Activity In Certain Brain Regions Research Articles

Influence of neck and back massage on the synchronicity of electrical brain activity

Due to busy working or learning schedules, people spend a lot of time in a sitting, motionless position, which could cause tension neck syndrome and promote other harmful consequences. Massage has been used for health support for many decades. However, there are a lot of different types of massages with different physiological effects, and our knowledge remains pure regarding the biological mechanisms of massage benefits. The question of the influence of massage on functional brain state attracts scientific interest as massage is an available and attractive health-supporting tool. Particular types of massage had been found to reduce frontal brain activity, but others were associated with the activation of certain brain regions. In our study, we aimed to evaluate the impact of combined general and point massage of the cervical-collar area on the electrical activity of the brain in terms of its synchronicity in healthy young subjects. Through cross-correlation analysis of EEG before and after massage, we found that massage of the cervical-collar area increased the synchronicity of electrical activity between the central and frontal regions during resting state with closed eyes and decreased the synchronicity between the central and occipital brain areas during resting state with opened eyes, which allows us to suggest that this type of massage optimizes functional brain state.

Changes of regional brain activity following Tuina therapy for patients with painful cervical spondylosis: a resting-state fMRI study.

The effectiveness of Tuina therapy has been confirmed in treating pain of patients with cervical spondylosis (CS), however, its therapeutic mechanism is still unclear. This study aimed to observe the changes of regional brain activity following Tuina therapy in patients with painful CS based on resting-state functional magnetic resonance imaging (rs-fMRI) data. A total of 27 patients with CS and 27 healthy subjects (HCs) were enrolled in this study. All patients received Tuina therapy every 2 days for 2 weeks. The clinical manifestations of patients were evaluated by the Visual Analog Scale (VAS) and Neck Disability Index (NDI) before and after treatment. In addition, rs-fMRI data were collected and preprocessed in all patients before and after treatment, as well as HCs. HCs underwent a 1-time rs-fMRI scan, whereas CS patients underwent 2-times of rs-fMRI scan. The measure of regional homogeneity (ReHo) was calculated and compared between groups. Finally, relationships between altered brain regions and clinical characteristics were evaluated by Pearson's correlation analysis. After Tuina therapy, VAS and NDI scores of patients decreased. Before treatment, CS patients showed higher ReHo values in the left middle temporal gyrus, left thalamus, right anterior and posterior cingulate gyrus, left inferior parietal gyrus and lower ReHo values in the right gyrus rectus when compared with HCs. After treatment, CS patients exhibited higher ReHo values in the left inferior temporal gyrus, right anterior and posterior cingulate gyrus, left inferior parietal gyrus and lower ReHo values in the right rectus gyrus when compared with HCs. CS patients after treatment demonstrated higher ReHo values in the left inferior occipital gyrus when compared with those before treatment. Positive correlations were found between ReHo values of the right rectus gyrus and VAS, NDI scores in CS patients before treatment. Differences of VAS scores between before and after treatment were negatively correlated with ReHo values of the left inferior temporal gyrus in CS patients after treatment. This study demonstrated the presence of asynchronous activity in certain brain regions in CS patients, which might be associated with pain and cervical spine dysfunction. Tuina therapy might modulate asynchronous activity of abnormal brain regions, which might contribute to the effectiveness of Tuina therapy in alleviating pain and cervical spine dysfunction in CS patients.

Efficacy prediction of acupuncture treatment for migraine without aura based on multimodal MRI: A study protocol.

