Department of Basic Medical Sciences, College of OsteopathicMedicine, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766, USA.
Eur J Pharmacol. 2009 Nov 10;622(1-3):15-24. doi: 10.1016/j.ejphar.2009.09.001. Epub 2009 Sep 14.
We examined whether estrogen negatively modulates cannabinoid-induced regulation of food intake, core body temperature and neurotransmission at proopiomelanocortin (POMC) synapses. Food intake was evaluated in ovariectomized female guinea pigs abdominally implanted with thermal DataLoggers and treated s.c. with the cannabinoid CB(1)/CB(2) receptor agonist WIN 55,212-2, the CB(1) receptor antagonist AM251 or their cremephor/ethanol/0.9% saline vehicle, and with estradiol benzoate (EB) or its sesame oil vehicle. Whole-cell patch clamp recordings were performed in slices through the arcuate nucleus. WIN 55,212-2 produced dose- and time-dependent increases in food intake. EB decreased food intake 8-24h after administration, but rapidly and completely blocked the increase in consumption caused by WIN 55,212-2. EB also attenuated the WIN 55,212-2-induced decrease in core body temperature. The AM251-induced decrease in food intake was unaffected. The diminution of the WIN 55,212-2-induced increase in food intake caused by EB correlated with a marked attenuation of cannabinoid receptor-mediated decreases in glutamatergic miniature excitatory postsynaptic current frequency occurring within 10-15min of steroid application. Furthermore, EB completely blocked the depolarizing shift in the inactivation curve for the A-type K(+) current caused by WIN 55,212-2. The EB-mediated, physiologic antagonism of these presynaptic and postsynaptic actions elicited upon cannabinoid receptor activation was observed in arcuate neurons immunopositive for phenotypic markers of POMC neurons. These data reveal that estrogens negatively modulate cannabinoid-induced changes in appetite, body temperature and POMC neuronal activity. They also impart insight into the neuroanatomical substrates and effector systems upon which these counter-regulatory factors converge in the control of energy homeostasis.
我们研究了雌激素是否会负调控大麻素诱导的进食、核心体温和 POMC 神经元突触神经递质的调节。通过给腹部植入热数据记录器的去卵巢雌性豚鼠皮下给予大麻素 CB1/CB2 受体激动剂 WIN 55,212-2、CB1 受体拮抗剂 AM251 或它们的 Cremephor/乙醇/0.9%生理盐水载体，以及雌二醇苯甲酸酯（EB）或其芝麻油载体，评估进食量。通过切片进行全细胞膜片钳记录穿过弓状核。WIN 55,212-2 产生剂量和时间依赖性的食物摄入量增加。EB 在给药后 8-24 小时减少进食量，但迅速且完全阻断 WIN 55,212-2 引起的消耗增加。EB 还减弱了 WIN 55,212-2 引起的核心体温下降。AM251 引起的食物摄入量减少不受影响。EB 引起的 WIN 55,212-2 诱导的食物摄入量增加减少与大麻素受体介导的谷氨酸能微小兴奋性突触后电流频率的减少相关，这种减少发生在类固醇应用后 10-15 分钟内。此外，EB 完全阻断了 WIN 55,212-2 引起的 A 型 K+电流失活曲线的去极化偏移。在弓状神经元中观察到 EB 介导的、对大麻素受体激活后产生的这些突触前和突触后作用的生理性拮抗作用，这些神经元免疫阳性表型标志物为 POMC 神经元。这些数据表明，雌激素负调控大麻素诱导的食欲、体温和 POMC 神经元活性的变化。它们还深入了解了这些反向调节因子在能量平衡控制中汇聚的神经解剖基质和效应系统。
