Beig Mirza I, Horiuchi Jouji, Dampney Roger A L, Carrive Pascal
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Department of Biomedical Engineering, Toyo University, Kawagoe, Saitama, Japan.
Clin Exp Pharmacol Physiol. 2015 Oct;42(10):1059-67. doi: 10.1111/1440-1681.12461.
Orexin/hypocretin neurons are located in and around the perifornical hypothalamus. Disinhibition of this area in the anaesthetized preparation evokes cardiorespiratory changes that can be reduced to nearly half or more by systemic Almorexant, a dual receptor antagonist of the two known orexin receptors, Ox1R and Ox2R. It is not clear if these reductions result from the blockade of one receptor or both. To determine the contribution of the two receptors, we compared the effects of Almorexant to those of the selective Ox1R antagonist ACT335827 and the selective Ox2R antagonists EMPA and TCS-OX2-29. Bicuculline (20 pmol) was injected in the perifornical hypothalamus of urethane-anaesthetized rats before and after administration of the drugs (all 15 mg/kg, intravenously). The pressor, tachycardic and tachypneic responses to bicuculline were attenuated/reduced by ACT335827 (by 19%, ns; 10%, ns and 24%, P < 0.01, respectively), EMPA (by 35% P < 0.01; 6%, ns; and 26% P < 0.05) and TCS-OX2-29 (by 13%, ns; 10%, ns and 42%, P < 0.001). These reductions represented only a fraction of the reduction after Almorexant (by 43%, P < 0.001; 42%, P < 0.001 and 65% P < 0.001). However, when the selective Ox1R and Ox2R antagonists were given in combination, the reductions were greater and closer to those of Almorexant (ACT335827 + EMPA, by 26%, P < 0.05; 24%, P < 0.05 and 47%, P < 0.001; ACT335827 + TCS-OX2-29, by 40%, P < 0.01; 26%, P < 0.001 and 59%, P < 0.0001). This was particularly clear with the tachypneic response. These results suggest that both orexin receptors contribute to the cardiorespiratory response evoked from the hypothalamus under anaesthesia. They are consistent with our previous study in the conscious animal.
食欲素/下丘脑泌素神经元位于穹窿周下丘脑及其周围。在麻醉制剂中对该区域进行去抑制会引发心肺变化，而全身给予阿莫瑞昔（一种已知的两种食欲素受体Ox1R和Ox2R的双重受体拮抗剂）可使这些变化减少近一半或更多。目前尚不清楚这些减少是由于阻断了一种受体还是两种受体。为了确定这两种受体的作用，我们比较了阿莫瑞昔与选择性Ox1R拮抗剂ACT335827以及选择性Ox2R拮抗剂EMPA和TCS - OX2 - 29的作用。在给药物（均为15mg/kg，静脉注射）前后，将荷包牡丹碱（20pmol）注射到乌拉坦麻醉大鼠的穹窿周下丘脑。ACT335827（分别为19%，无统计学意义；10%，无统计学意义和24%，P < 0.01）、EMPA（分别为35%，P < 0.01；6%，无统计学意义；和26%，P < 0.05）以及TCS - OX2 - 29（分别为13%，无统计学意义；10%，无统计学意义和42%，P < 0.001）可使对荷包牡丹碱的升压、心动过速和呼吸急促反应减弱/降低。这些降低仅占阿莫瑞昔给药后降低的一部分（分别为43%，P < 0.001；42%，P < 0.001和65%，P < 0.001）。然而，当联合给予选择性Ox1R和Ox2R拮抗剂时，降低幅度更大且更接近阿莫瑞昔的降低幅度（ACT335827 + EMPA，分别为26%，P < 0.05；24%，P < 0.05和47%，P < 0.001；ACT335827 + TCS - OX2 - 29，分别为40%，P < 0.01；26%，P < 0.001和59%，P < 0.0001）。这在呼吸急促反应中尤为明显。这些结果表明，两种食欲素受体均参与麻醉状态下由下丘脑引发的心肺反应。它们与我们之前在清醒动物中的研究结果一致。
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