外侧缰核在疼痛及其相关情绪调控中的研究进展

<正>2020年国际疼痛学会对“疼痛”的定义作了进一步修改：疼痛是一种与实际或潜在的组织损伤相关或类似的不愉快的感觉和情绪体验^[1]。在新版疼痛定义里,突出了不愉快的感觉和情绪体验作为主要特征和损伤的后果,进一步贴合了生物-心理-社会医学模式,有利于全面、深入地了解疼痛。外侧缰核(lateral habenula, LHb)是大脑的“反奖赏中心”,可被外界厌恶刺激和奖赏缺失所激活^[2]。基于这种特征,对于外侧缰核的研究一直集中在精神分裂症、     

下丘脑室旁核神经元亚群在应激反应中的作用与机制

下丘脑室旁核由多种类型神经元构成,是启动并调节应激反应的关键核团之一。在应激源的作用下,下丘脑室旁核神经元释放多种激素至垂体门脉系统或神经垂体,启动应激反应,并在生殖稳态、电解质平衡以及血压调节中发挥关键作用。本文综述了下丘脑室旁核的不同神经元亚群在应激中的作用与研究进展,旨在为应激的机制研究和药物研发提供新的思路。     

腺苷A1受体在双相呼气和吸气神经元电活动中的作用

目的探讨腺苷A1受体对双相呼气神经元和吸气神经元电活动的影响。方法制作新生大鼠体外延髓脑片标本，主要包含面神经后核内侧区(the medialregion of the nucleus retrofacialis，mNRF)，并保留舌下神经根的完整，以改良Kreb’s液灌流脑片，同步记录舌下神经根和双相呼气神经元/吸气神经元的放电活动。在灌流液中分别单独给予腺苷A1受体的特异性拮抗剂8-环戊-1，3-二丙基黄嘌呤(8-cyclopentyl-1，3-dipropylxa nthine，DPCPX)和特异性激动剂R-苯异丙基-腺苷(R—phenylisoprpyl—adeno sine，R-PIA)观察对神经元放电的影响。结果给予腺苷A1受体拮抗剂DPCPX后，双相呼气神经元/吸气神经元的呼吸周期和呼气时程明显缩短，单位放电峰频率显著性增大；给予相应激动剂R-PIA后，双相呼气神经元的呼气时程明显延长，放电频率和积分幅度显著降低，吸气神经元的放电时程和中期放电的频率和峰频率显著性降低，而早期和晚期的放电频率无明显改变。结论腺苷A1受体可能通过影响双相呼气神经元的电活动参与了呼吸时相的转换，并可能介导了吸气神经元的抑制性突触输入。     

PPARγ在脊髓损伤后潜在的治疗靶点中的作用

1过氧化物酶体增殖物激活受体γ过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor,PPAR)是一个细胞核激素受体家族,具有配体激活核转录因子的功能,有α、δ、γ3种类型[1],激活时须与类维生素A受体结合形成异二聚体而产生作用。类维生素A受体是9-顺势维A酸受体二聚化后PPAR/RXR复合体结合靶基     

GRK 2/3在大鼠下丘脑室旁核CRH分泌调节中的作用

目的探讨G蛋白偶联受体激酶2/3(GRK 2/3)在大鼠下丘脑室旁核促肾上腺皮质激素释放激素(CRH)分泌调节中的作用.方法采用10 nM CRH刺激离体培养的大鼠下丘脑脑片,对该离体模型进行研究.通过Western blot实验研究室旁核GRK 2/3的蛋白表达,逆转录多聚酶链反应(RT-PCR)技术研究室旁核CRH的转录活性.结果10 nM CRH刺激30 min、60 min可引起CRHmRNA表达非常显著地增强(P＜0.01);而GRK 2/3总蛋白在刺激30 min后非常显著地下降(P＜0.01),60 min后仍显著低于对照(P＜0.05).提前给予GRK的拮抗剂肝素1μM,处理2 h可非常显著地抑制GRK 2/3蛋白的表达(P＜0.01);同时非常显著地增加CRH mRNA的表达(P＜0.01).提前给予钙调蛋白(CaM)的特异性拮抗剂W-7 50μM,处理2 h可非常显著抑制CRH刺激30 min引起的GRK 2/3蛋白含量减少(P＜0.01);同时非常显著地抑制CRH mRNA含量(P＜0.01).结论应激早期下丘脑室旁核GRK 2/3在CRH分泌调节中作用不明显.这可能与该阶段CaM增加,抑制GRK 2/3的蛋白表达,削弱其对CRHR1的脱敏作用有关.     

