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Frontiers in Neuroscience 2023Visceral pain is a complex and heterogeneous pain condition that is often associated with pain-related negative emotional states, including anxiety and depression, and... (Review)
Review
Visceral pain is a complex and heterogeneous pain condition that is often associated with pain-related negative emotional states, including anxiety and depression, and can exert serious effects on a patient's physical and mental health. According to modeling stimulation protocols, the current animal models of visceral pain mainly include the mechanical dilatation model, the ischemic model, and the inflammatory model. Acupuncture can exert analgesic effects by integrating and interacting input signals from acupuncture points and the sites of pain in the central nervous system. The brain nuclei involved in regulating visceral pain mainly include the nucleus of the solitary tract, parabrachial nucleus (PBN), locus coeruleus (LC), rostral ventromedial medulla (RVM), anterior cingulate cortex (ACC), paraventricular nucleus (PVN), and the amygdala. The neural circuits involved are PBN-amygdala, LC-RVM, amygdala-insula, ACC-amygdala, claustrum-ACC, bed nucleus of the stria terminalis-PVN and the PVN-ventral lateral septum circuit. Signals generated by acupuncture can modulate the central structures and interconnected neural circuits of multiple brain regions, including the medulla oblongata, cerebral cortex, thalamus, and hypothalamus. This analgesic process also involves the participation of various neurotransmitters and/or receptors, such as 5-hydroxytryptamine, glutamate, and enkephalin. In addition, acupuncture can regulate visceral pain by influencing functional connections between different brain regions and regulating glucose metabolism. However, there are still some limitations in the research efforts focusing on the specific brain mechanisms associated with the effects of acupuncture on the alleviation of visceral pain. Further animal experiments and clinical studies are now needed to improve our understanding of this area.
PubMed: 38027491
DOI: 10.3389/fnins.2023.1243232 -
CNS Neuroscience & Therapeutics Feb 2024Autonomic dysfunction with central autonomic network (CAN) damage occurs frequently after intracerebral hemorrhage (ICH) and contributes to a series of adverse outcomes.... (Review)
Review
AIMS
Autonomic dysfunction with central autonomic network (CAN) damage occurs frequently after intracerebral hemorrhage (ICH) and contributes to a series of adverse outcomes. This review aims to provide insight and convenience for future clinical practice and research on autonomic dysfunction in ICH patients.
DISCUSSION
We summarize the autonomic dysfunction in ICH from the aspects of potential mechanisms, clinical significance, assessment, and treatment strategies. The CAN structures mainly include insular cortex, anterior cingulate cortex, amygdala, hypothalamus, nucleus of the solitary tract, ventrolateral medulla, dorsal motor nucleus of the vagus, nucleus ambiguus, parabrachial nucleus, and periaqueductal gray. Autonomic dysfunction after ICH is closely associated with neurological functional outcomes, cardiac complications, blood pressure fluctuation, immunosuppression and infection, thermoregulatory dysfunction, hyperglycemia, digestive dysfunction, and urogenital disturbances. Heart rate variability, baroreflex sensitivity, skin sympathetic nerve activity, sympathetic skin response, and plasma catecholamine concentration can be used to assess the autonomic functional activities after ICH. Risk stratification of patients according to autonomic functional activities, and development of intervention approaches based on the restoration of sympathetic-parasympathetic balance, would potentially improve clinical outcomes in ICH patients.
CONCLUSION
The review systematically summarizes the evidence of autonomic dysfunction and its association with clinical outcomes in ICH patients, proposing that targeting autonomic dysfunction could be potentially investigated to improve the clinical outcomes.
Topics: Humans; Autonomic Nervous System; Sympathetic Nervous System; Autonomic Nervous System Diseases; Vagus Nerve; Cerebral Hemorrhage; Heart Rate
PubMed: 38372446
DOI: 10.1111/cns.14544 -
CNS Neuroscience & Therapeutics Nov 2023Neuropathic pain after spinal cord injury (SCI) remains a common and thorny problem, influencing the life quality severely. This study aimed to elucidate the...
Neuropathic pain following spinal cord hemisection induced by the reorganization in primary somatosensory cortex and regulated by neuronal activity of lateral parabrachial nucleus.
AIMS
Neuropathic pain after spinal cord injury (SCI) remains a common and thorny problem, influencing the life quality severely. This study aimed to elucidate the reorganization of the primary sensory cortex (S1) and the regulatory mechanism of the lateral parabrachial nucleus (lPBN) in the presence of allodynia or hyperalgesia after left spinal cord hemisection injury (LHS).
