Bhargava H N, Das S, Bansinath M, Prasad R
Department of Pharmacodynamics, University of Illinois, Chicago 60612.
Pharmacol Biochem Behav. 1989 Sep;34(1):7-12. doi: 10.1016/0091-3057(89)90344-4.
The effect of chronic administration of morphine and subsequent withdrawal on brain and pituitary receptors for thyrotropin releasing hormone (TRH) was investigated in Sprague-Dawley rats. The rats were implanted subcutaneously with four morphine pellets (each containing 75 mg of morphine free base) during a 3-day period. Placebo pellets, which contained all the excipients of morphine pellets except the morphine, were implanted in rats which served as controls. Both tolerance and physical dependence on morphine have been shown to develop as a result of this procedure. TRH receptors were labeled with 3H-(3-MeHis2) TRH (MeTRH). 3H-MeTRH bound to brain membranes at a single high affinity site with Bmax (receptor density) value of 24.6 +/- 2.2 fmol/mg protein and Kd (apparent dissociation constant) value of 3.7 +/- 0.4 nM. The binding of 3H-MeTRH to five regions of the brain namely, hypothalamus, cortex, striatum, midbrain and pons + medulla, as well as pituitary was also investigated. The binding of 3H-MeTRH to pituitary membranes was increased during the development of tolerance, whereas the binding to membranes prepared from different brain regions was unaffected. Serum concentration of triiodothyronine (T3) and thyroxine (T4) were found to be lower in chronic morphine-treated rats when compared to placebo-treated rats, however, serum TSH level remained unaltered. Twenty-four hours after the removal of morphine pellets (natural withdrawal), the binding of 3H-MeTRH to pons + medulla membranes was greater than in placebo control group. Naloxone-precipitated withdrawal produced results which were qualitatively similar to those obtained in rats from which pellets had been removed. The results suggest that the development of tolerance to morphine may be associated with changes in the pituitary-thyroid axis.
在斯普拉格-道利大鼠中研究了长期给予吗啡及随后撤药对促甲状腺激素释放激素（TRH）脑和垂体受体的影响。在3天期间，给大鼠皮下植入4个吗啡丸（每个含75mg吗啡游离碱）。将含除吗啡外吗啡丸所有辅料的安慰剂丸植入作为对照的大鼠。已表明通过该程序会产生对吗啡的耐受性和身体依赖性。用3H-(3-甲基组氨酸2)TRH（MeTRH）标记TRH受体。3H-MeTRH以单一高亲和力位点与脑膜结合，Bmax（受体密度）值为24.6±2.2fmol/mg蛋白，Kd（表观解离常数）值为3.7±0.4nM。还研究了3H-MeTRH与脑的五个区域即下丘脑、皮质、纹状体、中脑和脑桥+延髓以及垂体的结合。在耐受性形成过程中，3H-MeTRH与垂体膜的结合增加，而与不同脑区制备的膜的结合未受影响。与安慰剂处理的大鼠相比，发现慢性吗啡处理的大鼠血清三碘甲状腺原氨酸（T3）和甲状腺素（T4）浓度较低，然而，血清促甲状腺激素（TSH）水平保持不变。去除吗啡丸（自然撤药）24小时后，3H-MeTRH与脑桥+延髓膜的结合大于安慰剂对照组。纳洛酮诱发的撤药产生的结果在质量上与去除丸剂的大鼠所获得的结果相似。结果表明对吗啡耐受性的形成可能与垂体-甲状腺轴的变化有关。
