The nuclei of origin of brain stem enkephalin and substance P projections to the rodent nucleus raphe magnus

The sites of origin of brain stem enkephalin and substance P projections to the rodent nucleus raphe magnus were studied utilizing the combined horseradish peroxidase retrograde transport-peroxidase-antiperoxidase immunohistochemical technique. Several brain stem areas were found to contain both enkephalin- and substance P-like immunoreactive double labeled neurons following injection of horseradish peroxidase into the raphe magnus. Nuclei providing both enkephalin and substance P inputs to the raphe magnus include the nucleus reticularis paragigantocellularis, the nucleus cuneiformis, the nucleus solitarius and the trigeminal subdivision of the lateral reticular nucleus. Enkephalin projections to the raphe magnus were also found to originate from the dorsal parabrachial nucleus, the nucleus reticularis gigantocellularis pars α and from an area which corresponds to the A5 group of Dahlström &; Fuxe. Additional neurons containing substance P-like immunoreactivity and horseradish peroxidase reaction product were identified in the superior central raphe nucleus and the nucleus pontis oralis. The midbrain periaqueductal gray contributes very few enkephalin and substance P fibers to the raphe magnus.The nucleus raphe magnus is a key structure in the intrinsic analgesia system and it has also been implicated in other diverse and non-nonciceptive functions. The present study identifies several brain stem sites which provide enkephalin and substance P input to this raphe nucleus. Several of these nuclei have been implicated in central analgesic mechanisms or in non-nociceptive autonomic functions. The present investigation raises the possibility that these brain stem regions may modulate neuronal activity in the raphe magnus via enkephalin or substance P projections and thus influence the involvement of the raphe magnus in both opiate related mechanisms of pain control and non-nociceptive functions.     

Effects of morphine and naloxone on spontaneous activity of fetal rats

Epileptic seizures were induced in immobilized, mechanically ventilated rats by intravenous injection of 1.2 mg/kg bicuculline. Immediately after the onset of electrocortical paroxysmal activity, blood pressure abruptly increased and pulmonary compliance and/or airways resistence increased, as evidenced by the rise in intratracheal pressure during mechanical ventilation. Although the blood pressure rise could be partially blocked by a rapid withdrawal of blood, hemorrhagic pulmonary edema developed which after 15 min led to progressive deterioration of the cardiorespiratory state and death of most animals within 30 to 60 min. Histological examination of the lungs revealed typical signs of respiratory distress due to interstitial and intraalveolar edema. The results obtained indicate that neurogenic pulmonary edema is a consistent complication of bicuculline-induced seizures which may seriously interfere with the seizure-induced metabolic and hemodynamic response of the brain.     

Bulbospinal neurons of the rat rostromedial medulla are highly collateralized

The rostromedial medulla participates in a large variety of sensory, motor, and autonomic functions. We asked whether individual bulbospinal neurons in this region have localized, target-specific terminal arbors or whether they collateralize broadly in the spinal cord. Collateralization was quantified along three spinal axes, rostrocaudal, left-right, and dorsoventral, by using double retrograde labeling. Fluorogold was applied to one target, and cholera toxin B chain (CTB) was applied to the second. We determined the prevalence of neurons that retrogradely label with both tracers in the constituent nuclei of the rostromedial medulla, the raphe nuclei, the gigantocellular reticular nucleus (Gi, bilaterally), the Gi pars alpha (GiA, bilaterally), and the midline medullary reticular formation. A large fraction of neurons in each of these nuclei had bulbospinal projections, ranging from > or =56% for the raphe nuclei to > or =14% for the Gi. For reasons discussed, these values are probably underestimates. Most of the neurons that projected to the lumbar spinal cord also projected to the cervical cord. Likewise, most neurons that projected to the ventral horn also had a collateral branch in the dorsal horn. However, relatively few had bilateral projections; most projected ipsilaterally or contralaterally. A considerable degree of collateralization was also seen among vestibulospinal neurons. The high level of collateralization of the descending projections of the rostromedial medulla suggests that neurons in this area ultimately act on peripheral target tissues or functions that are widely distributed in the body, or that they play a generalized modulatory role across functional modalities, rather than playing specific topographically delimited roles.     

