传入 C 纤维的兴奋在电针“足三里” 激活中缝大核中的作用

为了分析电针“足三里”是否以其伤害性刺激性质引起镇痛作用,我们试探了电刺激“足三里”穴区所引起的传人(顺行)冲动是否可以减小刺激腓总神经引起的逆行 C 波。碰撞实验表明刺激“足三里”确可兴奋了腓神经的一些 C 纤维。此外我们还观察到刺激“足三里”的强度达到或超过 C 纤维阈值时。可明显激活中缝大核神经元,当刺激强度达到可引起最大 c 波时,激活 NRM 的效应也达到最大。上述结果提示电针“足三里”除可以其非伤害性刺激性质引起镇痛作用外,可能主要是以其伤害性刺激,经 C 类纤维激活 NRM,再经过痛负反馈调制引起镇痛。     

大鼠下丘脑弓状核对导水管周围灰质—中缝大核系统的兴奋机制及其在电针效应中的作用

清醒箭毒化雄性大白鼠,在人工呼吸维持下,1.分析下丘脑弓状核(AR)兴奋中缝大核(NRM)的机制:观察到电刺激 AR 对 NRM 的兴奋效应,可因切断双侧 AR 至导水管周围灰质(PAG)的β-内啡肽(β-End)能束、PAG 内双侧注射纳洛酮或抗β-End 血清而绝大部分消失,提示 AR 对 NRM 的兴奋效应,主要通过 AR 区β-End 能神经元轴突与 PAG-NRM 系统的直接联系而实现;2.检验 AR 至 PAG-NRM 的神经通路在电针效应中的作用:实验显示上丘水平去大脑后,电针兴奋 NRM 的效应完全消失,表明此效应主要依赖中脑以上结构实现;进一步分别用 Halász 氏刀游离 AR、切断 AR 至 PAG 的β-End 能束、PAG 内注射纳洛酮或抗β-End 血清后,也使电针效应基本上完全消失,说明电针使 NRM神经元兴奋的效应,主要通过 AR 与 PAG-NRM 间的β-End 能神经通路实现。     

生长抑素通过中缝大核发挥镇痛和增强电针镇痛的作用

本工作以钾离子透入引起大鼠甩尾为痛指标,观察了中缝大核微量注射生长抑素、生长抑素的耗竭剂半胱胺和抗生长抑素血清对大鼠痛阈和电针镇痛效应的影响。中缝大核微量注射生长抑素可提高大鼠的痛阈,并使电针镇痛的效应加强。用半胱胺耗竭或用抗生长抑素血清中和中缝大核中的生长抑素,均可使大鼠的痛阈降低,并减弱电针镇痛的效应。这表明生长抑素可能通过中缝大核发挥镇痛和增强电针镇痛的作用。     

肾动脉内注射腺苷兴奋肾神经传入纤维的自发活动

应用记录肾神经传入纤维多单位和单位放电的方法,观察肾动脉内注射腺苷对麻醉家兔肾神经传入纤维自发放电活动的影响。结果表明：(1)肾动脉内注射50,100和200nmol／kg腺苷可呈剂量依赖性地兴奋肾神经传入纤维的活动,而动脉血压不变。(2)肾动脉内预先应用选择性腺苷A1受体阻断剂DPCPX(160nmol/kg),可部分阻断腺苷对肾神经传入纤维的兴奋作用。(3)静脉应用一氧化氮合酶抑制剂L-NAME(0．1mmol／kg)预处理,延长并增强了肾神经传入纤维对腺苷的反应。以上结果提示,肾动脉内应用腺苷可兴奋肾传入纤维的自发放电活动,一氧化氮作为抑制性因素参与腺苷诱导的肾神经传入纤维兴奋。     

肾神经传入纤维在DOCA—salt大鼠高血压形成中的作用

于大鼠皮下埋入含醋酸去氧皮质酮（ＤＯＣＡ）的交管以形成ＤＯＣＡ－ｓａｌｔ高血压,其中一组动物在埋管前切除（Ｔ９－Ｌ２）脊髓右侧背根神经,每周以尾套法测定大鼠收缩压,埋管后６周测定大鼠脑和血浆中儿茶酚胺（ＣＡ）和血管紧张素Ⅱ（ＡｎｇⅡ）的浓度,用电脑血管显微图像分析系统测量血管的结构变化。与对照鼠相比,ＤＯＣＡ－ｓａｌｔ高血压大鼠下丘脑和延脑 肾上腺素含量和ＡｎｇⅡ放免活性及血浆去甲肾上腺素（ＮＥ）     