IntroductionAcupuncture is an effective and safe therapy for patients with migraine without aura (MwoA), but only 41–59% of patients show improvement with this treatment. Screening positive responders to acupuncture treatment for MwoA can ensure that healthcare resources can be appropriately targeted to specific patients who would most benefit. The objective of this study is to determine whether the structure and functional activity in certain brain regions can predict analgesia response in patients with MwoA who receive acupuncture treatment.Methods and analysisA total of 72 patients with MwoA and 72 healthy controls (HCs) will be enrolled in this study. Resting-state structural and functional magnetic resonance imaging (MRI) data will be collected from each participant at baseline. Patients with MwoA will undergo 12 sessions of acupuncture treatment for 8 weeks, twice per week in the first 4 weeks and once per week for the last 4 weeks. The follow-up will be 12 weeks. The number of days with migraine, frequency of migraine attacks, and average visual analog scale scores will be recorded in detail at weeks 0, 4, 8, 12, and 16 and at the end of follow-up (week 20). The positive response rate will be calculated as the proportion of patients with ≥50% reduction in the number of migraine days during follow-up compared with baseline. Machine learning methods will be applied to classify patients with MwoA and HCs and predict patients with response or non-response to acupuncture treatment based on multimodal MRI parameters, such as gray matter volume, regional homogeneity, amplitude of low-frequency fluctuation, fractional anisotropy, and mean diffusivity.DiscussionThis study aims to establish brain structural and functional characteristics that can identify patients with MwoA who will derive analgesia benefits from acupuncture treatment.Trial registration numberhttp://www.chictr.org.cn/showproj.aspx?proj=65443, identifier: ChiCTR2100042915.

Analysis of the placebo response to the therapeutic environment

Placebo is critical for evaluating medical interventions, but it’s also clear that the biology underpinning the placebo effect in humans could have significant clinical and societal impacts. Placebo effects, real responses to false cues, potentially stand at odds with the view that, for adaptive reasons, organisms respond only to true environmental cues. In placebo effects, phenotypic responses are seen in the absence of a biologically active agent. The reason for the increase in the placebo response is largely unknown, but several attempts have been made to overcome this problem. How placebos work is still not quite understood, but it involves a complex neurobiological reaction that includes everything from increases in feel-good neurotransmitters, like endorphins and dopamine, to greater activity in certain brain regions linked to moods, emotional reactions, and self-awareness. All of it can have therapeutic benefit. Reacting to a placebo is not proof that a certain treatment doesn’t work, but rather that another, non-pharmacological mechanism may be present. If placebo responses seen in humans are the result of phenotypic plasticity, then placebo-like effects should be observable in other species—particularly in cases where the environment has been altered to disrupt its reliability. This is the case, and placebo-like effects are seen in a variety of model systems.

Alterations in resting-state gamma activity in patients with schizophrenia: a high-density EEG study.

Alterations of EEG gamma activity in schizophrenia have been reported during sensory and cognitive tasks, but it remains unclear whether changes are present in resting state. Our aim was to examine whether changes occur in resting state, and to delineate those brain regions where gamma activity is altered. Furthermore, we wanted to identify the associations between changes in gamma activity and psychopathological characteristics. We studied gamma activity (30-48Hz) in 60 patients with schizophrenia and 76 healthy controls. EEGs were acquired in resting state with closed eyes using a high-density, 256-channel EEG-system. The two groups were compared in absolute power measures in the gamma frequency range. Compared to controls, in patients with schizophrenia the absolute power was significantly elevated (false discovery rate corrected p < 0.05). The alterations clustered into fronto-central and posterior brain regions, and were positively associated with the severity of psychopathology, measured by the PANSS. Changes in gamma activity can lead to disturbed coordination of large-scale brain networks. Thus, the increased gamma activity in certain brain regions that we found may result in disturbances in temporal coordination of task-free/resting-state networks in schizophrenia. Positive association of increased gamma power with psychopathology suggests that altered gamma activity provides a contribution to symptom presentation.

Convolutional Neural Networks with 3D Input for P300 Identification in Auditory Brain-Computer Interfaces.

From allowing basic communication to move through an environment, several attempts are being made in the field of brain-computer interfaces (BCI) to assist people that somehow find it difficult or impossible to perform certain activities. Focusing on these people as potential users of BCI, we obtained electroencephalogram (EEG) readings from nine healthy subjects who were presented with auditory stimuli via earphones from six different virtual directions. We presented the stimuli following the oddball paradigm to elicit P300 waves within the subject's brain activity for later identification and classification using convolutional neural networks (CNN). The CNN models are given a novel single trial three-dimensional (3D) representation of the EEG data as an input, maintaining temporal and spatial information as close to the experimental setup as possible, a relevant characteristic as eliciting P300 has been shown to cause stronger activity in certain brain regions. Here, we present the results of CNN models using the proposed 3D input for three different stimuli presentation time intervals (500, 400, and 300 ms) and compare them to previous studies and other common classifiers. Our results show >80% accuracy for all the CNN models using the proposed 3D input in single trial P300 classification.