Postsynaptic inhibition of cat medullary dorsal horn neurons by stimulation of nucleus raphe magnus and other brain stem sites

Sensory responses of neurons in the medullary and spinal cord dorsal horn can be inhibited by stimulation of a number of brain stem regions. These regions include the nucleus raphe magnus (NRM), the nucleus reticularis gigantocellularis (NGC), the nucleus reticularis magnocellularis (NMC), the periaqueductal gray (PAG), and the nucleus cuneiformis (CU). The purpose of this study was to determine whether or not this inhibition is mediated by postsynaptic processes. Experiments were carried out on chloralose-anesthetized cats. The responses of 29 medullary dorsal horn (trigeminal subnucleus caudalis) cells were recorded with carbon-fiber microelectrodes. Included were cells which responded to noxious stimulation (nine cells) as well as cells which responded only to nonnoxious input. The presence of postsynaptic inhibition was tested by two indirect techniques. We studied the effects of conditioning stimulation of the five regions on the latency of antidromically activated cells and also on the firing rate of neurons excited by iontophoretically applied glutamate. Conditioning stimulation was associated with a block or increased latency of antidromic activation in 15 of 18 nociceptive and nonnociceptive neurons. These effects reflect membrane hyperpolarization, presumably resulting from postsynaptic inhibition. Furthermore, conditioning stimulation of these regions inhibited the glutamate-evoked firing of all 11 cells tested, also indicating a postsynaptic type of inhibition of medullary dorsal horn cells. Thus these results indicate that at least part of the inhibition induced by stimulation of the NRM, NGC, NMC, PAG, and the CU probably results from postsynaptic inhibitory mechanisms.     

Reproducibility of findings in modern PET neuroimaging: insight from the NRM2018 grand challenge

The reproducibility of findings is a compelling methodological problem that the neuroimaging community is facing these days. The lack of standardized pipelines for image processing, quantification and statistics plays a major role in the variability and interpretation of results, even when the same data are analysed. This problem is well-known in MRI studies, where the indisputable value of the method has been complicated by a number of studies that produce discrepant results. However, any research domain with complex data and flexible analytical procedures can experience a similar lack of reproducibility. In this paper we investigate this issue for brain PET imaging. During the 2018 NeuroReceptor Mapping conference, the brain PET community was challenged with a computational contest involving a simulated neurotransmitter release experiment. Fourteen international teams analysed the same imaging dataset, for which the ground-truth was known. Despite a plurality of methods, the solutions were consistent across participants, although not identical. These results should create awareness that the increased sharing of PET data alone will only be one component of enhancing confidence in neuroimaging results and that it will be important to complement this with full details of the analysis pipelines and procedures that have been used to quantify data.     

MAGIC biomarkers of acute graft-versus-host disease: Biology and clinical application

Acute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation and is the primary cause of early non-relapse mortality (NRM) after transplant. GVHD of the gastrointestinal (GI) tract fuels the systemic inflammatory reaction and consequently is the principal driver of mortality. Recently, the MAGIC algorithm probability (MAP) that is computed from two biomarkers of GI GVHD has been validated to accurately predict risk of NRM throughout the course of early acute GVHD. This review focuses on the biology, clinical evidence, and practical application of the biomarkers in the measurement of acute GVHD.     

Neurochemical changes in the RVM associated with peripheral inflammatory pain stimuli

A greater knowledge of the neurochemical changes occurring during pain states will undoubtedly aid in the discovery of effective pain pharmacotherapies. This study highlights the acute effects of inflammatory agents on neurochemical changes in the rostral ventromedial medulla (RVM), a supraspinal site involved in the processing of painful stimuli. Consistent with previous reports, a peripheral injection of 0.1 mg prostaglandin E(2) (PGE(2)) into the intraplantar area of the rat paw produced thermal hypersensitivity that peaked 10 min after administration. In vivo microdialysis studies in the same animals revealed that this behavioral response correlated with a greater than 2-fold increase (230%) in extracellular serotonin (5-HT) levels in the RVM. In contrast, levels of other neurotransmitters measured, including norepinephrine and dopamine, were not altered in animals receiving this inflammatory agent. Similar to PGE(2), an intraplantar injection of capsaicin (0.1 mg) produced a robust thermal hypersensitivity that was paralleled by a 3-fold increase in levels of 5-HT in the RVM. The next series of experiments showed that acute administration of the opioid analgesic, morphine (5.6 mg/kg; IP), attenuated PGE(2)-induced thermal hypersensitivity and reversed the increase in extracellular 5-HT observed in the RVM. Taken together, these findings extend previous reports of central neurochemical changes during inflammatory pain conditions and show that the combination of behavioral endpoints with microdialysis can yield important insights into the neurochemical environment of the pain circuitry.     