核因子κB在大鼠脑缺血耐受中的作用及其对细胞间黏附分子-1和Bcl-2表达的影响

目的探讨核因子κB(NFκB)在大鼠脑缺血耐受中的作用及其可能的参与途径。方法建立大鼠4血管闭塞的全脑缺血耐受模型。将实验动物随机分为4组：假手术组(sham)。缺血再灌注组(1／R)。缺血预处理加缺血再灌注组(IP I／R)。DTTC(NFκB的特异性抑制剂)加缺血预处理组加缺血再灌注组(Ip^DTTC I／R)。用凝胶电泳迁移率改变分析法检测NFκB的活性，免疫组化技术检测细胞间黏附分子=1(ICAM-1)和Bcl-2的表达。结果I／R中NFκB被激活。IP可抑制其激活，DTTC可逆转IP对I／R中NFCB的抑制效应；IP I／R组与I／R组相比。神经元计数明显增高，ICAM-1的表达降低．Bcl-2的表达增加；给予DTTC处理后，IP的神经保护作用明显减弱。Ip^DTTC I／R组与I／R组ICAM-1和Bcl-2的表达无显著性差异。结论IP的神经保护效应依赖于NFκB的激活，可能部分通过上调Bcl-2的表达，同时抑制I／R中NFκB的活性而减少ICAM-1的产生发挥作用。     

Cholecystokinin-containing and nociceptive neurons in rat edinger-westphal nucleus

The putative peptide neurotransmitter cholecystokinin (CCK) is co-localized witsubstance P (SP) in a dense cluster of neurons located in the rat Edinger-Westphal (EW) nucleus. In an attempt to record electrophysiologically from these CCK-containing neurons, we have identified a group of nociceptive neurons located within the confines of the EW nucleus. The firing pattern of these nociceptive neurons is erratic, sometimes wita bursting pattern and at other times witfairly regular rates whicvary generally from 1 to 7 Hz. These neurons respond to noxious stimuli, sucas toe pinch, witan increase in rate and sometimes enter an apparent depolarization blockade (preceded by an increase in the duration and a decrease in the amplitude of the action potential). Systemically administered morphine suppresses botthe spontaneous firing rate and the toe pinch-induced increase in firing rate. Naloxone is able to reverse the effects of morphine. Althougwe have identified in the EW area a moderate density of terminals containing enkephalin-like immunoreactivity, morphine locally applied via microiontophoresis is largely without effect on the firing of these neurons. We hypothesize that the opiate-induced suppression of these nociceptive neurons is not mediated directly on the EW cells, but rather indirectly througafferent systems.     

Pharmacology of the brachium conjunctivum: red nucleus synaptic system in the baboon.

Acetylcholine, biogenic amines, and certain amino acids were applied by microiontophoresis to parvicellular and magnocellular red nucleus (RN) neurons of baboon while recording brachium conjunctivum (BC)-evoked and amino acid-evoked unit discharge from these neurons. Glycine, gamma-aminobutyric acid, and beta-alanine were potent depressants of BC-RN synaptic transmission, amino acid-evoked firing, and spontaneous activity of all RN neurons studied. Glycine was clearly more potent than the other 2 depressant amino acids. L-Glutamic and DL-homocysteic acid were strong excitants of all RN neurons tested. Dopamine, noradrenaline, and 5-hydroxytryptamine depressed the excitability of both parvicellular and magnocellular RN neurons; no excitatory effects were observed with these biogenic amines on RN neurons. Acetylcholine increased the rate of firing of spontaneously discharging parvicellular RN neurons and facilitated the amino acid-induced firing of these same neurons. Acetylcholine did not facilitate BC-RN synaptic transmission nor could this transmission be blocked by cholinergic antagonists. Unlike parvicellular RN neurons, the responsiveness of magnocellular neurons was either unaltered by acetylcholine or slightly decreased. These experiments demonstrate a difference in the pharmacologic responsiveness of parvicellular and magnocellular RN neurons to acetylcholine but do not provide evidence for a cholinergic input to RN via the brachium conjunctivum.     

Inhibition of nociceptive evoked activity in spinal neurons through a dorsal column-brainstem-spinal loop

In decerebrate-decerebellate cats, dorsal column stimulation (DCst), rostral to bilateral dorsal column cuts, inhibited dorsal horn neurons discharging to various types of nociceptive stimuli. Similar inhibitory effects were observed from conditioning nucleus raphe magnus stimulation. Activation of this dorsal column-brainstem-spinal loop could be part of an important supraspinal "gating' system to account for the alleviation of pain both by DCst and peripheral nerve stimulation in man.     

Role of nucleus basalis in cholinergic control of cortical blood flow.

The present investigation was designed to determine the effect of lesions localized to the nucleus basalis/substantia innominata (NB) on resting and cholinergically activated regional cerebral cortical blood flow (rCBF). Ibotenic acid (10 micrograms) was infused locally at 1 mm caudal to bregma, 3 mm lateral to the midline, and 8 mm below the cortical surface. Effectiveness of lesions was demonstrated by histological verification of lesion sites and determination of choline acetyltransferase activity in cerebral cortex homogenates. rCBF was measured with the autoradiographic iodo-14C-antipyrine technique. Resting rCBF was similar in the hemisphere that received the NB lesion and in the contralateral (intact) side in all regions examined. Physostigmine intravenous infusion (3.3 micrograms.kg-1.min-1) enhanced rCBF in frontal, parietal, occipital, and temporal cortex. The increase was symmetrical, however, indicating inability of NB lesion to affect this phenomenon. It is concluded that the cortical cholinergic afferents originating in the NB are not involved in the control of rCBF.     

