Bull Philip M, Ludwig Mike, Blackburn-Munro Gordon J, Delgado-Cohen Helena, Brown Colin H, Russell John A
School of Biomedical and Clinical Laboratory Sciences, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK.
Eur J Neurosci. 2003 Nov;18(9):2545-51. doi: 10.1046/j.1460-9568.2003.03005.x.
Magnocellular oxytocin neurons develop morphine dependence after intracerebroventricular infusion for 5 days as revealed by their profound excitation following naloxone-induced withdrawal. Oxytocin neurons strongly express nitric oxide synthase (NOS) and nitric oxide (NO) inhibits their activity. This study investigated whether excitation of oxytocin neurons during morphine withdrawal involves reduced activity of NOS and NO. Neuron activity was measured in urethane-anaesthetized rats with blood sampling for oxytocin radioimmunoassay and extracellular single unit firing rate recording of supraoptic nucleus oxytocin neurons. To compare morphine-dependent and -naive rats oxytocin secretion was measured during stimulation by intravenous hypertonic saline infusion. Prior treatment with Nomega-nitro-l-arginine methyl ester, a NOS inhibitor, facilitated osmotically stimulated oxytocin secretion in both morphine-dependent and -naive rats. The facilitation was not different between these groups when corrected for the slower responses observed in morphine-dependent rats. Treatment of morphine-dependent rats with Nomega-nitro-l-arginine methyl ester also enhanced oxytocin secretion during naloxone-precipitated withdrawal. Oxytocin neurons excited by withdrawal were recorded during microdialysis application to the supraoptic nucleus of the NO donor sodium nitroprusside alone and in combination with the GABAA antagonist bicuculline. Sodium nitroprusside inhibited oxytocin neurons during naloxone-precipitated morphine withdrawal and, while bicuculline alone increased firing rate, it did not reduce the inhibition by sodium nitroprusside, in contrast with previous findings in naive rats. Together, these findings indicate that NO restraint of oxytocin secretion is not curtailed during morphine dependence and remains a potent inhibitor of withdrawal excitation despite reduced effectiveness on GABA innervation of the supraoptic nucleus. Hence there is no evidence that changes in NO regulation underlie excitation of oxytocin neurons during opiate withdrawal in morphine dependence.
脑室内注射5天后，大细胞性催产素神经元会产生吗啡依赖性，这可通过纳洛酮诱发戒断后它们的深度兴奋得以揭示。催产素神经元强烈表达一氧化氮合酶（NOS），而一氧化氮（NO）会抑制其活性。本研究调查了吗啡戒断期间催产素神经元的兴奋是否涉及NOS和NO活性的降低。在乌拉坦麻醉的大鼠中测量神经元活性，并采集血液用于催产素放射免疫测定以及视上核催产素神经元的细胞外单单位放电频率记录。为比较吗啡依赖和未依赖的大鼠，在静脉输注高渗盐水刺激期间测量催产素分泌。用NOS抑制剂Nω-硝基-L-精氨酸甲酯预先处理，可促进吗啡依赖和未依赖大鼠的渗透压刺激催产素分泌。校正吗啡依赖大鼠中观察到的较慢反应后，两组之间的促进作用并无差异。用Nω-硝基-L-精氨酸甲酯治疗吗啡依赖大鼠也可增强纳洛酮诱发戒断期间的催产素分泌。在向视上核微透析应用单独的NO供体硝普钠以及与GABAA拮抗剂荷包牡丹碱联合应用期间，记录了戒断引起兴奋的催产素神经元。硝普钠在纳洛酮诱发的吗啡戒断期间抑制催产素神经元，虽然单独使用荷包牡丹碱会增加放电频率，但与未处理大鼠的先前发现相反，它并未降低硝普钠的抑制作用。总之，这些发现表明，在吗啡依赖期间，NO对催产素分泌的抑制作用并未减弱，尽管对视上核GABA神经支配的有效性降低，但它仍然是戒断兴奋的有效抑制剂。因此，没有证据表明在吗啡依赖的阿片类药物戒断期间，NO调节的变化是催产素神经元兴奋的基础。