A Multidimensional Quantum Model of Brain Activity: the Exploration of Increased Neural Energy States in Daoist Meditation

In the study of high energy physics, as subatomic particles are in different energy states, a suitable accelerator is needed to explore information inside the atom at deeper and deeper levels. Particularly, there are different neural energy patterns or neuro-quantum states within the brain associated with meditative practices; to find out certain information inside the body, it is necessary to reach a meditative state having increased energy levels. Here we report that Chinese Original Quiet Sitting (COQS)—one style of Chinese Daoist meditation— exhibits noticeable results about different neural energy levels or quantum types using functional magnetic resonance imaging technique. Two different states within COQS were examined. Firstly, a prolonged rest-like meditative state, maintaining a relatively low energy level and showing both activation and deactivation of certain brain regions, was observed. Secondly, a higher energy state was found, showing different pattern with only positive activation of certain brain regions. In particular, it appears that there is a correlation between pineal activation and this high energy meditation practice. Also, the pineal body seems concerning with the “upper elixir field” which is an important region in Daoist meditation. Our results provide new evidence for a seldom studied aspect of human physiological performance which has life science implications. Also, a multidimensional quantum model of brain activity is established to offer a scientific description more properly.

Autonomous system for cross-organ investigation of ethanol-induced acute response in behaving larval zebrafish.

Ethanol is widely consumed and has been associated with various diseases in different organs. It is therefore important to study ethanol-induced responses in living organisms with the capability to address specific organs in an integrative manner. Here, we developed an autonomous system based on a series of microfluidic chips for cross-organ investigation of ethanol-induced acute response in behaving larval zebrafish. This system enabled high-throughput, gel-free, and anesthetic-free manipulation of larvae, and thus allowed real-time observation of behavioral responses, and associated physiological changes at cellular resolution within specific organs in response to acute ethanol stimuli, which would otherwise be impossible by using traditional methods for larva immobilization and orientation. Specifically, three types of chips ("motion," "lateral," and "dorsal"), based on a simple hydrodynamic design, were used to perform analysis in animal behavior, cardiac, and brain physiology, respectively. We found that ethanol affected larval zebrafish in a dose-dependent manner. The motor function of different body parts was significantly modulated by ethanol treatment, especially at a high dose of 3%. These behavioral changes were temporally associated with a slow-down of heart-beating and a stereotyped activation of certain brain regions. As we demonstrated in this proof-of-concept study, this versatile Fish-on-Chip platform could potentially be adopted for systematic cross-organ investigations involving chemical or genetic manipulations in zebrafish model.