METHODS
Through behavioral tests, we first identified mechanical allodynia and thermal hyperalgesia following LHS. We then applied two-photon microscopy to observe calcium activity in S1 during mechanical or thermal stimulation and long-term spontaneous calcium activity after LHS. By slice patch clamp recording, the electrophysiological characteristics of neurons in lPBN were explored. Finally, exploiting chemogenetic activation or inhibition of the neurons in lPBN, allodynia or hyperalgesia was regulated.
RESULTS
The calcium activity in left S1 was increased during mechanical stimulation of right hind limb and thermal stimulation of tail, whereas in right S1 it was increased only with thermal stimulation of tail. The spontaneous calcium activity in right S1 changed more dramatically than that in left S1 after LHS. The lPBN was also activated after LHS, and exploiting chemogenetic activation or inhibition of the neurons in lPBN could induce or alleviate allodynia and hyperalgesia in central neuropathic pain.
CONCLUSION
The neuronal activity changes in S1 are closely related to limb pain, which has accurate anatomical correspondence. After LHS, the spontaneously increased functional connectivity of calcium transient in left S1 is likely causing the mechanical allodynia in right hind limb and increased neuronal activity in bilateral S1 may induce thermal hyperalgesia in tail. This state of allodynia and hyperalgesia can be regulated by lPBN.
Topics: Humans; Hyperalgesia; Parabrachial Nucleus; Calcium; Somatosensory Cortex; Spinal Cord; Neuralgia; Neurons; Spinal Cord Injuries
PubMed: 37170721
DOI: 10.1111/cns.14258 -
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 -
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 -
Neuroscience Jan 2024The lateral parabrachial nucleus (LPBN) is known to play a key role in relaying noxious information from the spinal cord to the brain. Different LPBN efferent mediate...
The lateral parabrachial nucleus (LPBN) is known to play a key role in relaying noxious information from the spinal cord to the brain. Different LPBN efferent mediate different aspects of the nocifensive response. However, the function of the LPBN → lateral hypothalamus (LH) circuit in response to noxious stimuli has remained unknown. Here, we show that LPBN → LH circuit is activated by noxious stimuli. Interestingly, either activation or inhibition of this circuit induced analgesia. Optogenetic activation of LPBN afferents in the LH elicited spontaneous jumping and induced place aversion. Optogenetic inhibition inhibited jumping behavior to noxious heat. Ablation of LH glutamatergic neurons could abolish light-evoked analgesia and jumping behavior. Our study revealed a role for the LPBN → LH pathway in nocifensive behaviors.
Topics: Humans; Hypothalamic Area, Lateral; Parabrachial Nucleus; Pain; Brain; Neurons
PubMed: 38036057
DOI: 10.1016/j.neuroscience.2023.11.020 -
Science Translational Medicine Apr 2024Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical...
Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical studies. Here, we performed a comprehensive electroencephalogram/electromyogram analysis of sleep in several mouse models of chronic pain: neuropathic (spared nerve injury and chronic constriction injury), inflammatory (Freund's complete adjuvant and carrageenan, plantar incision) and chemical pain (capsaicin). We find that peripheral axonal injury drives fragmentation of sleep by increasing brief arousals from non-rapid eye movement sleep (NREMS) without changing total sleep amount. In contrast to neuropathic pain, inflammatory or chemical pain did not increase brief arousals. NREMS fragmentation was reduced by the analgesics gabapentin and carbamazepine, and it resolved when pain sensitivity returned to normal in a transient neuropathic pain model (sciatic nerve crush). Genetic silencing of peripheral sensory neurons or ablation of CGRP neurons in the parabrachial nucleus prevented sleep fragmentation, whereas pharmacological blockade of skin sensory fibers was ineffective, indicating that the neural activity driving the arousals originates ectopically in primary nociceptor neurons and is relayed through the lateral parabrachial nucleus. These findings identify NREMS fragmentation by brief arousals as an effective proxy to measure spontaneous neuropathic pain in mice.
Topics: Humans; Rats; Mice; Animals; Nociceptors; Eye Movements; Hyperalgesia; Rats, Sprague-Dawley; Neuralgia; Sleep; Disease Models, Animal
PubMed: 38630850
DOI: 10.1126/scitranslmed.adg3036 -
BioRxiv : the Preprint Server For... Aug 2023In the brain, connectivity determines function. Neurons in the parabrachial nucleus (PB) relay diverse information to widespread brain regions, but the connections and...
In the brain, connectivity determines function. Neurons in the parabrachial nucleus (PB) relay diverse information to widespread brain regions, but the connections and functions of PB neurons that express (neuropeptide S) remain mysterious. Here, we use Cre-dependent anterograde tracing and whole-brain analysis to map their output connections. While many other PB neurons project ascending axons through the central tegmental tract, NPS axons reach the forebrain via distinct periventricular and ventral pathways. Along the periventricular pathway, NPS axons target the tectal longitudinal column and periaqueductal gray then continue rostrally to target the paraventricular nucleus of the thalamus. Along the ventral pathway, NPS axons blanket much of the hypothalamus but avoid the ventromedial and mammillary nuclei. They also project prominently to the ventral bed nucleus of the stria terminalis, A13 cell group, and magnocellular subparafasciular nucleus. In the hindbrain, NPS axons have fewer descending projections, targeting primarily the superior salivatory nucleus, nucleus of the lateral lemniscus, and periolivary region. Combined with what is known about NPS and its receptor, the output pattern of -expressing neurons in the PB region predicts a role in threat response and circadian behavior.