Electrophysiological peculiarities of cortical inputs to the cat red nucleus

Complex multicomponent EPSPs of the red nucleus rubro-spinal neurons evoked by stimulation of the sensorimotor cortex and associative fields of the parietal cortex were studied in acute pentobarbitalized cats by intracellular recording technique. Complex cortical EPSPs were recorded in 2/3 of the neurons studied. Components of the EPSPs in question were distinguished by using stimulation of various frequency and intensity. The first component of the EPSPs appearing at the lowest threshold was found to have a short and stable latency, stable rising time for depolarization and was able to follow high frequencies of stimulation. The second component was more variable, although in some EPSPs it too had a short latency, was stable enough and, like the first component could be classified as monosynaptic. The complex character of the EPSPs recorded persisted after the removal of the cerebral gray and was observed when stimulating the white matter so excluding its cortical origin. The first two components of the EPSP were evoked by corticofugal impulsation propagating at an average velocity of 18.5 m/s and 7.5 m/s being supposedly the result of activation of the slow-conducting pyramidal and cortico-rubral neurons. In some rubro-spinal neurons they were characterized by a fast rising phase being apparently an electrophysiological manifestation of the activation of axosomatic synapses.     

Preservation of physical dimensions in a model of reactive synaptogenesis in the red nucleus

Electrical stimulation of the brainstem of 15 decerebrate cats produced stimulus-bound vomiting in only 4 animals. Vomiting was reproducible in only one cat. Effective stimulating sites were located in the solitary tract and reticular formation. Restricted localization of a 'vomiting center', stimulation of which evoked readily reproducible results, could not be obtained.     

Early red nucleus atrophy in relapse‐onset multiple sclerosis

No study has investigated red nucleus (RN) atrophy in multiple sclerosis (MS) despite cerebellum and its connections are elective sites of MS‐related pathology. In this study, we explore RN atrophy in early MS phases and its association with cerebellar damage (focal lesions and atrophy) and physical disability. Thirty‐seven relapse‐onset MS (RMS) patients having mean age of 35.6 ± 8.5 (18–56) years and mean disease duration of 1.1 ± 1.5 (0–5) years, and 36 age‐ and sex‐matched healthy controls (HC) were studied. Cerebellar and RN lesions and volumes were analyzed on 3 T‐MRI images. RMS did not differ from HC in cerebellar lobe volumes but significantly differed in both right (107.84 ± 13.95 mm³ vs. 99.37 ± 11.53 mm³, p = .019) and left (109.71 ± 14.94 mm³ vs. 100.47 ± 15.78 mm³, p = .020) RN volumes. Cerebellar white matter lesion volume (WMLV) inversely correlated with both right and left RN volumes (r = −.333, p = .004 and r = −.298, p = .010, respectively), while no correlation was detected between RN volumes and mean cortical thickness, cerebellar gray matter lesion volume, and supratentorial WMLV (right RN: r = −.147, p = .216; left RN: r = −.153, p = .196). Right, but not left, RN volume inversely correlated with midbrain WMLV (r = −.310, p = .008), while no correlation was observed between whole brainstem WMLV and either RN volumes (right RN: r = −.164, p = .164; left RN: r = −.64, p = .588). Finally, left RN volume correlated with vermis VIIb (r = .297, p = .011) and right interposed nucleus (r = .249, p = .034) volumes. We observed RN atrophy in early RMS, likely resulting from anterograde axonal degeneration starting in cerebellar and midbrain WML. RN atrophy seems a promising marker of neurodegeneration and/or cerebellar damage in RMS.     

Role of corticotropin-releasing factor and its receptor in nociceptive modulation in the central nucleus of amygdala in rats

Corticotropin-releasing factor (CRF) plays important physiological functions in the central nervous system. The present study was performed to investigate the role of CRF and CRF receptor in nociceptive modulation in the central nucleus of amygdala (CeA) of rats. The hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation increased significantly after intra-CeA administration of 0.1 and 0.01 nmol of CRF, but not 0.001 nmol, indicating that CRF induces antinociceptive effects in the CeA of rats. The antinociceptive effect may be due to the dose of CRF was attenuated by intra-CeA administration of 0.1 nmol alpha-hCRF9-41, a selective CRF receptor antagonist, suggesting that the CRF-induced antinociception is mediated by the CRF receptors in the CeA. Furthermore, the HWL to both thermal and mechanical stimulation decreased significantly after intra-CeA administration of alpha-hCRF9-41 alone, suggesting an involvement of endogenous CRF in the CeA in nociceptive modulation. The present study demonstrated that both exogenous and endogenous CRF plays an antinociceptive effect in the CeA, the effect is mediated by CRF receptor.