Effect of interruption of bulbospinal pathways on lordosis, posture, and locomotion

The effect of interruption of descending bulbospinal projections arising from (i) the medial medullary reticular formation: nucleus reticularis gigantocellularis (NGC) and nucleus reticularis magnocellularis (NMC), (ii) nucleus raphe magnus, and (iii) nucleus subceruleus on the lordosis reflex, posture, and locomotion was examined. After interruption of descending NGC-NMC fibers, time-dependent deficits in lordosis were observed during the first two postoperative weeks with subsequent reflex recovery. A syndrome of postural and locomotor deficits occurred after NGC-NMC lesions. Postoperatively, postural reflexes were dominated by increased extensor tone which resulted in limb hyperextension. Specific time-dependent deficits in the control of extensor and flexor muscle groups involved in locomotion resulted in a motor syndrome that is detailed. After interruption of NMC fibers alone, no postural or locomotor deficits occurred and effects on lordosis were limited to the first few postoperative days. The NMC data suggested that the majority of the functional deficits seen after NGC plus NMC lesions were due to destruction of the NGC descending projections. Interruption of NSC bulbospinal fibers resulted in a significant depletion of spinal cord noradrenaline (NA) but not serotonin (5-HT). Functional deficits, when present, were limited to the first few postoperative days. Although interruption of descending NRM fibers resulted in a significant depletion of spinal cord 5-HT concentrations, greater depletions occurred in the NGC plus NMC group. No functional deficits were observed in the NRM group. These data suggest that interruption of NGC-NMC fibers destroyed the descending output from neurons which integrate the hormonal and sensory information necessary for lordosis.     

Neural mechanism underlying acupuncture analgesia

Acupuncture has been accepted to effectively treat chronic pain by inserting needles into the specific "acupuncture points" (acupoints) on the patient's body. During the last decades, our understanding of how the brain processes acupuncture analgesia has undergone considerable development. Acupuncture analgesia is manifested only when the intricate feeling (soreness, numbness, heaviness and distension) of acupuncture in patients occurs following acupuncture manipulation. Manual acupuncture (MA) is the insertion of an acupuncture needle into acupoint followed by the twisting of the needle up and down by hand. In MA, all types of afferent fibers (Abeta, Adelta and C) are activated. In electrical acupuncture (EA), a stimulating current via the inserted needle is delivered to acupoints. Electrical current intense enough to excite Abeta- and part of Adelta-fibers can induce an analgesic effect. Acupuncture signals ascend mainly through the spinal ventrolateral funiculus to the brain. Many brain nuclei composing a complicated network are involved in processing acupuncture analgesia, including the nucleus raphe magnus (NRM), periaqueductal grey (PAG), locus coeruleus, arcuate nucleus (Arc), preoptic area, nucleus submedius, habenular nucleus, accumbens nucleus, caudate nucleus, septal area, amygdale, etc. Acupuncture analgesia is essentially a manifestation of integrative processes at different levels in the CNS between afferent impulses from pain regions and impulses from acupoints. In the last decade, profound studies on neural mechanisms underlying acupuncture analgesia predominately focus on cellular and molecular substrate and functional brain imaging and have developed rapidly. Diverse signal molecules contribute to mediating acupuncture analgesia, such as opioid peptides (mu-, delta- and kappa-receptors), glutamate (NMDA and AMPA/KA receptors), 5-hydroxytryptamine, and cholecystokinin octapeptide. Among these, the opioid peptides and their receptors in Arc-PAG-NRM-spinal dorsal horn pathway play a pivotal role in mediating acupuncture analgesia. The release of opioid peptides evoked by electroacupuncture is frequency-dependent. EA at 2 and 100Hz produces release of enkephalin and dynorphin in the spinal cord, respectively. CCK-8 antagonizes acupuncture analgesia. The individual differences of acupuncture analgesia are associated with inherited genetic factors and the density of CCK receptors. The brain regions associated with acupuncture analgesia identified in animal experiments were confirmed and further explored in the human brain by means of functional imaging. EA analgesia is likely associated with its counter-regulation to spinal glial activation. PTX-sesntive Gi/o protein- and MAP kinase-mediated signal pathways as well as the downstream events NF-kappaB, c-fos and c-jun play important roles in EA analgesia.     

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.     

Diencephalic modulation of activities of raphe-spinal neurons in the cat

The modulatory effects of diencephalic stimulation on the activities of raphe-spinal neurons were studied extracellularly in cats. Among 240 raphe neurons recorded, 57 neurons were activated antidromically by stimulation of the cervical dorsolateral funiculus. These raphe-spinal neurons were found in the caudal raphe nuclei, i.e., the raphe magnus (43 neurons), raphe obscurus (11), raphe pallidus (2), and raphe pontis (1). All of them responded to innocuous and/or noxious peripheral mechanical stimuli with a broad receptive field. The activities of the majority of these neurons were facilitated by trains of pulse stimulation of the rostral periaqueductal gray and the thalamic relay nucleus but not of the thalamic center median nucleus. The facilitation of firing persisted for more than 3 min after the cessation of train pulse stimulation when the stimulation was applied at 20 Hz for 5 to 30 s. This facilitation was not affected by decortication of the sensorimotor area bilaterally. The facilitatory response to periaqueductal gray stimulation was markedly suppressed by systemic administration of naloxone. On the other hand, that of the thalamic relay nucleus stimulation was found to be unaffected. Based on these findings, the mechanisms of pain relief by stimulation of the rostral periaqueductal gray and thalamic relay nucleus reported in human intractable pain appear to relate, at least partly, to the activation of raphe-spinal neurons. However, the paths to raphe-spinal neurons of stimuli from the periaqueductal gray and the thalamic relay nucleus are thought to be independent from each other based on the different effects of naloxone.     

