this study we assessed T-cell populations and cytokine production in female mice using the acid-induced chronic muscle pain model of FM before and after treatment with IL-5. Two unilateral injections of pH4.0 saline, five days apart, into the gastrocnemius muscle induce long-lasting widespread pain. We found that peripheral (blood) regulatory T_helper-cells (CD4⁺ FOXP3+) are downregulated in pH4.0-injected mice, with no differences in tissue (lymph nodes) or CD8⁺ T-cell populations. We tested the analgesic properties of IL-5 using a battery of spontaneous and evoked pain measures. Interestingly, IL-5 treatment induced place preference in mice previously injected with pH4.0 saline. Mice treated with IL-5 show limited changes in T-cell populations compared to controls, with a rescue in regulatory T-cells which positively correlates with improved mechanical hypersensitivity. The experiments in this study provide novel evidence that downregulation of regulatory T-cells play a role in chronic muscle pain pathology in the acidic saline model of FM and that IL-5 signaling is a promising target for future development of therapeutics.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0d/9a/10.1177_17448069221110691.PMC9926397.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9800420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutamate acts as a key neurotransmitter for itch in the mammalian spinal cord.","authors":"Qi-Yu Chen,&nbsp;Min Zhuo","doi":"10.1177/17448069231152101","DOIUrl":"https://doi.org/10.1177/17448069231152101","url":null,"abstract":"<p><p>Itch sensation is one of the major sensory experiences of humans and animals. Recent studies using genetic deletion techniques have proposed that gastrin-releasing peptide (GRP) is a key neurotransmitter for itch in the spinal cord. However, these studies are mainly based on behavioral responses and lack direct electrophysiological evidence that GRP indeed mediates itch information between primary afferent fibers and spinal dorsal horn neurons. In this review, we reviewed recent studies using different experimental approaches and proposed that glutamate but not GRP acts as the key neurotransmitter in the primary afferents in the transmission of itch. GRP is more likely to serve as an itch-related neuromodulator. In the cerebral cortex, we propose that the anterior cingulate cortex (ACC) plays a significant role in both itch and pain sensations. Only behavioral measurement of itch (scratching) is not sufficient for itch measurement, since scratching the itching area also produces pleasure. Integrative experimental approaches as well as better behavioral scoring models are needed to help to understand the neuronal mechanism of itch and aid future treatment for patients with pruritic diseases.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9846298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9193324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dehydrocorydaline alleviates sleep deprivation-induced persistent postoperative pain in adolescent mice through inhibiting microglial P2Y₁₂ receptor expression in the spinal cord.","authors":"Haikou Yang, Yufeng Zhang, Qingling Duan, Kun Ni, Yang Jiao, Jixiang Zhu, Jian Sun, Wei Zhang, Zhengliang Ma","doi":"10.1177/17448069231216234","DOIUrl":"10.1177/17448069231216234","url":null,"abstract":"<p><p>During adolescence, a second period of central nervous system (CNS) plasticity that follows the fetal period, which involves sleep deprivation (SD), becomes apparent. SD during adolescence may result in abnormal development of neural circuits, causing imbalance in neuronal excitation and inhibition, which not only results in pain, but increases the chances of developing emotion disorders in adulthood, such as anxiety and depression. The quantity of surgeries during adolescence is also consistently on the rise, yet the impact and underlying mechanism of preoperative SD on postoperative pain remain unexplored. This study demonstrates that preoperative SD induces upregulation of the P2Y₁₂ receptor, which is exclusively expressed on spinal microglia, and phosphorylation of its downstream signaling pathway p38Mitogen-activated protein/Nuclear