On the sentience of fish

Key’s (2016) target article, “Why fish do not feel pain,” is based on a moralistic fallacy where conclusions about natural conditions are drawn not from research and experiments, but from subjective moral views on how things should be. Moreover, the neurobiological findings purporting to show that fish do not feel pain are insufficient for drawing this conclusion. Pentti O. A. Haikonen pentti.haikonen@pp.inet.fi is Adjunct Professor at University of Illinois at Springfield. He is the author of Consciousness and Robot Sentience: Singapore: World Scientific (2012); Robot Brains; circuits and systems for conscious machines: UK: Wiley (2007); and The Cognitive Approach to Conscious Machines: UK: Imprint Academic (2003). https://www.youtube.com/user/PenHaiko The moralistic fallacy is a faulty form of reasoning where conclusions about natural conditions are drawn not from research and experiment, but from subjective moral views on how things ought to be. A well-known example is the denial of the heliocentric model. “The earth cannot orbit the sun, because this would undermine religion and morals.” It should be clear that in this day and age there is no place for this kind of reasoning in scientific research even when the moral conclusions are valid. Unfortunately, Key’s (2016) target article, “Why fish do not feel pain,” is based on precisely such reasoning, beginning with a description of the problems that might arise for the fishing industry and the economy in general were it to be shown that fish can feel pain. Key then notes that it would accordingly be very important to show that this is not the case, and then goes on to review some selected neurobiological findings and interprets them as showing that fish do not have the necessary brain structures for feeling pain. Even if we set the fallacy aside, does Key’s line of argument demonstrate that fish cannot feel pain? I am not convinced. He notes that pain is generated by neural processing in the brain and identifies the brain regions that according to him are necessary to feel pain. This list of painrelated brain regions is based on experiments showing neural activity in certain brain regions have been found to be correlated with pain. These areas include prefrontal cortex, anterior cingulate cortex, somatosensory areas SI and SII and the insular cortex. These (and possibly other) brain areas are active during pain, but not selectively so, as they are also active at other times. Key also cites reports where high-frequency EEG gamma oscillations in discrete cortical Animal Sentience 2016.014: Commentary on Key on Fish Pain 2 regions are associated with feeling pain and interpreted as possibly encoding pain. From these data he concludes that since the cortex is both necessary and sufficient for the feeling of pain in humans, it is reasonable to infer that fish do not feel pain because their brains lack many of the neuroanatomical features he views as necessary for pain. This reasoning has serious shortcomings. Key makes the implicit assumption that the neural processes that generate pain require rather large resources and brain areas. Obviously pain is in the brain and obviously pain-related activity in various parts (if not all) of the brain including the cortex can be detected by various methods. But these findings do not show that the activity detected during pain is actually generating the feeling of pain. These regions are also active during pain-free conditions; it is hence possible that these various regions just produce cognitive processing (Haikonen 2003, 2012) and other responses to pain whereas the actual feeling of pain is generated elsewhere and by other means. The neural mechanism that actually generates the feeling of pain is not yet known; thus, we do not know whether it is a simple one that can fit into the diminutive fish brain or a complex one calling for large cortical resources. The fact that we do not currently understand pain does not imply that it requires great neural complexity. The conclusion that the brain regions identified by Key are necessary for feeling pain is hence premature. The comparison of the fish brain and the human brain fails, as does Key’s ultimate conclusion that fish do not feel pain because their brain lacks the required neuroanatomical features of the human brain.

Subcomponents of brain T2* relaxation in schizophrenia, bipolar disorder and siblings: A Gradient Echo Plural Contrast Imaging (GEPCI) study

Investigating brain tissue T2* relaxation properties in vivo can potentially guide the uncovering of neuropathology in psychiatric illness, which is traditionally examined post mortem. We use an MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique that produces inherently co-registered images allowing quantitative assessment of tissue cellular and hemodynamic properties. Usually described as R2* (=1/T2*) relaxation rate constant, recent developments in GEPCI allow the separation of cellular-specific (R2*C) and hemodynamic (BOLD) contributions to the MRI signal decay. We characterize BOLD effect in terms of tissue concentration of deoxyhemoglobin, i.e. CDEOXY, which reflects brain activity. 17 control (CON), 17 bipolar disorder (BPD), 16 schizophrenia (SCZ), and 12 unaffected schizophrenia sibling (SIB) participants were scanned and post-processed using GEPCI protocols. A MANOVA of 38gray matter regions ROIs showed significant group effects for CDEOXY but not for R2*C. In the three non-control groups, 71–92% of brain regions had increased CDEOXY. Group effects were observed in the superior temporal cortex and the thalamus. Increased superior temporal cortex CDEOXY was found in SCZ (p=0.01), BPD (p=0.01) and SIB (p=0.02), with bilateral effects in SCZ and only left hemisphere effects in BPD and SIB. Thalamic CDEOXY abnormalities were observed in SCZ (p=0.003), BPD (p=0.03) and SIB (p=0.02). Our results suggest that increased activity in certain brain regions is part of the underlying pathophysiology of specific psychiatric disorders. High CDEOXY in the superior temporal cortex suggests abnormal activity with auditory, language and/or social cognitive processing. Larger studies are needed to clarify the clinical significance of relaxometric abnormalities.

