Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice
Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice
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DOI：
10.1152/japplphysiol.00075.2007
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发表时间：
2007-11-01
影响因子：
3.3
通讯作者：
Kuwaki, Tomoyuki
中科院分区：
文献类型：
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作者：
Deng, Ben-Shiang;Nakamura, Akira;Kuwaki, Tomoyuki
我们之前已经证明，前食欲素原敲除小鼠（ORX-KO）的高碳酸血症化学反射在清醒期间减弱，但在睡眠期间不会减弱。然而，在该研究中，由于在不扭曲动物警觉状态的情况下改变吸入气体混合物的成分的技术困难，高碳酸血症刺激已长期施加 6 小时。在本研究中，我们研究了食欲素在清醒期间急性呼吸化学反射中的可能参与。在脑室内施用食欲素或食欲素受体拮抗剂SB-334867之前和之后，连同脑电图和肌电图一起记录通气情况。将高碳酸血症（5或10% CO2）或低氧（15或10% O-2）气体混合物引入记录室5分钟。仅分析安静清醒时的呼吸参数。当小鼠呼吸正常的室内空气时，ORX-KO和野生型(WT)小鼠中的每分钟通气量增加，食欲素-A和食欲素-B但媒介物或SB-334867不增加。正如预期的那样，与 WT 小鼠（0.51 +/- 0.05 ml center dot min(-1)center dot g(-1)center dot% CO2-1）相比，媒介物处理的 ORXKO 小鼠（0.22 +/- 0.03 ml center dot min(-1) center dot g(-1)center dot% CO2-1）中的高碳酸血症化学反射显着减弱。补充orexin-A或-B（3 nmol）部分恢复了ORX-KO小鼠的高碳酸化学反射（orexin-A为0.28 +/- 0.03 ml center dot min(-1) center dot g(-1)center dot% CO2-1，orexin-A为0.32 +/- 0.04 ml center dot min(-1) center dot g(-1) center dot% CO2-1)食欲素B）。此外，在WT小鼠中注射SB-334867（30nmol）降低了高碳酸血症化学反射（0.39+/-0.04ml中心点min(-1)中心点g(-1)中心点%CO2-1）。另一方面，媒介物处理的ORX-KO和SB-334867处理的WT小鼠中的缺氧化学反射与相应对照中的没有不同。我们的研究结果表明，至少在小鼠清醒期间，食欲素在二氧化碳敏感性中起着至关重要的作用。
We have previously shown that hypercapnic chemoreflex in prepro- orexin knockout mice ( ORX- KO) is attenuated during wake but not sleep periods. In that study, however, hypercapnic stimulation had been chronically applied for 6 h because of technical difficulty in changing the composition of the inspired gas mixture without distorting the animal's vigilance states. In the present study we examined possible involvement of orexin in acute respiratory chemoreflex during wake periods. Ventilation was recorded together with electroencephalography and electromyography before and after intracerebroventricular administration of orexin or an orexin receptor antagonist, SB- 334867. A hypercapnic ( 5 or 10% CO2) or hypoxic ( 15 or 10% O-2) gas mixture was introduced into the recording chamber for 5 min. Respiratory parameters were analyzed only for quiet wakefulness. When mice breathed normal room air, orexin- A and orexin- B but not vehicle or SB- 334867 increased minute ventilation in both ORX- KO and wild- type ( WT) mice. As expected, hypercapnic chemoreflex in vehicle- treated ORXKO mice (0.22 +/- 0.03 ml center dot min(-1) center dot g(-1)center dot % CO2-1) was significantly blunted compared with that in WT mice (0.51 +/- 0.05 ml center dot min(-1)center dot g(-1)center dot% CO2-1). Supplementation of orexin- A or - B ( 3 nmol) partially restored the hypercapnic chemoreflex in ORX-KO mice (0.28 +/- 0.03 ml center dot min(-1) center dot g(-1)center dot% CO2-1 for orexin-A and 0.32 +/- 0.04 ml center dot min(-1) center dot g(-1) center dot% CO2-1 for orexinB). In addition, injection of SB- 334867 ( 30 nmol) in WT mice decreased the hypercapnic chemoreflex (0.39 +/- 0.04 ml center dot min(-1) center dot g(-1) center dot% CO2-1). On the other hand, hypoxic chemoreflex in vehicle- treated ORX- KO and SB- 334867- treated WT mice was not different from that in corresponding controls. Our findings suggest that orexin plays a crucial role in CO2 sensitivity at least during wake periods in mice.