transcription factor-κB (p38MAPK/NF-κB)in spinal microglia, thereby promoting microglia activation and microglial transformation into the proinflammatory M1 phenotype, resulting in increased expression of proinflammatory cytokines that exacerbate persisting postoperative incisional pain in adolescent mice. Both intrathecal minocycline (a microglia activation inhibitor) and MRS2395 (a P2Y₁₂ receptor blocker) effectively suppressed microglial activation and proinflammatory cytokine expression. Interestingly, supplementation with dehydrocorydaline (DHC), an extract of <i>Rhizoma Corydalis</i>, inhibited the P2Y₁₂/p38MAPK/NF-κB signaling pathway, microglia activation, and expression of pro-inflammatory cytokines in the model mice. Taken together, the results indicate that the P2Y₁₂ receptor and microglial activation are important factors in persistent postoperative pain caused by preoperative SD in adolescent mice and that DHC has analgesic effects by acting on these targets.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71522060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal alterations of pituitary adenylate cyclase activating polypeptide and its receptors in a rat model induced by recurrent chemical stimulations: Relevant to chronic migraine.","authors":"Hangfei Wu,&nbsp;Zhao Dong,&nbsp;Yinglu Liu,&nbsp;Qing Zhang,&nbsp;Mingjie Zhang,&nbsp;Guanqun Hu,&nbsp;Shengyuan Yu,&nbsp;Xun Han","doi":"10.1177/17448069231152129","DOIUrl":"https://doi.org/10.1177/17448069231152129","url":null,"abstract":"<p><p><b>Background</b>: Migraine is a common type of primary headache with disabling brain dysfunction. It has been found that pituitary adenylate cyclase activating polypeptide (PACAP) is involved in the pathogenesis of migraine, however, the role of PACAP and its receptors in chronic migraine remains unclear. Therefore, the present study aimed to explore the changes of PACAP and its receptors in different duration after recurrent dural inflammation soup stimulations and to investigate the co-expression between PACAP and calcitonin gene-related peptide (CGRP). <b>Methods</b>: Adult male rats were implanted with cannula surrounding superior sagittal sinus, which was followed by dural infusion of inflammatory soup (IS) or normal saline (NS). The rats were randomly divided into 4 groups (<i>n</i> = 8 for each group): IS stimulation for seven days (IS-7 group), IS stimulation for 14 days (IS-14 group), IS stimulation for 21 days (IS-21 group), and NS control for 21 days (CON group). The facial mechanical withdrawal threshold was daily measured during the whole experiment. The behavioral changes (ipsilateral and bilateral face grooming behavior) in a plastic cage of rats were observed and recorded. The expression of PACAP, its receptors (PAC1, VPAC1, VPAC2), and CGRP in the trigeminal ganglia (TG) and the trigeminal nucleus caudalis (TNC) was examined by immunohistochemistry. Immunofluorescence was used to explore the co-expression of PACAP, PAC1 receptor, and CGRP after repeated IS administration in the TG. <b>Results</b>: The ipsilateral facial grooming time of IS-21 group displayed an apparent increase than CON group after repeated stimulation on day 2, while significant differences were observed on day 14. No differences were found between the IS-21 and CON group in bilateral facial grooming. Dural IS stimulation induced a significantly decrease in facial mechanical withdrawal thresholds. PACAP positive cells in the regions of TNC were gradually decreased with the IS days increasing. PACAP and PAC1 receptor expression in the TG had a trend of increasing first and then decreasing. There was no significant difference in expression of VPAC1 and VPAC2 in the TG and the TNC. Immunofluorescence showed that PACAP was mainly expressed in TG neurons. PACAP and PAC1 receptor co-expression decreased gradually after repetitive IS stimulation. While the co-expression between PACAP and CGRP reached the peak in IS-7 group after repetitive IS stimulation, and then decreased. <b>Conclusions</b>: This study demonstrated that repetitive chemical stimulations induced a gradual decrease of PACAP in the TNC, while the PACAP and PAC1 receptor expression in TG showed dynamical changes of increasing first and then decreasing after repeated IS administration. These results suggested exhaustion of PACAP could be involved in the duration of chronic migraine and implied PACAP may contribute to the pathology of migraine through the PAC1 receptor, which was associated with CG","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ac/0a/10.1177_17448069231152129.PMC9869212.