Anti-cholinergics mecamylamine and scopolamine alleviate motion sickness-induced gastrointestinal symptoms through both peripheral and central actions

Qi, Ruirui; Shan, Yang; Pan, Leilei; Mao, Yuqi; Lü, Liang; Dai, Zhiqiang; Wang, Junqin; Cai, Yuyang

doi:10.1016/j.neuropharm.2018.12.006

Cited by 15 publications

(25 citation statements)

References 103 publications

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“…It was found that mice belonging to the MS group exhibited a higher score compared with the control groups NC and MNT50. This indicates that rotation increased piloerection, urination, tremor, and defecation in MS group which resembles earlier published reports (Qi et al., 2019; Wang et al., 2017; Zheng et al., 2014; Zhou et al., 2017). Pretreatment with MCD and MNT exhibited a reduction in the score of the symptoms (Figure 3b).…”

Section: Discussionsupporting

confidence: 90%

Menthol, a bioactive constituent of Mentha , attenuates motion sickness in mice model: Involvement of dopaminergic system

2021

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Motion sickness (MS) occurs due to contradicting vestibular and visual inputs to the brain causing nausea and vomiting. Antidopaminergic drugs being effective in reducing MS create a path for effective therapy against MS by regulating dopamine levels. We aimed to evaluate the role of the striatum and brainstem dopamine and dopamine D2 receptor (DRD2) in MS and the efficacy of menthol (MNT) to modulate dopamine and DRD2 in vitro and in vivo for possible amelioration of MS. Evaluation of efficacy of MNT to inhibit dopamine release from PC12 cells and anti‐MS efficacy in BALB/c mice model was performed. Dopamine, DRD2 expression in PC12 cells, mice striatum, and brainstem were detected using HPLC‐ECD, RT‐PCR, and Western blot analysis, respectively. DRD2 expression increased in calcium ionophore‐treated PC12 cells compared with control cells. Pretreatment with 50 μg/ml menthol decreased dopamine and DRD2 expression. Similarly, dopamine and DRD2 levels in mice striatum and brainstem of MS group (rotation induced) increased significantly compared with control group NC (no rotation). Pretreatment with menthol at 50 mg/kg concentration (rotation induced) showed decreased dopamine and DRD2 expression, thus indicating ameliorative effect on MS. Hence, we suggest that increased striatum and brainstem dopamine and DRD2 levels might lead to MS symptoms, and menthol could be used as a potent herbal alternative medicine for MS. Practical applications Antidopaminergic drugs being effective in reducing motion sickness (MS) creates a path for effective therapy against MS by regulating dopamine levels. Increased striatum and brainstem dopamine and Dopamine D2 receptor (DRD2) levels might lead to the MS symptoms induced by rotation stimulation in mice model. Menthol showed a prophylactic effect on rotation‐induced MS by reducing striatal and brainstem dopamine levels, DRD2 mRNA, and protein expression. Menthol could be used as an herbal alternative to antidopaminergics to minimize the associated adverse effects.

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Section: Discussionsupporting

confidence: 90%

Menthol, a bioactive constituent of Mentha , attenuates motion sickness in mice model: Involvement of dopaminergic system

2021

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“…But evidence regarding efferent activation of mAChRs on vestibular afferents and its sensitivity to mAChR antagonists, now including glycopyrrolate and methscopolamine, suggest we include mAChRs in the vestibular periphery as potential contributors ( Weerts et al, 2015 ; Holt et al, 2017 ; Ramakrishna et al, 2020 ; Schneider et al, 2021 ). While differences in the effectiveness of peripherally and centrally-active mAChR antagonists in alleviating motion sickness are mixed ( Kirsten and Schoener, 1975 ; Uijdehaage et al, 1993 ; Hasler et al, 1995 ; Lang et al, 1999 ; Spinks and Wasiak, 2011 ; Qi et al, 2019 ), glycopyrrolate has been utilized as a vestibular suppressant in Meniere’s patients and for treating vertigo after cochleostomy during cochlear implants ( Storper et al, 1998 ; Chakrabarty et al, 2011 ). Collectively, these data suggest that pharmacological targeting of mAChRs in the vestibular periphery may be of some utility in treating motion sickness, and that glycopyrrolate and methscopolamine could be used to distinguish the role of mAChRs in peripheral and central vestibular circuitry.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear

et al. 2021

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Stimulation of cholinergic efferent neurons innervating the inner ear has profound, well-characterized effects on vestibular and auditory physiology, after activating distinct ACh receptors (AChRs) on afferents and hair cells in peripheral endorgans. Efferent-mediated fast and slow excitation of vestibular afferents are mediated by α4β2*-containing nicotinic AChRs (nAChRs) and muscarinic AChRs (mAChRs), respectively. On the auditory side, efferent-mediated suppression of distortion product otoacoustic emissions (DPOAEs) is mediated by α9α10nAChRs. Previous characterization of these synaptic mechanisms utilized cholinergic drugs, that when systemically administered, also reach the CNS, which may limit their utility in probing efferent function without also considering central effects. Use of peripherally-acting cholinergic drugs with local application strategies may be useful, but this approach has remained relatively unexplored. Using multiple administration routes, we performed a combination of vestibular afferent and DPOAE recordings during efferent stimulation in mouse and turtle to determine whether charged mAChR or α9α10nAChR antagonists, with little CNS entry, can still engage efferent synaptic targets in the inner ear. The charged mAChR antagonists glycopyrrolate and methscopolamine blocked efferent-mediated slow excitation of mouse vestibular afferents following intraperitoneal, middle ear, or direct perilymphatic administration. Both mAChR antagonists were effective when delivered to the middle ear, contralateral to the side of afferent recordings, suggesting they gain vascular access after first entering the perilymphatic compartment. In contrast, charged α9α10nAChR antagonists blocked efferent-mediated suppression of DPOAEs only upon direct perilymphatic application, but failed to reach efferent synapses when systemically administered. These data show that efferent mechanisms are viable targets for further characterizing drug access in the inner ear.