中缝大核内微量注射5-羟色胺、P物质等对家兔胃运动胃电的影响

目的探讨中缝大核内微量注射5-羟色胺、P物质等对家兔胃运动及胃电的影响.方法通过中缝大核插管,分别向中缝大核内注射微量的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,并利用霍尔效应原理同步描记家兔胃运动与胃电慢波的变化.结果①中缝大核微量注入5-羟色胺、P物质可抑制家兔的胃运动和胃电慢波.②中缝大核微量注入赛庚啶、P物质拮抗剂后可使家兔的胃运动和胃电慢波增强.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.结论中缝大核内的5-羟色胺、P物质参与了家兔胃运动和胃电慢波的调节,而吗啡和去甲肾上腺素可能与中缝大核对胃运动及胃电的调节作用无关.     

Changes in thalamic nociception resulting from morphine- and meperidine-dependence in rats

Rats were injected with progressively increasing doses of morphine or meperidine during a period of 3 to 40 days. From this colony of animals individual rats were used at 3- to 4-day intervals for electrophysiologic experiments to analyze the activity of nociceptive neurons in the somesthetic thalamus. After an i.p. injection of chloralose-urethane and the appropriate preparation for a stereotaxic microelectrode penetration of the thalamus, a nociceptive neuron was identified in the nucleus ventralis posterolateralis by its unique spacing of spike potentials emitted in response to pricking the foot with a pin. In addition to the short-latency response that formed a high activity peak on poststimulus time histograms, spikes following the stimulus up to 500 ms also formed activity peaks. Single-pulse stimulation of the sciatic nerve evoked the same response as pinpricks, but innocuous stimuli (pin shielded with a piece of cork) evoked a response without the late activity peaks. Only neurons that exhibited this differential response were regarded as nociceptive. Their response and spontaneous activity were accumulated separately on a digital computer. Following this, naloxone was infused i.v. and the computer accumulations were repeated. It was found that during naloxone-precipitated narcotic withdrawal, innocuous stimuli evoked responses indicative of pain; the nociceptive system was sensitized. Furthermore, a small dose or morphine or meperidine heightened the sensitization. This action of the narcotic agents was reversed by 5-hydroxytryptophan, which assisted the narcotics in suppressing pain in morphine- or meperidine-dependent rats but had no demonstrable effect in control animals. The spontaneous tonic activity of the nociceptive neurons of the somesthetic thalamus was high in rats exhibiting narcotic dependence. Naloxone decreased the count, but not to the value of the control animals. The sensitization of nociception can be explained by a decreased action of a neural pathway that descends from the periaqueductal gray matter via the nucleus raphe magnus to the spinal cord and there blocks the excitation of the spinothalamic tract cells by A-delta and C fibers. The mechanisms that increase the spontaneous activity of the thalamic nociceptive neurons remain unclear.     

HLA-inferred extended haplotype disparity level is more relevant than the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N?=?889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p?=?0.000037, HR?=?10.68, 95%CI 5.50–32.5) and extended chronic GvHD (p?<?0.000001, HR?=?15.51, CI95% 5.36–44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p?=?0.00065, HR?=?4.05, CI95% 1.69–9.71) and non-relapse mortality (40% vs. 31%, p?=?0.00037, HR?=?5.63, CI95% 2.04–15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT.     

Involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception

Cannabinoids produce antinociceptive and antihyperalgesic effects mainly through activation of the inhibitory CB1 receptors. The demonstration that antinociceptive effects of systemic cannabinoids are significantly diminished following surgical dorsolateral funiculus lesion provides evidence that supraspinal sites and descending pain modulatory pathways play crucial roles in systemic cannabinoid analgesia. In this review, we will firstly provide a background, brief overview of descending modulatory pathways followed by descending pathways implicated in cannabinoid analgesia. We will then describe the recent evidence of the involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception. This review will provide evidences that systemically administered cannabinoids reinforce the descending serotonergic and noradrenergic pathways to produce acute antinociceptive effects via spinal 5-HT7, 5-HT2A and alpha-2 adrenoceptors activation.     

Effects of natural raw meal (NRM) on high-fat diet and dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6J mice

BACKGROUND/OBJECTIVESColitis is a serious health problem, and chronic obesity is associated with the progression of colitis. The aim of this study was to determine the effects of natural raw meal (NRM) on high-fat diet (HFD, 45%) and dextran sulfate sodium (DSS, 2% w/v)-induced colitis in C57BL/6J mice.MATERIALS/METHODSBody weight, colon length, and colon weight-to-length ratio, were measured directly. Serum levels of obesity-related biomarkers, triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), insulin, leptin, and adiponectin were determined using commercial kits. Serum levels of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were detected using a commercial ELISA kit. Histological study was performed using a hematoxylin and eosin (H&E) staining assay. Colonic mRNA expressions of TNF-α, IL-1β, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were determined by RT-PCR assay.RESULTSBody weight and obesity-related biomarkers (TG, TC, LDL, HDL, insulin, leptin, and adiponectin) were regulated and obesity was prevented in NRM treated mice. NRM significantly suppressed colon shortening and reduced colon weight-to-length ratio in HFD+DSS induced colitis in C57BL/6J mice (P < 0.05). Histological observations suggested that NRM reduced edema, mucosal damage, and the loss of crypts induced by HFD and DSS. In addition, NRM decreased the serum levels of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6 and inhibited the mRNA expressions of these cytokines, and iNOS and COX-2 in colon mucosa (P < 0.05).CONCLUSIONThe results suggest that NRM has an anti-inflammatory effect against HFD and DSS-induced colitis in mice, and that these effects are due to the amelioration of HFD and/or DSS-induced inflammatory reactions.