Reduction of Motion Sickness Through Targeting Histamine N-Methyltransferase in the Dorsal Vagal Complex of the Brain
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1521-0103/364/3/367–376$35.00 https://doi.org/10.1124/jpet.117.244475 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 364:367–376, March 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Reduction of Motion Sickness Through Targeting Histamine N-Methyltransferase in the Dorsal Vagal Complex of the Brain Miao-Miao Chen,1 Li-Hua Xu,1 Li Chang,1 Peng Yin, and Zheng-Lin Jiang Department of Neurophysiology and Neuropharmacology, Institute of Nautical Medicine and Co-innovation Center of Neuroregeneration, Nantong University, Chongchuan District, Nantong, Jiangsu, People’s Republic of China Received August 3, 2017; accepted December 20, 2017 ABSTRACT Downloaded from To investigate the role of histamine N-methyltransferase (HNMT) dose-dependently promoted MS in both animals and raised activity in the development of motion sickness (MS) in the dorsal histamine level in rat medulla oblongata; 3) blocking histaminer- vagal complex (DVC) to inform the development of new drugs for gic neurotransmission in the DVC with promethazine inhibited MS, Beagle dogs and Sprague-Dawley rats were rotated to MS; 4) rotatory stimulus induced an elevation in HNMT expres- simulate MS. HNMT expression in the brain stem and DVC was sion, and vestibular training elevated the basal level of HNMT in measured. The effects of systemic application of tacrine, an the DVC during habituation to MS; 5) in vivo transfection of a HNMT inhibitor, on the development of MS were observed. lentiviral vector packaged with the HNMT gene increased HNMT jpet.aspetjournals.org Moreover, we microinjected a histamine receptor H1 inhibitor, expression in the DVC and reduced MS; and 6) microinjection of promethazine, into the DVC to verify the involvement of hista- a lentiviral vector driving the interference of HNMT gene minergic neurotransmission in MS. Finally, lentiviral vectors were expression in vivo significantly inhibited HNMT expression in microinjected into the DVC to determine the effects of altered the DVC and exacerbated MS. In conclusion, HNMT expression HNMT expression on MS. We found the following: 1) HNMT in the brain stem is inversely correlated with MS development. expression in the medulla oblongata of dogs and rats insuscep- Increasing HNMT expression or stimulating its activity in the DVC tible to MS was higher than in susceptible animals; 2) tacrine could inhibit MS. at ASPET Journals on September 30, 2021 Introduction decrement in most subjects (Klöcker et al., 2001; Golding and Gresty, 2005; Herron, 2010; Murdin et al., 2011). Therefore, it Motion sickness develops after an abnormal vestibular is crucial to develop new drugs that can effectively prevent and/or visual stimulation during real or apparent motion motion sickness with fewer negative side effects, especially for and is accompanied by drowsiness, dizziness, cold sweats, people working in special environments. pallor, stomach discomfort, nausea, vomiting, and other Takeda et al. (1986) reported that histamine levels increased symptoms of autonomic nervous system distress (Golding in the hypothalamus and pons-medulla oblongata when rats and Gresty, 2005; Golding, 2006; Muth, 2006). Motion sick- were rotated about two parallel axes to produce motion ness affects many people traveling or working in special sickness, but histamine levels were unchanged in bilaterally environments, such as sailing, aviation, and spaceflight. labyrinthectomized rats. Moreover, a-fluoromethylhistidine, Effective medications for the prevention of motion sickness an inhibitor of a histamine-synthesizing enzyme, sup- include anticholinergics, antihistamines, sympathomimetic pressed motion sickness (Takeda et al., 1986). Similarly, when drugs, calcium antagonists, and medicinal herbs (Klöcker the rats were exposed to 2g hypergravity in an animal et al., 2001; Golding and Gresty, 2005; Murdin et al., 2011). centrifuge device to produce motion sickness, histamine release Among the anti–motion sickness drugs, dimenhydrinate and increased in the hypothalamus (Uno et al., 1997). In contrast, scopolamine are the most effective and most frequently used, neither increased histamine release nor motion sickness was but they can cause drowsiness, blurry vision, and performance induced by 2g hypergravity in bilaterally labyrinthectomized rats. Pretreatment with a-fluoromethylhistidine decreased This work was supported by the National Natural Science Foundation of both the basal and hypergravity-induced release of histamine China (Grants 81601639, 81372131, and 81671859) and the Administration of from the hypothalamus and suppressed motion sickness ’ Science and Technology of Jiangsu, People s Republic of China (BK20161282), induced by hypergravity (Uno et al., 1997). These findings and was partly funded by the Natural Science Foundation of Nantong University (15Z01) and the Priority Academic Program Development of suggest that vestibular stimulation activates the histaminer- Jiangsu Higher Education Institutions. No potential conflicts of interest gic neuron system in the brain and induces motion sickness. It relevant to this article were reported. 