Koyuncuŏglu H, Ariciŏglu F, Uresin Y, Dizdar Y, Esin Y
Istanbul Medical Faculty, Department of Pharmacology and Clinical Pharmacology, Turkey.
Pharmacol Biochem Behav. 1992 Aug;42(4):693-8. doi: 10.1016/0091-3057(92)90016-9.
It has previously been shown that subchronic and acute administration of L-asparaginase and glutaminase inhibitors D-Aspartic acid (D-ASP) and prolyl-leucyl-glycinamide (PLG) intensifies and attenuates morphine (M) physical dependence, respectively, by the inhibition of ASP and glutamic acid (GLU) production, and subsequently their normal releases. Tizanidine (TIZ) has long been known to be an alpha 2-adrenoceptor agonist and inhibitor of ASP and GLU release. Therefore, in this study TIZ has been administered subchronically during the development of M physical dependence to rats in which M-containing pellets had been implanted or acutely 30 min before naloxone (NL)-induced abstinence syndrome. The subchronic administration of TIZ intensified NL-precipitated abstinence syndrome whereas its acute administration attenuated it, as did D-ASP and PLG. On the other hand, TIZ added into the medium prevented the in vitro M-dependent-made guinea pig ileum from contracting following NL application. Furthermore, TIZ stopped the already started contraction by NL of the M-dependent ileum, which completely relaxed later. These effects of TIZ on M-dependent ileum were antagonized by the alpha 2-adrenoceptor antagonist yohimbine. The intensification by subchronic TIZ administration of abstinence syndrome was attributed to the lesser release of ASP and GLU, which resulted in the larger blockade of M of ASPergic/GLUergic receptors due to the lesser release of their endogenous agonist ASP and GLU and consequently the higher upregulation of the receptors. The attenuation by acute TIZ administration of NL-precipitated abstinence syndrome was explained with lesser release of ASP and GLU and concomitantly the lesser stimulation of the receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
先前的研究表明，亚慢性和急性给予L-天冬酰胺酶和谷氨酰胺酶抑制剂D-天冬氨酸（D-ASP）和脯氨酰-亮氨酰-甘氨酰胺（PLG），分别通过抑制天冬氨酸（ASP）和谷氨酸（GLU）的产生以及随后它们的正常释放，增强和减弱吗啡（M）的身体依赖性。长期以来，人们都知道替扎尼定（TIZ）是一种α2-肾上腺素能受体激动剂，也是ASP和GLU释放的抑制剂。因此，在本研究中，在M身体依赖性形成过程中，对植入含M药丸的大鼠亚慢性给予TIZ，或在纳洛酮（NL）诱导的戒断综合征前30分钟急性给予TIZ。TIZ的亚慢性给药增强了NL诱导的戒断综合征，而其急性给药则减弱了该综合征，D-ASP和PLG的作用也是如此。另一方面，将TIZ加入培养基中可防止体外M依赖的豚鼠回肠在应用NL后收缩。此外，TIZ可阻止NL已经引发的M依赖回肠的收缩，回肠随后会完全松弛。TIZ对M依赖回肠的这些作用可被α2-肾上腺素能受体拮抗剂育亨宾拮抗。亚慢性给予TIZ导致戒断综合征增强，这归因于ASP和GLU的释放减少，由于其内源性激动剂ASP和GLU的释放减少，导致M对ASP能/GLU能受体的阻断作用增强，从而使受体上调程度更高。急性给予TIZ减弱NL诱导的戒断综合征，其原因是ASP和GLU的释放减少，同时对受体的刺激也减少。（摘要截选至250字）
