Department of Anesthesiology, The First Clinical College, China Medical University, Shenyang, Liaoning 110001, China.
Neurosci Lett. 2011 Jan 20;488(2):188-92. doi: 10.1016/j.neulet.2010.11.026. Epub 2010 Nov 18.
The cerebrospinal fluid-contacting nucleus (CSF-CN), distributes and localizes in the ventral periaqueductal central gray (PAG) of the brainstem, which may influence actual composition of the cerebrospinal fluid (CSF) for non-synaptic signal transmission via releasing or absorbing bioactive substances. Many experiments have demonstrated that substance P (SP), a substance that is shown to be up-regulated in CSF-CN, plays an important role in the development of inflammatory pain and neuropathic pain. Thus in the present study, we hypothesize that SP in CSF-CN might contribute to morphine dependence in rats, inhibiting SP with (D-Pro2, D-Phe7, D-Trp9)-SP intracerebroventricular (i.c.v.) injection reduce chronic morphine dependence and withdrawal. Rats were repeatedly injected with morphine in five escalating doses for morphine physical dependence. Morphine withdrawal-like behavioral signs and morphine analgesia behaviors were monitored after naloxone administration following i.c.v. injection of (D-Pro2, D-Phe7, D-Trp9)-SP. And SP-expression of CSF-CN was evaluated with dual-label immunofluorescent technique on morphine withdrawal in rats. After i.c.v. treatment with (D-Pro2, D-Phe7, D-Trp9)-SP, the naloxone-precipitated withdrawal symptoms were significantly attenuated, paw withdrawal threshold/thermal withdrawal latency (PWT/TWL) were increased, and SP-expression in CSF-CN was significantly reduced than control group. SP, known a neurotransmitter/neuromodulator of nociception, has also been implicated in the signs of opioid withdrawal. This study provides the first evidence that SP in CSF-CN contributes to morphine physical dependence and withdrawal, which may provide an important and specific role in mediating the motivational aspects of opiates withdrawal via CSF - the parenchyma of the brain, and may represent a novel pharmacological route such as SP inhibitor i.c.v. injection for the control of drug abuse.
脑脊髓液接触核（CSF-CN）分布并定位于脑干腹侧导水管周围灰质（PAG），通过释放或吸收生物活性物质，可能影响脑脊髓液（CSF）的实际组成，从而实现非突触信号传递。许多实验表明，P 物质（SP）是 CSF-CN 中上调的物质，在炎症性疼痛和神经性疼痛的发展中发挥重要作用。因此，在本研究中，我们假设 CSF-CN 中的 SP 可能导致大鼠对吗啡的依赖，通过脑室（i.c.v.）内注射（D-Pro2，D-Phe7，D-Trp9）-SP 抑制 SP，可减少慢性吗啡依赖和戒断。大鼠连续接受递增剂量的吗啡注射，以建立吗啡躯体依赖模型。在脑室（i.c.v.）内注射（D-Pro2，D-Phe7，D-Trp9）-SP 后，给予纳洛酮，监测吗啡戒断样行为征象和吗啡镇痛行为。采用双重免疫荧光技术评价大鼠吗啡戒断时 CSF-CN 中 SP 的表达。脑室（i.c.v.）内给予（D-Pro2，D-Phe7，D-Trp9）-SP 治疗后，纳洛酮诱发的戒断症状明显减轻，足退缩阈值/热退缩潜伏期（PWT/TWL）增加，CSF-CN 中 SP 表达明显低于对照组。SP 作为痛觉的神经递质/神经调质，也与阿片类药物戒断的征象有关。本研究首次提供证据表明，CSF-CN 中的 SP 有助于吗啡躯体依赖和戒断，这可能通过 CSF-脑实质介导阿片类药物戒断的动机方面发挥重要和特定的作用，并可能代表一种新的药理学途径，如脑室（i.c.v.）内注射 SP 抑制剂，用于控制药物滥用。