室旁核在刺激肾神经传入纤维对血浆皮质醇浓度影响中的作用

本文在氯醛糖麻醉猫中探讨室旁核毁损前、后,电刺激肾神经传入纤维对血浆皮质醇浓度的影响。在动脉压力感受器完整猫中,刺激肾神经传入纤维对血浆皮质醇浓度无明显影响,但在动脉压力感受器去神经和迷走神经切断(SAD+VD)后,电刺激肾神经中枢端引起血浆皮质醇浓度升高。微量注射红藻氨酸毁损双侧室旁核后,可阻断刺激肾神经传入纤维引起的血浆皮质醇浓度升高,这些结果表明:动脉压力感受性反射可抑制刺激猫肾神经传入纤维引起的血浆皮质醇浓度升高;室旁核在刺激肾神经传入纤维引起的血浆皮质醇浓度升高效应中起重要作用。     

肾神经传入纤维在DOCA─salt大鼠高血压形成中的作用

于大鼠皮下埋入含醋酸去氧皮质酮（ＤＯＣＡ）的硅胶管以形成ＤＯＣＡ－ｓａｌｔ高血压,其中一组动物在埋管前切除（Ｔ＿９－Ｌ＿２）脊髓右侧背根神经,每周以尾套法测定大鼠收缩压,埋管后６周测定大鼠脑和血浆中儿茶酚胺（ＣＡ）和血管紧张素Ⅱ（ＡｎｇⅡ）的浓度,用电脑血管显微图像分析系统测量血管的结构变化。与对照鼠相比,ＤＯＣＡ－ｓａｌｔ高血压大鼠下丘脑和延脑的肾上腺素含量和ＡｎｇⅡ放免活性及血浆去甲肾上腺素（ＮＥ）浓度均明显增加,血浆ＡｎｇⅡ浓度降低,心系数（心重／体重）和肠系膜动脉的中层厚度、壁厚与腔径（壁腔）比值增大;切除脊髓背根可明显延缓ＤＯＣＡ－ｓａｌｔ高血压的形成、预防以上组织ＣＡ浓度和ＡｎｇⅡ放免活性增加以及缓解心肌和血管平滑肌的肥厚。提示,肾神经传入纤维在ＤＯＣＡ－ｓａｌｔ高血压形成中起作用,其机制可能通过影响脑内肾上腺素能神经元和激活脑肾素－血管紧张素系统增加交感传出而起作用。     

Descending influences from nucleus raphe magnus on fusimotor neurone activity in rats

1. 1.Single fusimotor fibres were isolated in the ventral roots of lumbosacral segments of urethane-anaesthetized rats, and effects of electrical stimulation of the nucleus raphe magnus (NRM) on their spontaneous activity were investigated. The experiments were carried out in rats whose bilateral preoptic and anterior hypothalamic regions (PO/AH) were electrolytically destroyed to eliminate the influences of these regions to fusimotor activity.

2. 2.Of 44 fusimotor fibres studied, 38 (86%) were found to be affected by NRM stimulation. The effects of NRM stimulation were classified according to their response pattern: primary depression (D-type, n = 24), facilitation followed by depression (F-D-type, n = 5) and primary facilitation (F-type, n = 8). The most predominant effect of NRM stimulation upon fusimotor activity was characterized by a strong depression followed by a complete cessation of firing lasting either for a short period or for more than 30 min (D- and F-D-type).

3. 3.In three fusimotor fibres studied in the different preparations, it was observed that a NRM-evoked depression response was blocked by an intraperitoneal administration of a serotonin antagonist, p-chlorophenylalamine (p-CPA) (10 mg/kg).

4. 4.The results indicate that the NRM exerts descending inhibitory or facilitatory influences on fusimotor neurones, and suggest that cold shivering is controlled by modulating fusimotor neurone activity via the serotonergic raphe-signal pathways.

Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats

Currently, opioid-based drugs are the most effective pain relievers that are widely used in the treatment of pain. However, the analgesic efficacy of opioids is significantly limited by the development of tolerance after repeated opioid administration. Glutamate receptors have been reported to critically participate in the development and maintenance of opioid tolerance, but the underlying mechanisms remain unclear. Using whole-cell voltage-clamp recordings in brainstem slices, the present study investigated chronic morphine-induced adaptations in glutamatergic synaptic transmission in neurons of the nucleus raphe magnus (NRM), a key supraspinal relay for pain modulation and opioid analgesia. Chronic morphine significantly increased glutamate synaptic transmission exclusively in one class of NRM cells that contains μ-opioid receptors in a morphine-tolerant state. The adenylyl cyclase activator forskolin and the cAMP analog 8-bromo-cAMP mimicked the chronic morphine effect in control neurons and their potency in enhancing the glutamate synaptic current was significantly increased in neurons from morphine-tolerant rats. MDL12330a, an adenylyl cyclase inhibitor, and H89, a protein kinase A (PKA) inhibitor, reversed the increase in glutamate synaptic transmission induced by chronic morphine. In addition, PMA, a phorbol ester activator of protein kinase C (PKC), also showed an increased potency in enhancing the glutamate synaptic current in these morphine-tolerant cells. The PKC inhibitor GF109203X attenuated the chronic morphine effect. Taken together, these results suggest that chronic morphine increases presynaptic glutamate release in μ receptor-containing NRM neurons in a morphine-tolerant state, and that the increased glutamate synaptic transmission appears to involve an upregulation of both the cAMP/PKA pathway and the PKC pathway. This glutamate-mediated activation of these NRM neurons that are thought to facilitate spinal pain transmission may contribute to the reduced opioid analgesia during opioid tolerance.     

Effect of arginine vasopressin in the nucleus raphe magnus on antinociception in the rat

Previous work has shown that arginine vasopressin (AVP) regulates antinociception through brain nuclei rather than the spinal cord and peripheral organs. The present study investigated the nociceptive effect of AVP in the nucleus raphe magnus (NRM) of the rat. Microinjection of AVP into the NRM increased pain threshold in a dose-dependent manner, while local administration of AVP-receptor antagonist-d(CH2)5Tyr(Et)DAVP decreased the pain threshold. Pain stimulation elevated AVP concentration in the NRM perfuse liquid. NRM pretreatment with AVP-receptor antagonist completely reversed AVP's effect on pain threshold in the NRM. The data suggest that AVP in the NRM is involved in antinociception.     

Arginine vasopressin in hypothalamic paraventricular nucleus is transferred to the nucleus raphe magnus to participate in pain modulation

Hypothalamic paraventricular nucleus (PVN) is one of the main sources of arginine vasopressin (AVP) synthesis and secretion. AVP is the most important bioactive substance in PVN regulating pain process. Our pervious study has pointed that pain stimulation induced AVP increase in the nucleus raphe magnus (NRM), which plays a role in pain modulation. The present study was designed to investigate the source of AVP in the rat NRM during pain process using the methods of nucleus push–pull perfusion and radioimmunoassay. The results showed that pain stimulation increased the AVP concentration in the NRM perfusion liquid, PVN cauterization inhibited the role that pain stimulation induced the increase of AVP concentration in the NRM perfusion liquid, and PVN microinjection of l-glutamate sodium, which excited the PVN neurons, could increase the AVP concentration in the NRM perfusion liquid. The data suggested that AVP in the PVN might be transferred to the NRM to participate in pain modulation.     

Involvement of neuropeptide Y and Y1 receptor in antinociception in nucleus raphe magnus of rats

The nociceptive response latencies increased significantly after intra-nucleus raphe magnus administration of 0.1 or 0.4 nmol of neuropeptide Y, but not 0.04 nmol, in rats. The neuropeptide Y-induced increases in hindpaw withdrawal latency were reversed by following injection of 0.42 nmol of the Y1 antagonist, NPY(28-36). The results indicate that NPY plays an antinociceptive role in nucleus raphe magnus in rats, which is mediated by the Y1 receptor. Furthermore, the neuropeptide Y-induced increases in hindpaw withdrawal latency were attenuated by following intra-nucleus raphe magnus injection of 6 nmol of the opioid antagonist naloxone, indicating that there is an interaction between NPY and opioids in nucleus raphe magnus.     