Application of Magnetic Resonance Spectroscopy in Patients with Alternating Hemiplegia of Childhood: Findings on Metabolic Dysfunctions

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental syndrome of uncertain etiology. Although the use of magnetic resonance spectroscopy (MRS) for the study of neurologic diseases has grown rapidly over the past decade, its use for AHC patients is quite new. This study was aimed at investigating changes of brain metabolites in patients with alternating hemiplegia of childhood (AHC) during the hemiplegic ictal phases and interictal phases by proton magnetic resonance spectroscopy ((1)H-MRS). (1)H-MRS was used in AHC patients during the hemiplegic ictal phases and interictal phases to evaluate functional activity in certain brain regions. A total of 10 unmedicated, healthy volunteers served as controls. N-acetylaspartate (NAA)/Creatine(Cr) ratio of the frontal lobes, basal ganglia, and temporal lobes in contralateral hemiplegic hemisphere of AHC patients during the ictal phases was significantly lower than that in AHC patients during interictal phases and control subjects. Significantly increased choline-containing compounds (Cho)/Cr were obtained in corresponding regions. These findings suggest neuronal metabolic dysfunctions in frontal lobes, temporal lobes and basal ganglia in AHC patients during ictal phases that perhaps are involved in the pathogenesis of AHC.

The contribution of the dorsolateral prefrontal cortex to the preparation for deception and truth-telling

Recent neuroimaging evidence suggests that the dorsolateral prefrontal cortex is associated with creating deceptive responses. However, the neural basis of the preparatory processes that create deception has yet to be explored. Previous neuroimaging studies have demonstrated that the preparation for a certain task activates brain areas relevant to the execution of that task, leading to the question of whether dorsolateral prefrontal activity is observed during the preparation for deception. In the present study, we used functional magnetic resonance imaging (fMRI) to determine whether dorsolateral prefrontal activity, which increases during the execution of deception compared with the execution of truth-telling, also increases during the preparation for deception compared with the preparation for truth-telling. Our data show that the execution of deception was associated with increased activity in several brain regions, including the left dorsolateral prefrontal cortex, compared with truth-telling, confirming the contribution of this region to the production of deceptive responses. The results also reveal that the preparations for both deception and truth-telling were associated with increased activity in certain brain regions, including the left dorsolateral prefrontal cortex. These findings suggest that the preparations for truth-telling and deception make similar demands on the brain and that the dorsolateral prefrontal activity identified in the preparation phase is associated with general preparatory processes, regardless of whether one is telling a lie or the truth.

Commentary: The only way is down. Augmented deactivation of the default mode network by increased catecholamine transmission - a general mechanism? Reflections on Liddle et al. (2011)

Commentary: The only way is down. Augmented deactivation of the default mode network by increased catecholamine transmission - a general mechanism? Reflections on Liddle et al. (2011)

New pathophysiological mechanisms in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a functional, multifactorial disease characterized by abdominal pain and erratic bowel habit. Changes in gastrointestinal motor function, enhanced perception of stimuli arising from the gut wall and psychosocial factors are thought to be major contributors for symptom generation. In recent years, several additional factors have been identified and postulated to interact with these classical mechanisms. Reduced ability to expel intestinal gas with consequent gas trapping and bowel distension may contribute to abdominal discomfort/pain and bloating. Abnormal activation of certain brain regions following painful stimulation of the rectum suggests altered processing of afferent signals. An acute gastrointestinal infection is now a recognized aetiological factor for symptom development in a subset of IBS patients (i.e. post-infectious IBS), who are probably unable to down-regulate the initial inflammatory stimulus efficiently. Furthermore, low-grade inflammatory infiltration and activation of mast cells in proximity to nerves in the colonic mucosa may also participate in the frequency and severity of perceived abdominal pain in post-infectious and non-specific IBS. Initial evidence suggests the existence of changes in gut microflora, serotonin metabolism and a genetic contribution in IBS pathophysiology. These novel mechanisms may aid a better understanding of the complex pathophysiology of IBS and to develop new therapies.

Brain response to cecal infection with Campylobacter jejuni: analysis with Fos immunohistochemistry

Infections with bacterial pathogens can induce increased anxiety-like behaviors in rodents without otherwise noticeable behavioral or physiological symptoms of sickness, as shown with the food-borne pathogen Campylobacter jejuni. This observation implicates the ability of the brain to sense, and respond to, such an infection. We tested our hypothesis that intestinal infection with the gram-negative bacterium C. jejuni leads to activation of certain brain regions that process gastro-intestinal sensory information. The induction of c-Fos protein as a marker for neuronal activation was assessed in the brains of mice inoculated orally with live C. jejuni, as compared to saline-treated controls. Upon colonization of the intestines, C. jejuni activated visceral sensory nuclei in the brainstem (the nucleus of the solitary tract and the lateral parabrachial nucleus) both one and two days after the oral challenge. In addition, increased c-Fos expression occurred in the hypothalamic paraventricular nucleus on the second day. This neural response occurred in the absence of measurable systemic immune activation, as serum levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 were undetectable and/or unchanged. These findings support the notion that information about infection with C. jejuni in the gut is indeed relayed to the visceral sensory structures in the brain. The brain responses observed could contribute to changes in behavior observed after infection.