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“…Immediately after Rot or Sta treatment, animals were taken out of the rotation containers and received spontaneous locomotion recording in an enclosed soundproof room following the same procedures as described in our previous study (Zhou et al, 2017 ; Qi et al, 2019 ). The apparatus consisted of a dark 40 × 40 × 45 cm rectangular chamber with the floor marked with a 16 × 16 grid.…”

Section: Methodsmentioning

confidence: 99%

“…As the lack of vomiting reflex, varieties of behavioral measurements have been widely used to assess multi-dimensional responses of MS in rodents. Conditioned gaping response that can be elicited during exposure to a context previously paired with nauseant agents or provocative motion can be alleviated by corresponding anti-emetic and anti-MS drugs, making it plausible to serve as a rat model of conditioned nausea (Limebeer et al, 2008 ; Parker, 2014 ; Zhou et al, 2017 ; Qi et al, 2019 ; Rock et al, 2022 ). In addition, defecation response and decreased spontaneous locomotion activity were also observed in rats and mice exposed to whole-body rotation (Ossenkopp and Frisken, 1982 ; Ossenkopp et al, 1994 ; Yu et al, 2007 ; Limebeer et al, 2008 ; Morita et al, 2017 ; Wang et al, 2017 ; Deshetty et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…The effects of stroboscopic light synchronized or unsynchronized to the acceleration–deceleration phase of rotation were examined, and the influence of color temperature and lighting intensity was also observed. MS-related gastrointestinal responses were assessed by measuring conditioned gaping and defecation responses due to the absence of vomiting reaction in rodents (Wang et al, 2012 , 2017 ; Zhou et al, 2017 ; Qi et al, 2019 ; Devuono et al, 2020 ). Motor and balance performance were evaluated using spontaneous locomotion test and balance beam test (Manno et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Stroboscopic lighting with intensity synchronized to rotation velocity alleviates motion sickness gastrointestinal symptoms and motor disorders in rats

Mao

Pan²,

Shuhua³

et al. 2022

Front. Integr. Neurosci.

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Motion sickness (MS) is caused by mismatch between conflicted motion perception produced by motion challenges and expected “internal model” of integrated motion sensory pattern formed under normal condition in the brain. Stroboscopic light could reduce MS nausea symptom via increasing fixation ability for gaze stabilization to reduce visuo-vestibular confliction triggered by distorted vision during locomotion. This study tried to clarify whether MS induced by passive motion could be alleviated by stroboscopic light with emitting rate and intensity synchronized to acceleration–deceleration phase of motion. We observed synchronized and unsynchronized stroboscopic light (SSL: 6 cycle/min; uSSL: 2, 4, and 8 cycle/min) on MS-related gastrointestinal symptoms (conditioned gaping and defecation responses), motor disorders (hypoactivity and balance disturbance), and central Fos protein expression in rats receiving Ferris wheel-like rotation (6 cycle/min). The effects of color temperature and peak light intensity were also examined. We found that SSL (6 cycle/min) significantly reduced rotation-induced conditioned gaping and defecation responses and alleviated rotation-induced decline in spontaneous locomotion activity and disruption in balance beam performance. The efficacy of SSL against MS behavioral responses was affected by peak light intensity but not color temperature. The uSSL (4 and 8 cycle/min) only released defecation but less efficiently than SSL, while uSSL (2 cycle/min) showed no beneficial effect in MS animals. SSL but not uSSL inhibited Fos protein expression in the caudal vestibular nucleus, the nucleus of solitary tract, the parabrachial nucleus, the central nucleus of amygdala, and the paraventricular nucleus of hypothalamus, while uSSL (4 and 8 cycle/min) only decreased Fos expression in the paraventricular nucleus of hypothalamus. These results suggested that stroboscopic light synchronized to motion pattern might alleviate MS gastrointestinal symptoms and motor disorders and inhibit vestibular-autonomic pathways. Our study supports the utilization of motion-synchronous stroboscopic light as a potential countermeasure against MS under abnormal motion condition in future.

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Anti-cholinergics mecamylamine and scopolamine alleviate motion sickness-induced gastrointestinal symptoms through both peripheral and central actions

Cited by 15 publications

References 103 publications

Menthol, a bioactive constituent of Mentha , attenuates motion sickness in mice model: Involvement of dopaminergic system

Menthol, a bioactive constituent of Mentha , attenuates motion sickness in mice model: Involvement of dopaminergic system

Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear

Stroboscopic lighting with intensity synchronized to rotation velocity alleviates motion sickness gastrointestinal symptoms and motor disorders in rats

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