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NeuroImage Aug 2022Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic...
Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex.
INTRODUCTION
Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN).
METHODS
In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN.
RESULTS
Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.
Topics: Amygdala; Brain Mapping; Capsaicin; Chronic Pain; Gyrus Cinguli; Humans; Magnetic Resonance Imaging; Parabrachial Nucleus; Periaqueductal Gray
PubMed: 35523367
DOI: 10.1016/j.neuroimage.2022.119278 -
The Journal of Physiology May 2021Arousal from sleep in response to CO is a life-preserving reflex that enhances ventilatory drive and facilitates behavioural adaptations to restore eupnoeic breathing.... (Review)
Review
Arousal from sleep in response to CO is a life-preserving reflex that enhances ventilatory drive and facilitates behavioural adaptations to restore eupnoeic breathing. Recurrent activation of the CO -arousal reflex is associated with sleep disruption in obstructive sleep apnoea. In this review we examine the role of chemoreceptors in the carotid bodies, the retrotrapezoid nucleus and serotonergic neurons in the dorsal raphe in the CO -arousal reflex. We also provide an overview of the supra-medullary structures that mediate CO -induced arousal. We propose a framework for the CO -arousal reflex in which the activity of the chemoreceptors converges in the parabrachial nucleus to trigger cortical arousal.
Topics: Arousal; Carbon Dioxide; Chemoreceptor Cells; Respiration; Sleep
PubMed: 33759184
DOI: 10.1113/JP281305 -
Brain Sciences Oct 2023Accumulated evidence has demonstrated that the gut microbiome can contribute to pain modulation through the microbiome-gut-brain axis. Various relevant microbiome... (Review)
Review
Accumulated evidence has demonstrated that the gut microbiome can contribute to pain modulation through the microbiome-gut-brain axis. Various relevant microbiome metabolites in the gut are involved in the regulation of pain signaling in the central nervous system. In this review, we summarize recent advances in gut-brain interactions by which the microbiome metabolites modulate pain, with a focus on orofacial pain, and we further discuss the role of gut-brain crosstalk in the central mechanisms of orofacial pain whereby the gut microbiome modulates orofacial pain via the vagus nerve-mediated direct pathway and the gut metabolites/molecules-mediated indirect pathway. The direct and indirect pathways both contribute to the central regulation of orofacial pain through different brain structures (such as the nucleus tractus solitarius and the parabrachial nucleus) and signaling transmission across the blood-brain barrier, respectively. Understanding the gut microbiome-regulated pain mechanisms in the brain could help us to develop non-opioid novel therapies for orofacial pain.
PubMed: 37891825
DOI: 10.3390/brainsci13101456 -
Anatomical Record (Hoboken, N.J. : 2007) Jul 2019Lateral parabrachial nucleus (LPB) is a critical region in the integration and transmission of peripheral nociceptive information. The parabrachio-amygdaloid (P-Amy)...
Lateral parabrachial nucleus (LPB) is a critical region in the integration and transmission of peripheral nociceptive information. The parabrachio-amygdaloid (P-Amy) pathway and parabrachio-ventral tegmental area (P-VTA) pathway is thought to be significant in regulation of pain-related negative emotions. In present study, retrograde tract tracers Fluoro-gold (FG) and tetramethylrhodramine-dextran (TMR) were stereotaxically injected into the right central amygdaloid nucleus (CeA) and right VTA, respectively. Then, part of these rats were performed with the spare nerve injury (SNI) in the controlateral side of FG and TMR injection. Afterwards, double- or triple-immunofluorescent histochemistry was used to examine FG/TMR double- and FG/TMR/FOS or FG/TMR/CGRP triple-labeled neurons in the LPB. The results showed that all of FG, TMR single- and FG/TMR double-labeled neurons were distributed in the LPB bilaterally with an ipsilateral predominance. The proportion of FG/TMR double-labeled neurons to the total number of FG- and TMR-labeled neurons was 10.78% and 13.07%, respectively. Nearly all of the FG/TMR double-labeled neurons (92.67%) showed calcitonin gene-related peptide (CGRP) immunopositive. On the other hand, in the SNI rats, about 89.49% and 77.87% of FG- and TMR-labeled neurons were FG/FOS- and TMR/FOS-positive neurons; about 93.33% of the FG/TMR double-labeled neurons were FOS-LI. Our results suggest that the part of CGRP immunopositive neurons in the LPB send projection fibers to both the CeA and VTA by the way of axon collaterals, which are activated by the nociceptive stimulation in the SNI condition, and may play an important role in the transmission of peripheral nociceptive information. Anat Rec, 302:1178-1186, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
Topics: Animals; Central Amygdaloid Nucleus; Disease Models, Animal; Humans; Male; Neural Pathways; Neuralgia; Neurons; Nociception; Parabrachial Nucleus; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Stereotaxic Techniques; Ventral Tegmental Area
PubMed: 30332715
DOI: 10.1002/ar.23983 -
Frontiers in Public Health 2022Neuropeptide S (NPS) is a neuropeptide primarily produced within three brainstem regions including locus coeruleus, trigeminal nerve nucleus, and lateral parabrachial... (Review)
Review
Neuropeptide S (NPS) is a neuropeptide primarily produced within three brainstem regions including locus coeruleus, trigeminal nerve nucleus, and lateral parabrachial nucleus. NPS is involved in the central regulation of stress, fear, and cognitive integration. NPS is a mediator of behavior, seeking food, and the proliferation of new adipocytes in the setting of obesity. So far, current research of NPS is only limited to animal models; data regarding its functions in humans is still scarce. Animal studies showed that anxiety and appetite might be suppressed by the action of NPS. The discovery of this neuromodulator peptide is effective considering its strong anxiolytic action, which has the potential to be an interesting therapeutic option in treating neuropsychiatric disorders. In this article, we aimed to analyze the pharmaceutical properties of NPS as well as its influence on several neurophysiological aspects-modulation of behavior, association with obesity, as well as its potential application in rehabilitation and treatment of psychiatric disorders.
