Jolas T, Nestler E J, Aghajanian G K
Department of Psychiatry and Pharmacology, Yale University School of Medicine and the Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven 06508, USA.
Neuroscience. 2000;95(2):433-43. doi: 10.1016/s0306-4522(99)00436-4.
Major adaptations after chronic exposure to morphine include an up-regulation of the adenosine 3',5'-monophosphate pathway. Acute opioids, via mu-opioid receptors, disinhibit midbrain serotonergic neurons by suppressing inhibitory GABAergic transmission in the dorsal raphe nucleus and adjacent periaqueductal gray. This study examined whether chronic morphine induces a compensatory increase in GABA inputs to 5-hydroxytryptamine neurons and whether this was associated with an up-regulation of the adenosine 3',5'-monophosphate pathway. The firing rate of serotonergic neurons was reduced in brain slices from morphine-dependent rats, an effect reversed by the GABA(A) antagonist bicuculline. The reduction in firing rate was accompanied by an increased frequency of spontaneous GABAergic inhibitory postsynaptic currents, indicating increased GABA tone in the slice. The increase in GABA tone in brain slices from dependent rats was associated with increased induction of inhibitory postsynaptic currents by the adenylyl cyclase activator forskolin, suggesting an up-regulation of the adenosine 3',5'-monophosphate pathway. Indeed, chronic morphine increased levels of adenylyl cyclase VIII (but not of adenylyl cyclase I, III or V) immunoreactivity in the dorsal raphe nucleus area. Two adenosine 3',5'-monophosphate-mediated mechanisms for the increase in GABA tone were discerned. The first, which predominated when impulse-flow was blocked by tetrodotoxin, involves protein kinase A since it was sensitive to protein kinase A inhibitors. The second, seen when impulse-flow was intact (i.e. absence of tetrodotoxin), was insensitive to protein kinase A inhibitors but was suppressed by ZD7288, a blocker of hyperpolarizing-activated Ih channels which are directly activated by adenosine 3',5'-monophosphate. We conclude that chronic morphine induces an up-regulation of the adenosine 3',5'-monophosphate pathway in GABAergic inputs to serotonergic cells, resulting in an increase in spontaneous and impulse-flow dependent GABA release. These changes would lead to an increase in GABA tone and subsequently to the reported decrease in serotonergic activity during opiate withdrawal.
长期接触吗啡后的主要适应性变化包括3',5'-单磷酸腺苷途径的上调。急性阿片类药物通过μ-阿片受体，通过抑制中缝背核和相邻导水管周围灰质中的抑制性γ-氨基丁酸能传递，解除对中脑5-羟色胺能神经元的抑制。本研究探讨了慢性吗啡是否会导致γ-氨基丁酸对5-羟色胺能神经元的输入代偿性增加，以及这是否与3',5'-单磷酸腺苷途径的上调有关。吗啡依赖大鼠脑片中5-羟色胺能神经元的放电频率降低，γ-氨基丁酸A受体拮抗剂荷包牡丹碱可逆转这一效应。放电频率的降低伴随着自发性γ-氨基丁酸能抑制性突触后电流频率的增加，表明脑片中γ-氨基丁酸张力增加。依赖大鼠脑片中γ-氨基丁酸张力的增加与腺苷酸环化酶激活剂福斯可林诱导的抑制性突触后电流增加有关，提示3',5'-单磷酸腺苷途径上调。事实上，慢性吗啡增加了中缝背核区域腺苷酸环化酶VIII（而非腺苷酸环化酶I、III或V）的免疫反应性水平。发现了两种由3',5'-单磷酸腺苷介导的γ-氨基丁酸张力增加的机制。第一种机制在河豚毒素阻断冲动流时占主导地位，涉及蛋白激酶A，因为它对蛋白激酶A抑制剂敏感。第二种机制在冲动流完整时（即无河豚毒素）出现，对蛋白激酶A抑制剂不敏感，但被ZD7288抑制，ZD7288是一种超极化激活的Ih通道阻滞剂，该通道由3',5'-单磷酸腺苷直接激活。我们得出结论，慢性吗啡诱导了5-羟色胺能细胞γ-氨基丁酸能输入中3',5'-单磷酸腺苷途径的上调，导致自发性和冲动流依赖性γ-氨基丁酸释放增加。这些变化将导致γ-氨基丁酸张力增加，随后导致阿片类药物戒断期间5-羟色胺能活性降低。