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9193321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemokine CCL7 mediates trigeminal neuropathic pain <i>via</i> CCR2/CCR3-ERK pathway in the trigeminal ganglion of mice.","authors":"Lin-Peng Zhu, Meng-Lin Xu, Bao-Tong Yuan, Ling-Jie Ma, Yong-Jing Gao","doi":"10.1177/17448069231169373","DOIUrl":"10.1177/17448069231169373","url":null,"abstract":"<p><strong>Background: </strong>Chemokine-mediated neuroinflammation plays an important role in the pathogenesis of neuropathic pain. The chemokine CC motif ligand 7 (CCL7) and its receptor CCR2 have been reported to contribute to neuropathic pain via astrocyte-microglial interaction in the spinal cord. Whether CCL7 in the trigeminal ganglion (TG) involves in trigeminal neuropathic pain and the involved mechanism remain largely unknown.</p><p><strong>Methods: </strong>The partial infraorbital nerve transection (pIONT) was used to induce trigeminal neuropathic pain in mice. The expression of <i>Ccl7</i>, <i>Ccr1</i>, <i>Ccr2</i>, and <i>Ccr3</i> was examined by real-time quantitative polymerase chain reaction. The distribution of CCL7, CCR2, and CCR3 was detected by immunofluorescence double-staining. The activation of extracellular signal-regulated kinase (ERK) was examined by Western blot and immunofluorescence. The effect of CCL7 on neuronal excitability was tested by whole-cell patch clamp recording. The effect of selective antagonists for CCR1, CCR2, and CCR3 on pain hypersensitivity was checked by behavioral testing.</p><p><strong>Results: </strong><i>Ccl7</i> was persistently increased in neurons of TG after pIONT, and specific inhibition of CCL7 in the TG effectively relieved pIONT-induced orofacial mechanical allodynia. Intra-TG injection of recombinant CCL7 induced mechanical allodynia and increased the phosphorylation of ERK in the TG. Incubation of CCL7 with TG neurons also dose-dependently enhanced the neuronal excitability. Furthermore, pIONT increased the expression of CCL7 receptors <i>Ccr1</i>, <i>Ccr2</i>, and <i>Ccr3</i>. The intra-TG injection of the specific antagonist of CCR2 or CCR3 but not of CCR1 alleviated pIONT-induced orofacial mechanical allodynia and reduced ERK activation. Immunostaining showed that CCR2 and CCR3 are expressed in TG neurons, and CCL7-induced hyperexcitability of TG neurons was decreased by antagonists of CCR2 or CCR3.</p><p><strong>Conclusion: </strong>CCL7 activates ERK in TG neurons via CCR2 and CCR3 to enhance neuronal excitability, which contributes to the maintenance of trigeminal neuropathic pain. CCL7-CCR2/CCR3-ERK pathway may be potential targets for treating trigeminal neuropathic pain.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/08/d0/10.1177_17448069231169373.PMC10413901.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9976553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sound-induced analgesia cannot always be observed in adult mice.","authors":"Qi-Yu Chen,&nbsp;Jinjin Wan,&nbsp;Mianxian Wang,&nbsp;Shanshan Hong,&nbsp;Min Zhuo","doi":"10.1177/17448069231197158","DOIUrl":"10.1177/17448069231197158","url":null,"abstract":"<p><p>Music seems promising as an adjuvant pain treatment in humans, while its mechanism remains to be illustrated. In rodent models of chronic pain, few studies reported the analgesic effect of music. Recently, Zhou et al. stated that the analgesic effects of sound depended on a low (5 dB) signal-to-noise ratio (SNR) relative to ambient noise in mice. However, despite employing multiple behavioral analysis approaches, we were unable to extend these findings to a mice model of chronic pain listening to the 5 dB SNR.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/00/2a/10.1177_17448069231197158.PMC10467218.