Topics: Animals; Anxiety; Humans; Mental Disorders; Neuropeptides; Obesity; Receptors, Neuropeptide
PubMed: 35558538
DOI: 10.3389/fpubh.2022.872430 -
Proceedings of the National Academy of... Feb 2024Neuropeptide S (NPS) was postulated to be a wake-promoting neuropeptide with unknown mechanism, and a mutation in its receptor (NPSR1) causes the short sleep duration...
Neuropeptide S (NPS) was postulated to be a wake-promoting neuropeptide with unknown mechanism, and a mutation in its receptor (NPSR1) causes the short sleep duration trait in humans. We investigated the role of different NPS nuclei in sleep/wake regulation. Loss-of-function and chemogenetic studies revealed that NPS neurons in the parabrachial nucleus (PB) are wake-promoting, whereas peri-locus coeruleus (peri-LC) NPS neurons are not important for sleep/wake modulation. Further, we found that a NPS nucleus in the central gray of the pons (CGPn) strongly promotes sleep. Fiber photometry recordings showed that NPS neurons are wake-active in the CGPn and wake/REM-sleep active in the PB and peri-LC. Blocking NPS-NPSR1 signaling or knockdown of supported the function of the NPS-NPSR1 pathway in sleep/wake regulation. Together, these results reveal that NPS and NPS neurons play dichotomous roles in sleep/wake regulation at both the molecular and circuit levels.
Topics: Humans; Sleep; Pons; Locus Coeruleus; Neurons; Neuropeptides; Receptors, G-Protein-Coupled
PubMed: 38381789
DOI: 10.1073/pnas.2320276121 -
Brain Communications 2022Drug relapse is a big clinical challenge in the treatment of addiction, but its neural circuit mechanism is far from being fully understood. Here, we identified a novel...
Drug relapse is a big clinical challenge in the treatment of addiction, but its neural circuit mechanism is far from being fully understood. Here, we identified a novel cholinergic pathway from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPB) to the GABAergic neurons in the central nucleus of the amygdala (CeA) and explored its role in methamphetamine priming-induced reinstatement of conditioned place preference. The anatomical structure and functional innervation of the eLPB-CeA pathway were investigated by various methods such as fluorescent micro-optical sectioning tomography, virus-based neural tracing, fibre photometry, patch-clamp and designer receptor exclusively activated by a designer drug. The role of the eLPB-CeA pathway in methamphetamine relapse was assessed using methamphetamine priming-induced reinstatement of conditioned place preference behaviours in male mice. We found that the eLPB neurons mainly projected to the central nucleus of the amygdala. A chemogenetic activation of the eLPB neurons or triggered the excitabilities of the CeA neurons, which is at least in part mediated via the cholinergic receptor system. Most importantly, the chemogenetic activation of either the eLPB neurons or the eLPB neurons that project onto the central nucleus of the amygdala decreased the methamphetamine priming-induced reinstatement of conditioned place preference in mice. Our findings revealed a previously undiscovered cholinergic pathway of the eLPB-CeA and showed that the activation of this pathway decreased the methamphetamine priming-induced reinstatement of conditioned place preference.
