Comparison of Brain-and non-brain Penetrating Anti-Histamines Against Motion-induced Emesis in Suncus Murinus (House Musk Shrew)
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摘要Anti-histamines are used in the treatment of motion sickness, but the precise mechanism of action is unknown. In the present studies, we used Suncus murinus to investigate the anti-emetic potential of highly selective brain penetrating histamine H1 receptor antagonist, mepyramine in comparison with the less brain penetrating histamine H1 receptor antagonist, cetirizine; the muscarinic receptor antagonist, scopolamine was used as a positive control.

Motion (4 cm horizontal displacement, 1 Hz, 10 min) induced emesis (8.4 ± 0.6 episodes), reduced sniffing activity (p<0.001) and increased scratching activity (p<0.001). Mepyramine (50 mg/kg, i.p.) and scopolamine (10 mg/kg, i.p.), but not cetirizine (10 mg/kg, i.p.), antagonized significantly motion-induced emesis (P<0.05). The short duration of motion that we used failed to induce quantifiable c-fos expression in area postrema, nucleus tractus solitaries, medial vestibular nucleus and hypothalamus. However, mepyramine, but not cetirizine or scopolamine, caused significant increase in c-fos expression in brain compared with vehicle group. Mepyramine alone without motion also induced significant increases in c-fos expression in brain. The mepyramine-treated animals also were sedated, and had fewer episodes of scratching during the motion test (p<0.001).

Our previous studies using Suncus murinus have shown that stimuli inducing 6-20 episodes of emesis (average from all studies ~10 episodes) are associated with increases of c-fos expression in the brain1, 2. Yet our motion stimulus, which produced ~10 episodes, did not. Moreover, we identified that mepyramine could induce large increases in c-fos expression, independent of whether the animals experienced emesis or not. The pattern of c-fos activation is paradoxical, being more expected from treatments that induce (e.g. cisplatin, others), rather than those that inhibit emesis. Our findings suggest that short periods of provocative motion do not transduce through c-fos to induce emesis. Conversely, the ability of mepyramine but not cetirizine to reduce emesis and scratching and cause sedation appears involve c-fos and H1 receptors located centrally. It is possible that the unexpected profile of action of mepyramine relates its inverse agonist properties opening up new perspectives on emesis control and on mechanisms of side effects involving H1 receptors.
著者Tu Longlong, Rudd John A.
會議名稱Histamine 2017

上次更新時間 2018-22-01 於 09:20