Up-regulation of methionine-enkephalin-like immunoreactivity by 2,3,7,8-tetrachlorodibenzo- p-dioxin treatment in the forebrain of the Long-Evans rat

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) is considered to be one of the most toxic environmental contaminants, named dioxin. Exposure to TCDD induces a plethora of intoxication symptoms, including anorexia and hypothermia, in several mammals and human. Enkephalin, an endogenous pentapeptide, is an important neuroregulator of autonomic functions, such as food intake and body temperature. In this study, we investigated the effects of TCDD gastric administration on methionine-enkephalin (MEK) immunoreactivity in the brain of the Long-Evans rat, the species strain considered to be the most TCDD-susceptible, using immunohistochemical staining. A single dose of TCDD (dissolved in olive oil, 50 μg/kg) or olive oil alone was administrated to the rats by gavage. Compared with the vehicle-treated rat, a marked increase in the density of MEK immunoreactive cell bodies, fibers and terminals was found 2 weeks after TCDD treatment in the forebrain of the TCDD-treated rat, i.e. the central amygdaloid nucleus, field CA3 of the hippocampus, paraventricular hypothalamic nucleus, medial preoptic nucleus, interstitial nucleus of the posterior limb of the anterior commissure, lateral globus pallidus, ventral pallidum and lateral division of the bed nucleus of the stria terminalis. These results demonstrated for the first time a site-specific increased enkephalinergic activity in certain brain regions of the Long-Evans rat. It is suggested that the increased MEK immunoreactivity may act as a compensatory adaptation for the pathophysiological alterations caused by TCDD exposure.

The Neural Mechanisms of Moral Cognition: A Multiple-Aspect Approach to Moral Judgment and Decision-Making

We critically review the mushrooming literature addressing the neural mechanisms of moral cognition (NMMC), reaching the following broad conclusions: (1) research mainly focuses on three inter-related categories: the moral emotions, moral social cognition, and abstract moral reasoning. (2) Research varies in terms of whether it deploys ecologically valid or experimentally simplified conceptions of moral cognition. The more ecologically valid the experimental regime, the broader the brain areas involved. (3) Much of the research depends on simplifying assumptions about the domain of moral reasoning that are motivated by the need to make experimental progress. This is a valuable beginning, but as more is understood about the neural mechanisms of decision-making, more realistic conceptions will need to replace the simplified conceptions. (4) The neural correlates of real-life moral cognition are unlikely to consist in anything remotely like a "moral module" or a "morality center." Moral representations, deliberations and decisions are probably highly distributed and not confined to any particular brain sub-system. Discovering the basic neural principles governing planning, judgment and decision-making will require vastly more basic research in neuroscience, but correlating activity in certain brain regions with well-defined psychological conditions helps guide neural level research. Progress on social phenomena will also require theoretical innov- ation in understanding the brain's distinctly biological form of computation that is anchored by emotions, needs, drives, and the instinct for survival.

Effect of Chronic Administration of [D-Pen 2, D-Pen 5]Enkephalin on the Activity of Nitric Oxide Synthase in Brain Regions and Spinal Cord of Mice

