Zhou Q, Karlsson K, Liu Z, Johansson P, Le Grevés M, Kiuru A, Nyberg F
Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, Uppsala University, P.O. Box 591, S-751 24, Uppsala, Sweden.
Neuropharmacology. 2001 Aug;41(2):246-53. doi: 10.1016/s0028-3908(01)00055-7.
In this study the level of a substance P endopeptidase (SPE)-like activity was measured in different regions of the rat central nervous system (CNS) after chronic administration of morphine. Male rats (200-220 g) were randomly divided into four groups. Two groups were injected (s.c.) with morphine (10 mg/kg) twice daily, whereas the other two received saline under identical conditions. After 8 days, when animals were completely tolerant to morphine, one of the morphine-treated groups and one group of saline-injected rats were given naloxone (s.c. 2 mg/kg). Withdrawal signs were observed and recorded. The enzyme activity was measured in extracts of the various CNS tissues by following the conversion of synthetic substance P (SP) to its N-terminal fragment SP(1-7) using a radioimmunoassay detecting this product. In discrete CNS areas including periaqueductal grey, spinal cord, substantia nigra and ventral tegmental area (VTA) a significant increase in enzyme activity was observed in the withdrawal group, while tolerant rats exhibited decreased SPE-like activity in the striatum (see Table 1). The enhanced enzyme activity during withdrawal is in agreement with our previous observation that the levels of SP(1-7) in rat brain are affected following naloxone precipitated withdrawal. In some tissues, including VTA, a correlation between the SPE-like activity and the intensity of the opioid abstinence was observed. Our result suggests that the elevated SPE-like activity is responsible for enhanced release of SP(1-7) in rats during morphine withdrawal, affirming a modulatory or regulative role of this enzyme in this state of opioid dependence.
在本研究中，对慢性给予吗啡后大鼠中枢神经系统（CNS）不同区域的P物质内肽酶（SPE）样活性水平进行了测定。雄性大鼠（200 - 220克）被随机分为四组。两组每天皮下注射两次吗啡（10毫克/千克），而另外两组在相同条件下注射生理盐水。8天后，当动物对吗啡完全耐受时，对其中一组吗啡处理组和一组注射生理盐水的大鼠皮下注射纳洛酮（2毫克/千克）。观察并记录戒断症状。通过使用检测该产物的放射免疫测定法，跟踪合成P物质（SP）向其N端片段SP(1 - 7)的转化，来测定各种CNS组织提取物中的酶活性。在包括导水管周围灰质、脊髓、黑质和腹侧被盖区（VTA）在内的离散CNS区域，戒断组的酶活性显著增加，而耐受大鼠纹状体中的SPE样活性降低（见表1）。戒断期间酶活性增强与我们之前的观察结果一致，即纳洛酮诱发戒断后大鼠脑中SP(1 - 7)的水平受到影响。在包括VTA在内的一些组织中，观察到SPE样活性与阿片类戒断强度之间存在相关性。我们的结果表明，升高的SPE样活性导致吗啡戒断期间大鼠体内SP(1 - 7)释放增加，证实了该酶在这种阿片类依赖状态中的调节作用。
