Abstract
Motion sickness occurs under a variety of circumstances and is common in the general population. It is usually associated with changes in gastric motility, and hypothermia, which are argued to be surrogate markers for nausea; there are also reports that respiratory function is affected. As laboratory rodents are incapable of vomiting, Suncus murinus was used to model motion sickness and to investigate changes in gastric myoelectric activity (GMA) and temperature homeostasis using radiotelemetry, whilst also simultaneously investigating changes in respiratory function using whole body plethysmography. The anti-emetic potential of the highly selective histamine H1 receptor antagonists, mepyramine (brain penetrant), and cetirizine (non-brain penetrant), along with the muscarinic receptor antagonist, scopolamine, were investigated in the present study. On isolated ileal segments from Suncus murinus, both mepyramine and cetirizine non-competitively antagonized the contractile action of histamine with pKb values of 7.5 and 8.4, respectively; scopolamine competitively antagonized the contractile action of acetylcholine with pA2 of 9.5. In responding animals, motion (1 Hz, 4 cm horizontal displacement, 10 min) increased the percentage of the power of bradygastria, and decreased the percentage power of normogastria whilst also causing hypothermia. Animals also exhibited an increase in respiratory rate and a reduction in tidal volume. Mepyramine (50 mg/kg, i.p.) and scopolamine (10 mg/kg, i.p.), but not cetirizine (10 mg/kg, i.p.), significantly antagonized motion-induced emesis but did not reverse the motion-induced disruptions of GMA, or hypothermia, or effects on respiration. Burst analysis of plethysmographic-derived waveforms showed mepyramine also had increased the inter-retch+vomit frequency, and emetic episode duration. Immunohistochemistry demonstrated that motion alone did not induce c-fos expression in the brain. Paradoxically, mepyramine increased c-fos in brain areas regulating emesis control, and caused hypothermia; it also appeared to cause sedation and reduced the dominant frequency of slow waves. In conclusion, motion-induced emesis was associated with a disruption of GMA, respiration, and hypothermia. Mepyramine was a more efficacious anti-emetic than cetirizine, suggesting an important role of centrally-located H1 receptors. The ability of mepyramine to elevate c-fos provides a new perspective on how H1 receptors are involved in mechanisms of emesis control.
Highlights
Motion sickness, known as kinetosis and travel sickness, is a common but complex syndrome which is characterized by a cluster of signs and symptoms including cold sweating, facial pallor, drowsiness, hypersalivation, “stomach awareness”, and nausea and vomiting (Golding and Gresty, 2015)
The contractile action was significantly reduced by 52% by tetrodotoxin (1 μM) (p < 0.01), but not by atropine (1 μM) or hexamethonium (500 μM) (Figure 2B)
Body temperature was ∼35◦C and gastric myoelectric activity (GMA) was typified by a dominant frequency (DF) of 15 cpm, with 44% of the percentage power being in the normogastric range, which is consistent with our previous studies (Percie du Sert et al, 2010)
Summary
Known as kinetosis and travel sickness, is a common but complex syndrome which is characterized by a cluster of signs and symptoms including cold sweating, facial pallor, drowsiness, hypersalivation, “stomach awareness”, and nausea and vomiting (Golding and Gresty, 2015). Two main classes of drug, anticholinergics (e.g., scopolamine) and antihistamines (e.g., promethazine) are the most common treatments for motion sickness (Schmäl, 2013; Golding and Gresty, 2015) These types of agents are variably efficacious in motion sickness and are associated with unwanted side effects including sedation, drowsiness, blurred vision, depression, and dry mouth/nose/throat (Spinks and Wasiak, 2011; Schmäl, 2013). Other non-brain penetrant compounds such as cetirizine and fexofenadine (the active metabolite of terfenadine) failed to prevent motion sickness, their side effect profiles were not documented (Cheung et al, 2003) In these clinical studies, the motion sicknessrating scores were related to “nausea” and not “vomiting.” It remains unknown, whether highly selective, nonbrain penetrant histamine H1 receptor antagonists are able to affect vomiting, as opposed to nausea or associated physiological changes, in the absence of undesirable side effects
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