Bland Sondra T, Hutchinson Mark R, Maier Steven F, Watkins Linda R, Johnson Kirk W
Department of Psychology & Center for Neuroscience, Campus Box 345, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.
Brain Behav Immun. 2009 May;23(4):492-7. doi: 10.1016/j.bbi.2009.01.014. Epub 2009 Feb 3.
Glial activation has recently been discovered to modulate several effects of morphine, including analgesia, tolerance, and dependence. The present studies extend this line of investigation by exploring whether glial activation may also affect extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) shell, a neurochemical corollary of morphine-induced drug reward, during a challenge dose of morphine in experiments both with and without precipitated withdrawal. Morphine or vehicle was administered s.c. for 4 days (starting at 15 mg/kg/day up to 20 mg/kg/day), and the glial activation inhibitor AV411 (7.5 mg/kg) or vehicle was administered twice daily. A challenge dose of morphine (22.5 mg/kg) or saline was then given during dialysis. In the first experiment, naloxone (10 mg/kg) was administered 1h after morphine during dialysis in AV411- or vehicle-treated rats, and behavioral signs of somatic withdrawal were assessed during microdialysis. In the second experiment, using the same dosing regimen, sampling continued 3 h after morphine or saline in AV411- or vehicle-treated rats. NAc DA increased in vehicle-treated rats significantly more than in AV411-treated rats before naloxone treatment, and withdrawal symptoms were significantly reduced in AV411-treated rats. The decrease in morphine-induced NAc DA by AV411 was persistent, lasting 3+h post-morphine. These results indicate that glial activation contributes to the effects of morphine on NAc DA, which is associated with somatic signs of precipitated withdrawal.
最近发现，胶质细胞激活可调节吗啡的多种作用，包括镇痛、耐受性和依赖性。本研究通过探讨在有或无戒断反应的实验中，在给予吗啡激发剂量时，胶质细胞激活是否也可能影响伏隔核（NAc）壳中的多巴胺（DA）细胞外水平，这是吗啡诱导药物奖赏的一种神经化学表现，从而扩展了这一研究方向。皮下注射吗啡或赋形剂4天（开始剂量为15mg/kg/天，最高至20mg/kg/天），并每天两次给予胶质细胞激活抑制剂AV411（7.5mg/kg）或赋形剂。然后在透析期间给予吗啡激发剂量（22.5mg/kg）或生理盐水。在第一个实验中，在AV411或赋形剂处理的大鼠透析期间，吗啡给药1小时后给予纳洛酮（10mg/kg），并在微透析期间评估躯体戒断的行为体征。在第二个实验中，采用相同的给药方案，在AV411或赋形剂处理的大鼠中，吗啡或生理盐水给药3小时后继续取样。在纳洛酮治疗前，赋形剂处理的大鼠中NAc DA的增加显著高于AV411处理的大鼠，且AV411处理的大鼠戒断症状显著减轻。AV411对吗啡诱导的NAc DA的降低是持续性的，在吗啡给药后持续3小时以上。这些结果表明，胶质细胞激活有助于吗啡对NAc DA的作用，这与戒断反应的躯体体征相关。