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10127227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sophoridine alleviates hyperalgesia and anxiety-like behavior in an inflammatory pain mouse model induced by complete freund's adjuvant.","authors":"Zheng Rong,&nbsp;Le Yang,&nbsp;Yue Chen,&nbsp;Yan Qin,&nbsp;Cai-Yan Cheng,&nbsp;Jun Zhao,&nbsp;Long-Fei Li,&nbsp;Xue Ma,&nbsp;Yu-Mei Wu,&nbsp;Shui-Bing Liu,&nbsp;Yan-Ni Liang,&nbsp;Ming-Gao Zhao","doi":"10.1177/17448069231177634","DOIUrl":"https://doi.org/10.1177/17448069231177634","url":null,"abstract":"<p><p>Chronic pain, along with comorbid psychiatric disorders, is a common problem worldwide. A growing number of studies have focused on non-opioid-based medicines, and billions of funds have been put into digging new analgesic mechanisms. Peripheral inflammation is one of the critical causes of chronic pain, and drugs with anti-inflammatory effects usually alleviate pain hypersensitivity. Sophoridine (SRI), one of the most abundant alkaloids in Chinese herbs, has been proved to exert antitumor, antivirus and anti-inflammation effects. Here, we evaluated the analgesic effect of SRI in an inflammatory pain mouse model induced by complete Freund's adjuvant (CFA) injection. SRI treatment significantly decreased pro-inflammatory factors release after LPS stimuli in microglia. Three days of SRI treatment relieved CFA-induced mechanical hypersensitivity and anxiety-like behavior, and recovered abnormal neuroplasticity in the anterior cingulate cortex of mice. Therefore, SRI may be a candidate compound for the treatment of chronic inflammatory pain and may serve as a structural basis for the development of new drugs.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/16/d8/10.1177_17448069231177634.PMC10201643.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9514254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polysorbate 80 blocked a peripheral sodium channel, Na_v1.7, and reduced neuronal excitability.","authors":"Ryeong-Eun Kim,&nbsp;Jin-Sung Choi","doi":"10.1177/17448069221150138","DOIUrl":"https://doi.org/10.1177/17448069221150138","url":null,"abstract":"<p><p>Polysorbate 80 is a non-ionic detergent derived from polyethoxylated sorbitan and oleic acid. It is widely used in pharmaceuticals, foods, and cosmetics as an emulsifier. Na_v1.7 is a peripheral sodium channel that is highly expressed in sympathetic and sensory neurons, and it plays a critical role in determining the threshold of action potentials (APs). We found that 10 μg/mL polysorbate 80 either abolished APs or increased the threshold of the APs of dorsal root ganglions. We thus investigated whether polysorbate 80 inhibits Na_v1.7 sodium current using a whole-cell patch-clamp recording technique. Polysorbate 80 decreased the Na_v1.7 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC₅₀) of 250.4 μg/mL at a holding potential of -120 mV. However, the IC₅₀ was 1.1 μg/mL at a holding potential of -90 mV and was estimated to be 0.9 μg/mL at the resting potentials of neurons, where most channels are inactivated. The activation rate and the voltage dependency of activation of Na_v1.7 were not changed by polysorbate 80. However, polysorbate 80 caused hyperpolarizing shifts in the voltage dependency of the steady-state fast inactivation curve. The blocking of Na_v1.7 currents by polysorbate 80 was not reversible at a holding potential of -90 mV but was completely reversible at -120 mV, where the channels were mostly in the closed state. Polysorbate 80 also slowed recovery from inactivation and induced robust use-dependent inhibition, indicating that it is likely to bind to and stabilize the inactivated state. Our results indicate that polysorbate 80 inhibits Na_v1.7 current in concentration-, state-, and use-dependent manners when used even below commercial concentrations. This suggests that polysorbate 80 may be helpful in pain medicine as an excipient. In addition, <i>in vitro</i> experiments using polysorbate 80 with neurons should be conducted with caution.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/db/69/10.1177_17448069221150138.PMC9829885.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10645664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}