Koyuncuoğlu H, Nurten A, Enginar N, Ozerman B, Kara I
University of Istanbul, Institute for Experimental Medicine (DTAE), Department of Neuroscience, Sehremini, Istanbul, Vakif Guraba Cad. 34280, Turkey.
Pharmacol Res. 2001 Mar;43(3):245-50. doi: 10.1006/phrs.2000.0771.
The glutamatergic system is deeply involved in the development of opiate dependence and in the manifestation of opiate abstinence syndrome. In this study the effect of the increase in the endogenous glutamate (GLU) release due to 4-aminopyridine (4-AP), a potassium channel blocker, during the development of morphine (M) physical dependence and during the naloxone (NL)-precipitated abstinence syndrome was investigated. For the development of physical dependence M was intraperitoneally (i.p.) injected for 9 days 105 min following i.p. saline administration to a group of rats. In the first 3 days the dose of M was 10 mg x kg(-1). In the second 3 days the initial dose was doubled (20 mg x kg(-1)) and in the last 3 days the dose of M was raised to 40 mg x kg(-1). On day 10, the rats were divided into three groups at random and these three groups were i.p. given saline 105 min before 80 mg x kg(-1)M, 2 mg x kg(-1) 4-AP 105 min after 80 mg x kg(-1) M, and 80 mg x kg(-1) M 105 min before 2 mg x kg(-1) 4-AP, respectively. In a second group of rats, the rats were i.p. given 2 mg x kg(-1) 4-AP 105 min prior to M administration, which was increased every 3 days (10 mg x kg(-1), 20 mg x kg(-1), 40 mg x kg(-1)). On day 10, the rats were divided into two groups whose first injection was saline and 2 mg x kg(-1) 4-AP, respectively. The second injections of both groups after an interval of 105 min following the first one contained 80 mg x kg(-1) M. In contrast, one group of rats received only i.p. saline at every other injection time (the control group). Furthermore, another group of rats was i.p. administered 2 mg x kg(-1) 4-AP once a day, as the first injection. At the second injection time they were i.p. given saline. After a period of 15 min following the last administration on day 10, the rats belonging to all groups were i.p. injected with 2 mg x kg(-1) NL and immediately placed in a metal cage. Body weight loss (g), teeth chattering, rearing, wet-dog shaking, grooming, and jumping were determined or counted for 15 min. Penile erection, defecation, and diarrhoea were separately scored with one point for every individual occurrence, and the total score was named 'total number of others'. The administration of 4-AP before M appeared to intensify the development of dependence, and was most probably due to the Ca2+-induced inactivation of NMDA receptors as a result of excess release of GLU when the 4-AP took effect. The inactivation of NMDA receptors should have acted as a transient blockade of the receptors during the chronic administration period, and as well as after a single administration on day 10 before M injection and before abstinence. The intensification of the abstinence syndrome may be dependent on the excessive GLU released by 4-AP.
谷氨酸能系统与阿片类药物依赖的发展以及阿片类药物戒断综合征的表现密切相关。在本研究中，研究了钾通道阻滞剂4-氨基吡啶（4-AP）导致内源性谷氨酸（GLU）释放增加，在吗啡（M）身体依赖形成过程以及纳洛酮（NL）诱发的戒断综合征期间的影响。为了形成身体依赖，在一组大鼠腹腔注射生理盐水105分钟后，腹腔注射M，持续9天。在前3天，M的剂量为10mg·kg⁻¹。在第二个3天，初始剂量加倍（20mg·kg⁻¹），在最后3天，M的剂量提高到40mg·kg⁻¹。在第10天，大鼠被随机分为三组，这三组分别在腹腔注射80mg·kg⁻¹M前105分钟腹腔注射生理盐水、在腹腔注射80mg·kg⁻¹M后105分钟腹腔注射2mg·kg⁻¹4-AP、在腹腔注射2mg·kg⁻¹4-AP前105分钟腹腔注射80mg·kg⁻¹M。在另一组大鼠中，在腹腔注射M前105分钟腹腔注射2mg·kg⁻¹4-AP，M的剂量每3天增加一次（10mg·kg⁻¹、20mg·kg⁻¹、40mg·kg⁻¹）。在第10天，大鼠被分为两组，第一次注射分别是生理盐水和2mg·kg⁻¹4-AP。两组在第一次注射105分钟后的第二次注射均含有80mg·kg⁻¹M。相比之下，一组大鼠在每隔一次注射时仅腹腔注射生理盐水（对照组）。此外，另一组大鼠每天腹腔注射一次2mg·kg⁻¹4-AP作为第一次注射。在第二次注射时腹腔注射生理盐水。在第10天最后一次给药后15分钟，所有组的大鼠腹腔注射2mg·kg⁻¹NL，并立即放入金属笼中。测定或计数15分钟内的体重减轻（g）、牙齿打颤、竖毛、湿狗样抖动、梳理毛发和跳跃情况。阴茎勃起、排便和腹泻分别按每次发生计1分，总分称为“其他总数”。在M之前给予4-AP似乎会加剧依赖的发展，这很可能是由于4-AP起效时GLU过度释放导致Ca²⁺诱导的NMDA受体失活。NMDA受体的失活在慢性给药期间以及在第10天M注射前和戒断前单次给药后应起到对受体的短暂阻断作用。戒断综合征的加剧可能取决于4-AP释放的过量GLU。