Antinociceptive role of oxytocin in the nucleus raphe magnus of rats, an involvement of mu-opioid receptor

Recent studies showed that oxytocin plays an important role in nociceptive modulation in the central nervous system. The present study was undertaken to investigate the role of oxytocin in antinociception in the nucleus raphe magnus (NRM) of rats and the possible interaction between oxytocin and the opioid systems. Intra-NRM injection of oxytocin induced dose-dependent increases in hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulation in rats. The antinociceptive effect of oxytocin was significantly attenuated by subsequent intra-NRM injection of the oxytocin antagonist 1-deamino-2-D-Tyr-(Oet)-4-Thr-8-Orn-oxytocin. Intra-NRM injection of naloxone dose-dependently antagonized the increased HWLs induced by preceding intra-NRM injection of oxytocin, indicating an involvement of opioid receptors in oxytocin-induced antinociception in the NRM of rats. Furthermore, the antinociceptive effect of oxytocin was dose-dependently attenuated by subsequent intra-NRM injection of the mu-opioid antagonist beta-funaltrexamine (beta-FNA), but not by the kappa-opioid antagonist nor-binaltorphimine (nor-BNI) or the delta-opioid antagonist naltrindole. The results demonstrated that oxytocin plays an antinociceptive role in the NRM of rats through activating the oxytocin receptor. Moreover, mu-opioid receptors, not kappa and delta receptors, are involved in the oxytocin-induced antinociception in the NRM of rats.     

G protein-coupled receptor kinase 2 mediates mu-opioid receptor desensitization in GABAergic neurons of the nucleus raphe magnus

Nucleus raphe magnus (NRM) sends the projection to spinal dorsal horn and inhibits nociceptive transmission. Analgesic effect produced by mu-opioid receptor agonists including morphine partially results from activating the NRM-spinal cord pathway. It is generally believed that mu-opioid receptor agonists disinhibit spinally projecting neurons of the NRM and produce analgesia by hyperpolarizing GABAergic interneurons. In the present study, whole-cell patch-clamp recordings combined with single-cell RT-PCR analysis were used to test the hypothesis that DAMGO ([D-Ala(2),N-methyl-Phe(4),Gly-ol(5)]enkephalin), a specific mu-opioid receptor agonist, selectively hyperpolarizes NRM neurons expressing mRNA of glutamate decarboxylase (GAD(67)). Homologous desensitization of mu-opioid receptors in NRM neurons could result in the development of morphine-induced tolerance. G protein-coupled receptor kinase (GRK) is believed to mediate mu-opioid receptor desensitization in vivo. Therefore, we also investigated the involvement of GRK in mediating homologous desensitization of DAMAMGO-induced electrophysiological effects on NRM neurons by using two experimental strategies. First, single-cell RT-PCR assay was used to study the expression of GRK2 and GRK3 mRNAs in individual DAMGO-responsive NRM neurons. Whole-cell recording was also performed with an internal solution containing the synthetic peptide, which corresponds to G(betagamma)-binding domain of GRK and inhibits G(betagamma) activation of GRK. Our results suggest that DAMGO selectively hyperpolarizes NRM GABAergic neurons by opening inwardly rectifying K(+) channels and that GRK2 mediates short-term homologous desensitization of mu-opioid receptors in NRM GABAergic neurons.     

蓝斑核、中缝大核和迷走神经背核在胃运动调节中的关系

目的：探讨蓝斑（LC）、中缝大核（NRM）和迷走神经背核（DMV）,及其相关递质和受体对胃运动的调节途径及机制,阐明它们在调节胃运动中的相互关系。方法：实验采用了核团定位电刺激、损毁和核团微量注射等实验方法,以记录胃内压,统计胃收缩幅度作为胃运动变化的指标。结果：①刺激LC显著降低胃收缩幅度（P〈0.01）,损毁DMV可以减弱此效应,而阻断DMV上的肾上腺素能α受体,可以反转此抑胃效应。②刺激NRM显著降低胃收缩幅度（P〈0.01）,损毁DMV后此效应被消除;阻断DMV上的5-HT2A受体使胃收缩幅度大幅度降低（P〈0.01）,此时再刺激NRM不能进一步的抑制胃运动;而损毁LC后刺激NRM,可消除NRM的抑胃效应,在LC注射5-HT2A受体阻断剂也可以消除该效应。结论：①LC可能通过DMV的5-HT2A受体和α受体对生理条件下正常胃的运动起着重要的双向调节作用;②NRM通过LC上的5-HT2A受体而发挥其对胃运动的抑制效应。     

损毁中缝大核对在鼠胃酸排出量及血清胃泌素水平的影响

Medullary raphe nucleus complex plays an important role in the regulation of visceral function. The effects of electrical damage of the nucleus raphe magnus on gastric acid output and serum gastrin level in anesthetized rats were observed. The experiments showed that damage of nucleus raphe magnus increased gastric acid output and serum gastrin level, which could be prevented by vagotomy but not by coeliac and superior mesenteric ganglionectomy.