Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn

eLife, Год журнала: 2023, Номер 12

Опубликована: Фев. 7, 2023

Spinally projecting serotonergic neurons play a key role in controlling pain sensitivity and can either increase or decrease nociception depending on physiological context. It is currently unknown how mediate these opposing effects. Utilizing virus-based strategies Tph2-Cre transgenic mice, we identified two anatomically separated populations of hindbrain located the lateral paragigantocellularis (LPGi) medial hindbrain, which respectively innervate superficial deep spinal dorsal horn have contrasting effects sensory perception. Our tracing experiments revealed that LPGi were much more susceptible to transduction with spinally injected AAV2retro vectors than neurons. Taking advantage this difference, employed intersectional chemogenetic approaches demonstrate activation projections decreases thermal sensitivity, whereas increases mechanical von Frey stimulation. Together results suggest there are functionally distinct classes differ their anatomical location postsynaptic targets cord, impact nociceptive sensitivity. The give rise rather global bilateral throughout rostrocaudal extent cord appear be ideally poised contribute widespread systemic control.

Язык: Английский

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Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation

Science Advances, Год журнала: 2024, Номер 10(17)

Опубликована: Апрель 26, 2024

The supraspinal descending pain modulatory system (DPMS) shapes perception via monoaminergic modulation of sensory information in the spinal cord. However, role and synaptic mechanisms noradrenergic signaling remain unclear. Here, we establish that neurons locus coeruleus (LC) are essential for opioid antinociception. While much previous work has emphasized serotonergic pathways, find antinociception is primarily driven by excitatory output from ventrolateral periaqueductal gray (vlPAG) to LC. Furthermore, identify a previously unknown opioid-sensitive inhibitory input rostroventromedial medulla (RVM), suppression which disinhibits LC drive We describe pain-related activity throughout this circuit report presence prominent bifurcating outputs vlPAG RVM. Our findings substantially revise current models DPMS antinociceptive pathway may contribute multiple forms modulation.

Язык: Английский

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The ‘in’s and out’s’ of descending pain modulation from the rostral ventromedial medulla

Trends in Neurosciences, Год журнала: 2024, Номер unknown

Опубликована: Май 1, 2024

Язык: Английский

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Morphine-responsive neurons that regulate mechanical antinociception

Science, Год журнала: 2024, Номер 385(6712)

Опубликована: Авг. 29, 2024

Opioids are widely used, effective analgesics to manage severe acute and chronic pain, although they have recently come under scrutiny because of epidemic levels abuse. While these compounds act on numerous central peripheral pain pathways, the neuroanatomical substrate for opioid analgesia is not fully understood. By means single-cell transcriptomics manipulation morphine-responsive neurons, we identified an ensemble neurons in rostral ventromedial medulla (RVM) that regulates mechanical nociception mice. Among these, forced activation or silencing excitatory RVM

Язык: Английский

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Brainstem serotonin amplifies nociceptive transmission in a mouse model of Parkinson’s disease

npj Parkinson s Disease, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 7, 2025

Abstract Parkinson’s disease arises from the degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to motor symptoms such as akinesia, rigidity, and tremor at rest. The non-motor component includes increased neuropathic pain, prevalence which is 4 5 times higher than general rate. By studying a mouse model induced by 6-hydroxydopamine, we assessed impact dopamine depletion on pain modulation. Mice exhibited mechanical hypersensitivity associated with hyperexcitability dorsal horn spinal cord (DHSC). Serotonin (5-HT) levels cord, correlating reduced tyrosine hydroxylase (TH) immunoreactivity nucleus raphe magnus (NRM) excitability 5-HT neurons. Selective optogenetic inhibition attenuated DHSC hyperexcitability. In addition, blockade 2A 3 receptors hypersensitivity. These results reveal, for first time, that PD-like triggers spinal-mediated hypersensitivity, serotonergic hyperactivity NRM, opening up new therapeutic avenues disease-associated targeting systems.

Язык: Английский

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Postcolitis Alterations in Dose‐Dependent Effects of 5‐HT1A Agonist Buspirone on Nociceptive Activity of the Raphe Magnus and Dorsal Raphe Neurons in Rats

European Journal of Neuroscience, Год журнала: 2025, Номер 61(2)

Опубликована: Янв. 1, 2025

ABSTRACT The serotonergic raphe magnus (RMg) and dorsal (DR) nuclei are crucial pain–regulating structures, which nociceptive activity is shown to be altered in gut pathology, but the underlying neuroplastic changes remain unclear. Considering importance of 5‐HT1A receptors modulating both pain neuronal activity, this study, we aimed determine whether 5‐HT1A‐dependent visceral somatic processing within RMg DR modified postcolitis conditions. In anaesthetised male Wistar rats, healthy control recovered from TNBS‐induced colitis, microelectrode recordings neuron responses noxious colorectal distension (CRD) or tail squeezing (TS) were performed prior after intravenous administration agonist, buspirone. animals, autoreceptor‐ heteroreceptor‐activating high doses buspirone (2 4 mg/kg) lost normally occurring ability facilitate CRD‐ TS‐evoked activation neurons, causing inhibition local signalling similar autoreceptor‐activating low (0.1 0.5 mg/kg). Conversely, inherent property at all reduce pain–related excitation was weakened colitis. These phenomena associated with a loss inhibitory effect compound's on hemodynamic reactions CRD TS, revealing deficient antinociceptive action systemic level. data suggest buspirone‐dependent heteroreceptor‐mediated signalling, can directly indirectly lead reduced increased excitation, impairing their functioning control.

Язык: Английский

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Understanding of Spinal Wide Dynamic Range Neurons and Their Modulation on Pathological Pain

Journal of Pain Research, Год журнала: 2024, Номер Volume 17, С. 441 - 457

Опубликована: Фев. 1, 2024

The spinal dorsal horn (SDH) transmits sensory information from the periphery to brain. Wide dynamic range (WDR) neurons within this relay site play a critical role in modulating and integrating peripheral inputs, as well process of central sensitization during pathological pain. This group multi-receptive has attracted considerable attention pain research due their capabilities for encoding location intensity nociception. Meanwhile, transmission, processing, modulation incoming afferent WDR also establish underlying basis investigating integration acupuncture signals. review aims provide comprehensive examination distinctive features involvement Specifically, we will examine regulation diverse supraspinal nuclei on these analyze potential elucidating mechanisms analgesia.

Язык: Английский

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Parabrachial neurons promote nociplastic pain

Trends in Neurosciences, Год журнала: 2024, Номер 47(9), С. 722 - 735

Опубликована: Авг. 14, 2024

The parabrachial nucleus (PBN) in the dorsal pons responds to bodily threats and transmits alarm signals forebrain. Parabrachial neuron activity is enhanced during chronic pain, inactivation of PBN neurons mice prevents establishment neuropathic, pain symptoms. Chemogenetic or optogenetic activation all glutamatergic PBN, just subpopulation that expresses Calca gene, sufficient establish phenotypes, including long-lasting tactile allodynia, scale with extent stimulation, thereby promoting nociplastic defined as diffuse without tissue inflammation nerve injury. This review focuses on role(s) molecularly downstream nodes brain contribute establishing pain.

Язык: Английский

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An intra-brainstem circuitry for pain-induced inhibition of itch

Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Dissecting neural circuits from rostral ventromedial medulla to spinal trigeminal nucleus bidirectionally modulating craniofacial mechanical sensitivity

Progress in Neurobiology, Год журнала: 2023, Номер 232, С. 102561 - 102561

Опубликована: Дек. 22, 2023

Язык: Английский

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