Roles of central opioid, adenosine and peripheral adrenal systems in morphine-induced tolerance and dependence in rat

本研究应用脑内微量注射技术，观察腺苷抑制吗啡耐受的作用部位。中心给药腺苷通过腺苷A1受体和茶碱和/或特异性A1受体拮抗剂抑制吗啡诱导的镇痛能够抑制吗啡诱导的耐受的发展。在大鼠中脑网状细胞核（NRGC）/巨细胞旁网状核（NRPG）和中脑导水管周围灰质（PAG）内微量注射吗啡，可使痛阈显著升高。这些影响被抑制与N6-环己基腺苷（CHA），一个特定的A1激动剂的同时治疗。在NRGC/NRPG和（或）PAG内微量注射N-乙酰- β -内啡肽（1-27）（NABE）也能抑制吗啡的镇痛作用。CHA和NABE的抑制作用可被A1特异性拮抗剂8-环戊基茶碱（CPT）逆转。在吗啡耐受大鼠中，单次微量注射吗啡到NRGC/NRPG和PAG中，不再产生痛阈的增加。吗啡和CPT同时作用于NRGC/NRPG和PAG后，吗啡的镇痛作用恢复。这些结果表明，中枢腺苷系统在吗啡诱导耐受的形成中发挥重要作用。另一方面，在吗啡依赖大鼠，侧脑室（I。C.（五）注射CHA和/或CGS 21680，一种特异性A2受体激动剂。因此，在吗啡依赖的条件下，中央腺苷可能通过A1和A2受体在抑制吗啡戒断症状中发挥作用。

In this studies we examined to determine the site of suppressive action of adenosine to morphine-tolerance by using intracerebral micro-injection technique. Centrally administered adenosine depressed morphine-induced analgesia via adenosine A1 receptor and theophylline and/or specific A1 receptor antagonists were able to suppressed the development of morphine-induced tolerance. In native rats, the micro-injections of morphine into the nucleus reticulates gigantocellularis (NRGC)/the nucleus reticularis paragigantocellularis (NRPG) and the periaqueductal gray matter (PAG), produced significant elevation of pain threshold. These effects were suppressed with simultaneous treatment of N6-cyclohexyladenosine (CHA), a specific A1 agonist. When micro-injected into the NRGC/NRPG and/or PAG, N-acetyl- β -endorphin(1-27)(NABE) also suppressed morphine-induced analgesia. The suppressive effects of CHA and NABE were reversed with simultaneous treatment of 8-cyclopentytheophylline (CPT), a specific A1 antagonist. In morphine-tolerant rats, a single micro-injection of morphine into the NRGC/NRPG and PAG, no longer produced an increase in pain threshold. However, analgesic effect of morphine were recovered with simultaneous treatment of morphine and CPT into the NRGC/NRPG and PAG. These results suggest that central adenosine system plays an important role in the formation of morphine-induced tolerance. On the other hand, in morphine-dependent rat, naloxone-induced abstinence signs were suppressed by intracerebroventricular (I. C. v.) injections of CHA and/or CGS21680, a specific A2 receptor agonist. Therefore, in the morphine-dependent condition, central adenosine may play a role in the suppression of morphine-withdrawal signs via A1 and A2 receptors.