PubMed: 36213311
DOI: 10.1093/braincomms/fcac219 -
Frontiers in Neuroscience 2021Research over the last 20 years regarding the link between circadian rhythms and chronic pain pathology has suggested interconnected mechanisms that are not fully... (Review)
Review
Research over the last 20 years regarding the link between circadian rhythms and chronic pain pathology has suggested interconnected mechanisms that are not fully understood. Strong evidence for a bidirectional relationship between circadian function and pain has been revealed through inflammatory and immune studies as well as neuropathic ones. However, one limitation of many of these studies is a focus on only a few molecules or cell types, often within only one region of the brain or spinal cord, rather than systems-level interactions. To address this, our review will examine the circadian system as a whole, from the intracellular genetic machinery that controls its timing mechanism to its input and output circuits, and how chronic pain, whether inflammatory or neuropathic, may mediate or be driven by changes in these processes. We will investigate how rhythms of circadian clock gene expression and behavior, immune cells, cytokines, chemokines, intracellular signaling, and glial cells affect and are affected by chronic pain in animal models and human pathologies. We will also discuss key areas in both circadian rhythms and chronic pain that are sexually dimorphic. Understanding the overlapping mechanisms and complex interplay between pain and circadian mediators, the various nuclei they affect, and how they differ between sexes, will be crucial to move forward in developing treatments for chronic pain and for determining how and when they will achieve their maximum efficacy.
PubMed: 34276301
DOI: 10.3389/fnins.2021.705173 -
Experimental Neurology Nov 2021We examined cell type-specific expression and distribution of rat brain angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, in the rodent brain. ACE2 is...
We examined cell type-specific expression and distribution of rat brain angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, in the rodent brain. ACE2 is ubiquitously present in brain vasculature, with the highest density of ACE2 expressing capillaries found in the olfactory bulb, the hypothalamic paraventricular, supraoptic, and mammillary nuclei, the midbrain substantia nigra and ventral tegmental area, and the hindbrain pontine nucleus, the pre-Bötzinger complex, and nucleus of tractus solitarius. ACE2 was expressed in astrocytes and astrocytic foot processes, pericytes and endothelial cells, key components of the blood-brain barrier. We found discrete neuronal groups immunopositive for ACE2 in brainstem respiratory rhythm generating centers, including the pontine nucleus, the parafascicular/retrotrapezoid nucleus, the parabrachial nucleus, the Bötzinger, and pre-Bötzinger complexes and the nucleus of tractus solitarius; in the arousal-related pontine reticular nucleus and gigantocellular reticular nuclei; in brainstem aminergic nuclei, including substantia nigra, ventral tegmental area, dorsal raphe, and locus coeruleus; in the epithalamic habenula, hypothalamic paraventricular and supramammillary nuclei; and in the hippocampus. Identification of ACE2-expressing neurons in rat brain within well-established functional circuits facilitates prediction of possible neurological manifestations of brain ACE2 dysregulation during and after COVID-19 infection.
Topics: Angiotensin-Converting Enzyme 2; Animals; Brain; COVID-19; Central Nervous System Diseases; Male; Rats; Rats, Wistar; SARS-CoV-2
PubMed: 34400158
DOI: 10.1016/j.expneurol.2021.113837 -
European Journal of Pharmacology Jun 2011The hypothalamic arcuate nucleus contains two anatomically and functionally distinct populations of neurons-the agouti-related peptide (AgRP)- and pro-opiomelanocortin... (Review)
Review
The hypothalamic arcuate nucleus contains two anatomically and functionally distinct populations of neurons-the agouti-related peptide (AgRP)- and pro-opiomelanocortin (POMC)-expressing neurons that integrate various nutritional, hormonal, and neuronal signals to regulate food intake and energy expenditure, and thereby help achieve energy homeostasis. AgRP neurons, also co-release neuropeptide Y (NPY) and γ-aminobutyric acid (GABA) to promote feeding and inhibit metabolism through at least three possible mechanisms: (1) suppression of the melanocortin signaling system through competitive binding of AgRP with the melanocortin 4 receptors; (2) NPY-mediated inhibition of post-synaptic neurons that reside in hypothalamic nuclei; (3) GABAergic inhibition of POMC neurons in their post-synaptic targets including the parabrachial nucleus (PBN), a brainstem structure that relays gustatory and visceral sensory information. Acute ablation of AgRP neurons in adult mice by the action of diphtheria toxin (DT) results in precipitous reduction of food intake, and eventually leads to starvation within 6days of DT treatment. Chronic delivery of bretazenil, a GABA(A) receptor partial agonist, into the PBN is sufficient to restore feeding and body weight when AgRP neurons are ablated, whereas chronic blockade of melanocortin 4 receptor signaling is inadequate. This review summarizes the physiological roles of a neural circuitry regulated by AgRP neurons in control of feeding behavior with particular emphasis of the GABA output to the parabrachial nucleus. We also describe a compensatory mechanism that is gradually engaged after ablation of AgRP neurons that allows mice to continue eating without them.
Topics: Agouti-Related Protein; Animals; Anorexia; Energy Metabolism; Humans; Neurons; Peptide Fragments; Receptors, Melanocortin; Signal Transduction; gamma-Aminobutyric Acid
PubMed: 21211531
DOI: 10.1016/j.ejphar.2010.10.110