PubMed: 37645772
DOI: 10.1101/2023.08.13.553140 -
Neuropsychopharmacology : Official... Feb 2024The spino-ponto-amygdaloid pathway is a major ascending circuit relaying nociceptive information from the spinal cord to the brain. Potentiation of excitatory synaptic...
The spino-ponto-amygdaloid pathway is a major ascending circuit relaying nociceptive information from the spinal cord to the brain. Potentiation of excitatory synaptic transmission in the parabrachial nucleus (PBN) to central amygdala (CeA) pathway has been reported in rodent models of persistent pain. However, the functional significance of this pathway in the modulation of the somatosensory component of pain was recently challenged by studies showing that spinal nociceptive neurons do not target CeA-projecting PBN cells and that manipulations of this pathway have no effect on reflexive-defensive somatosensory responses to peripheral noxious stimulation. Here, we showed that activation of CeA-projecting PBN neurons is critical to increase both stimulus-evoked and spontaneous nociceptive responses following an injury in male and female mice. Using optogenetic-assisted circuit mapping, we confirmed a functional excitatory projection from PBN→CeA that is independent of the genetic or firing identity of CeA cells. We then showed that peripheral noxious stimulation increased the expression of the neuronal activity marker Fos in CeA-projecting PBN neurons and that chemogenetic inactivation of these cells decreased behavioral hypersensitivity in models of neuropathic and inflammatory pain without affecting baseline nociception. Lastly, we showed that chemogenetic activation of CeA-projecting PBN neurons is sufficient to induced bilateral hypersensitivity without injury. Together, our results indicate that the PBN→CeA pathway is a key modulator of pain-related behaviors that can increase reflexive-defensive and affective-motivational responses to somatosensory stimulation in injured states without affecting nociception under normal physiological conditions.
Topics: Mice; Male; Female; Animals; Central Amygdaloid Nucleus; Pain; Parabrachial Nucleus; Neurons; Synaptic Transmission
PubMed: 37542159
DOI: 10.1038/s41386-023-01673-6 -
Brain Research Bulletin Sep 2023The nucleus tractus solitarii (NTS) is the primary central station that integrates visceral afferent information and regulates respiratory, gastrointestinal,...
The nucleus tractus solitarii (NTS) is the primary central station that integrates visceral afferent information and regulates respiratory, gastrointestinal, cardiovascular, and other physiological functions. Leptin receptor b (LepRb)-expressing neurons of the NTS (NTS neurons) are implicated in central respiration regulation, respiratory facilitation, and respiratory drive enhancement. Furthermore, LepRb dysfunction is involved in obesity, insulin resistance, and sleep-disordered breathing. However, the monosynaptic inputs and outputs of NTS neurons in whole-brain mapping remain to be elucidated. Therefore, the exploration of its whole-brain connection system may provide strong support for comprehensively understanding the physiological and pathological functions of NTS neurons. In the present study, we used a cell type-specific, modified rabies virus and adeno-associated virus with the Cre-loxp system to map monosynaptic inputs and outputs of NTS neurons in LepRb-Cre mice. The results showed that NTS neurons received inputs from 48 nuclei in the whole brain from five brain regions, including especially the medulla. We found that NTS neurons received inputs from nuclei associated with respiration, such as the pre-Bötzinger complex, ambiguus nucleus, and parabrachial nucleus. Interestingly, some brain areas related to cardiovascular regulation-i.e., the ventrolateral periaqueductal gray and locus coeruleus-also sent a small number of inputs to NTS neurons. In addition, anterograde tracing results demonstrated that NTS neurons sent efferent projections to 15 nuclei, including the dorsomedial hypothalamic nucleus and arcuate hypothalamic nucleus, which are involved in regulation of energy metabolism and feeding behaviors. Quantitative statistical analysis revealed that the inputs of the whole brain to NTS neurons were significantly greater than the outputs. Our study comprehensively revealed neuronal connections of NTS neurons in the whole brain and provided a neuroanatomical basis for further research on physiological and pathological functions of NTS neurons.
Topics: Mice; Animals; Solitary Nucleus; Receptors, Leptin; Neurons; Brain Mapping; Obesity
PubMed: 37348822
DOI: 10.1016/j.brainresbull.2023.110693