前庭神经核与中缝大核的纤维联系研究

目的:观察大鼠前庭神经核群向中缝大核的投射纤维特征。方法:选择8周龄SD大鼠10只,TMR逆行追踪观察前庭神经核向中缝大核的纤维联系;3 d后荧光显微镜下定位并计数前庭核内标记细胞。结果:将TMR注入中缝大核后,在前庭核群均可见到标记阳性细胞,在前庭内侧核吻侧及外侧核观察到较多阳性神经元,在前庭神经下核标记细胞较少,在前庭神经上核标记细胞最少。结论:前庭核群与中缝大核之间存在双向神经纤维联系。提示中缝大核在前庭信息的传递和处理中发挥作用,可能对身体的平衡及情绪的活动起调节作用。     

Opioid neurons and pain modulation: an ultrastructural analysis of enkephalin in cat superficial dorsal horn

To clarify the circuitry through which opioid compounds modulate spinal and trigeminal nociceptive transmission, we have examined the synaptic associations formed by leucine-enkephalin-containing (enkephalin) neurons in the superficial dorsal horn of the cat. As described previously, punctate enkephalin immunoreactivity is concentrated in the marginal layer (lamina I) and in both the outer and inner layers of the substantia gelatinosa (lamina IIo and IIi). In colchicine treated cats, enkephalin perikarya are most numerous in lamina I and at the border between laminae I and II. Ultrastructural analysis reveals that enkephalin cells receive a diverse afferent input. The majority of afferent inputs are presynaptic to the enkephalin dendrites; few axosomatic synapses are seen. Among these presynaptic axonal profiles are unlabeled axons which resemble primary afferent terminals, including the characteristic central axonal varicosity. Enkephalin dendrites are also postsynaptic to enkephalin immunoreactive axons. Two types of enkephalin axonal profiles appear in the superficial dorsal horn. Class I profiles are only found in lamina I. These are large profiles which form few synapses; those synapses made are axodendritic. Class II enkephalin axons are smaller and are distributed in both layers I and II. While Class II axons most commonly form axo-dendritic synapses, they also form axo-axonic synapses with flat vesicle-containing profiles; the latter are generally presynaptic to the enkephalin terminals. Serial analysis further revealed that both the enkephalin and the flat vesicle-containing profile synapse onto a common dendrite. Although enkephalin axons frequently lie adjacent to round vesicle-containing profiles, anatomical evidence that opioid axons form synapses with this type of ending was not found. An additional type of enkephalin vesicle containing-profile is found in layer IIi; its morphological features do not clearly distinguish its axonal or dendritic origin. These endings are typically postsynaptic to unlabelled central endings, and provide minimal presynaptic input to other elements in the neuropil. Like some class II axons, these labelled profiles contain vesicles which cluster at the membrane immediately adjacent to unlabelled central axons. These results indicate that spinal enkephalin neurons receive a variety of synaptic inputs. These include inputs which may derive from primary afferent axons. Enkephalin neurons, in turn, influence nociceptive transmission predominantly through postsynaptic mechanisms. Finally, while we did not observe enkephalin terminals presynaptic in an axoaxonic relationship, the possibility that enkephalin neurons modulate the excitability of fine fiber nociceptive and nonnociceptive afferents via "nonsynaptic interactions" is discussed.     

中缝大核对胃运动胃电调节作用的实验研究

目的 探讨中缝大核对家兔胃运动和胃电的调节作用。方法 采用中缝大核损毁及微量注射5-羟色胺、赛庚啶、P物质、P物质拮抗剂、吗啡和去甲肾上腺素等方法，并利用霍尔效应原理同步描记家兔胃运动与胃电的变化。结果 1．中缝大核损毁后家兔的胃运动和胃电增强；2．中缝大核微量注入5-羟色胺或P物质可抑制家兔的胃运动和胃电，而微量注入赛庚啶或P物质拮抗剂后可使家兔的胃运动和胃电增强。3．中缝大核微量注入吗啡、去甲肾上腺素后对家兔的胃运动和胃电均无影响。结论 中缝大核参与了家兔胃运动和胃电的调节．该核团内的5-羟色胺和P物质与此调节作用有关，而吗啡和去甲肾上腺素可能与此作用无关。