Bhargava, H. N. and Y. J. Cao. Effect of chronic administration of [D-Pen 2, D-Pen 5]enkephalin on the activity of nitric oxide synthase in brain regions and spinal cord of mice. Peptides 19(1) 113–117, 1998.—The effect of multiple intracerebroventricular (ICV) injections of [D-Pen 2, D-Pen 5]enkephalin (DPDPE), a δ-opioid receptor agonist, on the activity of nitric oxide synthase (NOS) was determined in the brain regions and spinal cord of the mouse. Male Swiss Webster mice were injected twice daily with DPDPE (20 μg/mouse, ICV) or its vehicle for 4 days. This procedure has previously been shown to induce tolerance to the antinociceptive actions of DPDPE in mice. On day 5, the animals treated with DPDPE were either sacrificed 20 min after an ICV injection of DPDPE (tolerant) or without any injection (abstinent i.e., 16 h after the last injection of DPDPE). NOS activity in brain regions (cortex, striatum, hippocampus, midbrain, pons/medulla, hypothalamus and cerebellum) and spinal cord was determined by the rate of conversion of arginine into citrulline. Tolerance to DPDPE was associated increases in NOS activity in midbrain (49%) and pons/medulla (32%) and decreases in cerebellum (28%) and spinal cord (44%). However, NOS activity was unchanged in the cortex, corpus striatum, hippocampus and hypothalamus. On the other hand, during abstinence from DPDPE, NOS activity increased in midbrain (84%) and hypothalamus (35%) but decreased in cerebral cortex (27%), cerebellum (27%) and spinal cord (20%). NOS activity was unchanged in the corpus striatum, hippocampus and pons/medulla. Previous studies from this laboratory had demonstrated that chronic administration of μ- and κ-opioid receptor agonists results in increases NOS activity in certain brain regions and that tolerance to μ- and κ-, but not to δ-opioid receptor agonists, is attenuated by NOS inhibitors. The present studies, for the first time, demonstrate decreases in NOS activity in certain brain regions and spinal cord of mice treated chronically with δ-opioid receptor agonist. Furthermore, these findings may explain the inability of NOS inhibitors to attenuate tolerance to DPDPE in mice.

Time course of the changes in central nitric oxide synthase activity following chronic treatment with morphine in the mouse: Reversal by naltrexone

1. 1. The time course of the effect of chronic administration of morphine on the activity of nitric oxide synthase (NOS) in the brain regions and spinal cord of the mouse was determined. The effect of naltrexone by itself on the NOS activity and that induced by morphine also were determined. 2. 2. Male Swiss Webster mice were implanted subcutaneously with a pellet containing 25 mg of morphine free base for 4 days. Placebo pellet implanted mice served as controls. 3. 3. Twenty-four hours after treatment with morphine, NOS activity decreased in the cerebellum, midbrain, cortex and remainder of the brain as well as in the spinal cord. Forty-eight and 72 hr after the treatment with morphine, NOS activity increased in the cerebellum and cortex, but no change was observed in the other brain regions and spinal cord. Twenty-four hours after morphine pellet removal (withdrawal), NOS activity in all brain regions and the spinal cord had returned to normal. 4. 4. Implantation of a pellet containing 10 mg of naltrexone did not alter NOS activity in any brain region or spinal cord for 24, 48 and 72 hr or 24 hr after removal of the pellet. 5. 5. Implantation of a naltrexone pellet in conjunction with a morphine pellet blocked the changes in NOS activity in the brain region and spinal cord induced by morphine. 6. 6. It is concluded that the initial decrease in NOS activity by morphine may be related to enhanced motor activity, whereas the increase in NOS activity in certain brain regions may be associated with tolerance-physical dependence development. Additionally, the changes in central NOS activity by morphine appear to be mediated by opioid receptors because they were blocked by concurrent treatment with naltrexone.

Alterations in the expression of the genes encoding specific muscarinic receptor subtypes in the hypothalamus of spontaneously hypertensive rats.

A significant body of evidence exists that is consistent with the possibility that heightened cholinergic activity in certain brain regions, such as the hypothalamus, leads to increased sympathetic tone and subsequent hypertension. The increase in cholinergic activity is mediated at least in part through enhanced sensitivity of muscarinic receptors. In this study, we used the technique of reverse transcriptase-polymerase chain reaction to estimate the relative levels of mRNA encoding the five known subtypes of muscarinic receptors within the hypothalamus of spontaneously hypertensive rats (SHR), a genetic model of the disease, and their normotensive counterparts (Wistar-Kyoto rats). SHR exhibited a significant increase (40% to 50%) in the excitatory M1 subtype (confirmed by receptor binding) and a decrease in the inhibitory M4 subtype of muscarinic receptors before and during the establishment of hypertension. Such alterations may form part of the genotypic profile of inherited hypertension.