Maldonado R, Valverde O, Garbay C, Roques B P
Département of Pharmacochimie Moléculaire et Structurale, U266 INSERM, URA D1500 CNRS, UFR des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Faculté de Pharmacie, Paris, France.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Nov;352(5):565-75. doi: 10.1007/BF00169392.
The aim of this study was to evaluate the role played in the behavioral expression of morphine withdrawal syndrome by protein kinases in the locus coeruleus and the periaqueductal gray matter. Two different families of specific protein kinases have been investigated: serine/threonine and tyrosine kinases. Rats were implanted with cannulas into both the lateral ventricle and the locus coeruleus or the periaqueductal gray matter. Physical dependence was induced by chronic peripheral administration of morphine (from 7 to 30 mg/kg) and withdrawal syndrome was precipitated by injection of naloxone (2 micrograms) into the lateral ventricle. The administration of the serine/threonine kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, H7 (1, 3, 10, and 30 nmol per side) into the locus coeruleus induced a strong attenuation of morphine withdrawal behavior. Signs related to the motor component of abstinence, such as jumping, rearing, and hyperactivity, were the most severely reduced. However, this effect was not dose-dependent, and the response was almost the same with all the doses used. A similar attenuation was observed after the injection of H7 (1, 3, and 10 nmol per side) into the periaqueductal gray matter, but in this case motor signs were less strongly reduced and a larger number of signs were modified, mainly when using the highest dose. The administration of the tyrosine kinase inhibitor 2-hydroxy-5-[N(2,5-dihydroxyphenyl)methyl]amino]-benzoic acid 3-phenylpropyl ester, KB23 (0.3, 1, and 3 nmol per side) into the locus coeruleus or the periaqueductal gray matter had no effect on the withdrawal syndrome behavior, except on teeth chattering. These results suggest that in the locus coeruleus and in the periaqueductal gray matter, serine/threonine kinases are implicated in the behavioral expression of morphine abstinence. In these brain structures, tyrosine kinases appear not to be involved.
本研究的目的是评估蓝斑核和导水管周围灰质中的蛋白激酶在吗啡戒断综合征行为表现中所起的作用。研究了两类不同的特异性蛋白激酶：丝氨酸/苏氨酸激酶和酪氨酸激酶。给大鼠双侧脑室及蓝斑核或导水管周围灰质植入套管。通过慢性外周给予吗啡（7至30mg/kg）诱导身体依赖性，通过向侧脑室内注射纳洛酮（2微克）引发戒断综合征。向蓝斑核注射丝氨酸/苏氨酸激酶抑制剂1-(5-异喹啉磺酰基)-2-甲基哌嗪，H7（每侧1、3、10和30nmol）可强烈减轻吗啡戒断行为。与戒断运动成分相关的体征，如跳跃、竖毛和多动，减轻最为明显。然而，这种作用不依赖剂量，所有使用剂量的反应几乎相同。向导水管周围灰质注射H7（每侧1、3和10nmol）后也观察到类似的减轻，但在这种情况下，运动体征减轻程度较小，更多的体征发生改变，主要是在使用最高剂量时。向蓝斑核或导水管周围灰质注射酪氨酸激酶抑制剂2-羟基-5-[N(2,5-二羟基苯基)甲基]氨基]-苯甲酸3-苯丙酯，KB23（每侧0.3、1和3nmol）对戒断综合征行为没有影响，除了对牙齿打颤有影响。这些结果表明，在蓝斑核和导水管周围灰质中，丝氨酸/苏氨酸激酶与吗啡戒断的行为表现有关。在这些脑结构中，酪氨酸激酶似乎不参与其中。