1M.-M.C., L.-H.X., and L.C. contributed equally to this work. is well known that antihistamines are effective in preventing https://doi.org/10.1124/jpet.117.244475. motion sickness (Klöcker et al., 2001; Golding and Gresty, ABBREVIATIONS: CNS, central nervous system; DVC, dorsal vagal complex; GFP, green fluorescent protein; HNMT, histamine N- methyltransferase; HPLC, high-performance liquid chromatography; HRP, horseradish peroxidase; qRT-PCR, quantitative real-time polymerase chain reaction; shRNA, short hairpin RNA; SSS, saccharin sodium solution. 367 368 Chen et al. 2005; Herron, 2010; Murdin et al., 2011). Overall, the hista- minergic neuron system in the brain may play an important role in the development of motion sickness (Takeda et al., 1986; Uno et al., 1997; Bergquist and Dutia, 2006). Histaminergic modulation of the vestibular nucleus and pons-medulla oblon- Fig. 1. Protocols of the conditioned taste aversion test in rats. gata (including the vomiting center) may also be involved (Bergquist and Dutia, 2006; Haas et al., 2008). In the mammalian brain, histaminergic neurons are located reported by Crampton and Lucot (1985) and described in our previous exclusively in the tuberomammillary nucleus of the posterior study (Li et al., 2005). To induce motion sickness, dogs and rats in the hypothalamus and send their axons all over the central stimulator were rotated in an alternate acceleration and deceleration nervous system (CNS) (Haas et al., 2008; Thakkar, 2011). mode. The acceleration rate was 16°/s2 for a duration of 7.5 seconds, Blocking histamine H1 receptors with antihistamine drugs and a maximal velocity of 120°/s was reached. A duration of 2.5 induces numerous side effects due to the widespread distri- seconds was used for deceleration with a rate of 48°/s2. Clockwise and bution of histaminergic fibers and H1 receptors in the CNS counterclockwise rotations were alternately repeated for 30 minutes (Haas et al., 2008; Thakkar, 2011). After release, histamine is for the dogs and 120 minutes for the rats. inactivated by methylation almost exclusively by the enzyme, Vomiting served as the index of motion sickness in the dogs. The same rotatory test was repeated 2 weeks later. After averaging the histamine-N-methyltransferase (HNMT) in the CNS (Haas results of two tests, the dogs with a vomiting onset time of less than Downloaded from et al., 2008; Thakkar, 2011). With our knowledge of the 30 minutes were considered susceptible to motion sickness, whereas histamine degradation pathway, we designed an alternative dogs with a vomiting onset time of more than 30 minutes were method that modulated histamine degradation through al- considered insusceptible. tered expression of HNMT in a specific area of the brain stem Conditioned taste aversion, as suggested by the literature to see whether we could prevent motion sickness. (Ossenkopp, 1983; Fox and McKenna, 1988; Sutton et al., 1988; Gallo et al., 1999; Li et al., 2005), was used as the index of rat motion sickness. Before the rotatory stimulus, saccharin sodium solution jpet.aspetjournals.org Materials and Methods (SSS; 0.15%) was provided for the rats to drink for 45 minutes when they had been deprived of water for a 24-hour period and had become Animals and Chemicals. For GeneChip analysis, 16 Beagle dogs familiar with this novel fluid 1 day before water deprivation through consisting of 8 males and 8 females (7.5–10.5 kg b.wt.) were purchased free access to 0.15% SSS in addition to tap water for another 24 hours. from the Teaching and Practicing Farm, Institute of Agriculture, After a 24-hour period of rest with free access to tap water, the rats Shanghai Communication University (Shanghai, People’s Republic of were rotated, and, after another 24-hour period of water deprivation, China). The purchase was qualified and certified by Shanghai 0.15% SSS was then provided for 45 minutes and the SSS intake Laboratory Animal Management Committee [SCXK(Hu)2007-0004]. volume was measured. The same rotatory test was repeated 2 weeks at ASPET Journals on September 30, 2021 For the motion sickness test, another 12 Beagle dogs consisting of later. After averaging the results of two tests, the rats with a decrease 6 males and 6 females (7.8–10.2 kg b.wt.) were purchased from in 0.15% SSS intake of less than 15% were considered insusceptible to Yangzhou Sifang Experimental