Molecular and cellular targets of GABAergic anesthetics in the mesopontine tegmentum that enable pain-free surgery DOI Open Access
Mark S. Baron,

Kristina Vaso,

Angham Ibraheem

et al.

Pain, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 31, 2024

Abstract The mesopontine tegmental anesthesia area (MPTA) is a focal brainstem locus which, when exposed to GABAergic agents, induces brain-state transitioning from wakefulness unconsciousness. Correspondingly, MPTA lesions render animals relatively insensitive anesthetics delivered systemically. Using chemogenetics, we recently identified neuronal subpopulation within the whose excitation this same pro-anesthetic effect. However, very few of these “effector-neurons” express synaptic γ 2 -containing GABA A receptor isoforms and none extrasynaptic δ -subunit containing receptors, suggesting that they are not direct cellular target agents. Here used pharmacological tools in rats define molecular target(s) GABAergics MPTA. microinjected into at nanomolar concentrations, selective for -Rs, proved be as was blocking reuptake. Likewise, low-concentration gaboxadol/THIP, also effective, whereas benzodiazepines zolpidem, which selectively were not. pentobarbital propofol applied low concentrations present brain after systemic dosing. Glycinergic agonists inhibitory, but infective on other non-GABAergic tested, most only marginally effective. We conclude -Rs primary Immunolabeling revealed -R isoform expressed exclusively by distinct “δ-cells” reside close apposition effector neurons. This suggests during wakefulness, δ-cells serve inhibitory interneurons silenced disinhibit (excite) effector-neurons, triggering transition

Language: Английский

Neural ensembles that encode nocifensive mechanical and heat pain in mouse spinal cord DOI Creative Commons
Mingdong Zhang, Jussi Kupari, Jie Su

et al.

Nature Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

Acute pain is an unpleasant experience caused by noxious stimuli. How the spinal neural circuits attribute differences in quality of information remains unknown. By means genetic capturing, activity manipulation and single-cell RNA sequencing, we identified distinct ensembles adult mouse cord encoding mechanical heat pain. Reactivation or silencing these potentiated stopped, respectively, paw shaking, lifting licking within but not across stimuli modalities. Within ensembles, polymodal Gal+ inhibitory neurons with monosynaptic contacts to A-fiber sensory gated transmission independent modality. Peripheral nerve injury led inferred microglia-driven inflammation ensemble transition decreased recruitment increased excitatory drive. Forced activation reversed hypersensitivity associated neuropathy. Our results reveal existence a representation that forms basis discriminative defensive qualities acute pain, are under control shared feed-forward inhibition.

Language: Английский

Citations

1
Diffuse Noxious Inhibitory Controls in Chronic Pain States: Insights from Pre-Clinical Studies DOI Open Access
Raquel Pereira-Silva, Fani Neto, Isabel Martins

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 402 - 402

Published: Jan. 5, 2025

Diffuse noxious inhibitory control (DNIC), also known as conditioned pain modulation (CPM) in humans, is a paradigm wherein the heterotopic application of stimulus results attenuation another spatially distant input. The pre-clinical and clinical studies show involvement several neurochemical systems DNIC/CPM point to major contribution noradrenergic, serotonergic, opioidergic systems. Here, we thoroughly review latest data on monoaminergic studies, focusing particularly models chronic pain. We conduct an in-depth analysis these by integrating available with descending modulatory circuits therein bring light mechanisms involved regulation DNIC. most recent suggest that DNIC may have dual outcome encompassing not only analgesic effects but hyperalgesic effects. This duality might be explained underlying circuitry receptor subtypes therein. Acknowledging this contribute validating prognostic nature paradigm. Additionally, serve robust predictive value for guiding treatment through more effective targeting modulation.

Language: Английский

Citations

0
Electroacupuncture produces analgesic effects via cannabinoid CB1 receptor-mediated GABAergic neuronal inhibition in the rostral ventromedial medulla DOI Creative Commons

Ke-Xing Wan,

Qian Xu,

Yulong Shi

et al.

Chinese Medicine, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 4, 2025

Electroacupuncture (EA) is commonly used for pain control in clinical practice, yet the precise mechanisms underlying its action are not fully understood. The rostral ventromedial medulla (RVM) plays a crucial role modulation of pain. GABAergic neurons RVM (GABARVM neurons) facilitate nociceptive transmission by inhibiting off-cells activity. This research examined GABARVM analgesic effects EA. Nociceptive behavior was evaluated using inflammatory models induced complete Freund's adjuvant (CFA) and neuropathic chronic constrictive injury (CCI). Also, situ hybridization, chemogenetics, vivo mouse calcium imaging, electrophysiological recordings were to determine neuronal activity neural circuitry. EA at "Zusanli" (ST36) on affected side produced significant effect both CFA CCI models. treatment elevated neurons. reduced activity, firing rates, c-Fos expression Chemogenetic inhibition increased thresholds. activation caused sensitivity mice negated Moreover, reducing cannabinoid CB1 receptors counteracted CCI-induced study indicates that facilitated receptor-mediated

Language: Английский

Citations

0
A pontine center in descending pain control DOI
Tianming Li, Wenjie Zhou, Ke Jin

et al.

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Single-nucleus RNA sequencing of rostral ventromedial medulla in mice with trigeminal neuralgia DOI
Xia Zhang, Lin Guo,

Jingyan Lyu

et al.

International Journal of Neuroscience, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 13

Published: May 2, 2025

To investigate the transcriptional changes and cell interactions following trigeminal neuralgia in different types rostral ventromedial medulla (RVM). In present study, neuropathic pain was induced mice by ligating left infraorbital nerve. Ten days after nerve ligation, we performed single-nucleus RNA sequencing of RVM cells from Sham TN (trigeminal neuralgia) groups. We identified neurons, astrocytes, microglial cells, oligodendrocytes, oligodendrocyte progenitor Purkinje neuroblasts, endothelial fibroblasts tissue. After analyzing cell-type-specific found that number neurons increased. Furthermore, differentially expressed genes (DEGs) astrocytes between two groups identified. The downregulated DEGs were significantly enriched GABAergic synapse (such as Gabrg3 Gabra2). upregulated glutamatergic voltage-gated ion channels. involved regulation postsynaptic membrane synaptic enriched. Notably, CellChat analysis highlights Slit2-Robo 1/2 signaling pathway a key route communication ligation. study analyzed responses to pain, possible neuralgia. inferred cell-state-specific various types. Our findings provide potential targets such 1/2, Gabrg3, Gabra2, Grm4, Grik2, Cadps2 Camk4 on therapeutic strategies for or orofacial pain.

Language: Английский

Citations

0
Opioid circuit opens path to pain relief DOI
Caitlynn C. De Preter,

Mary M. Heinricher

Science, Journal Year: 2024, Volume and Issue: 385(6712), P. 932 - 933

Published: Aug. 29, 2024

Manipulation of neural circuits targeted by morphine enables pain relief without opioids

Language: Английский

Citations

1
Molecular and cellular targets of GABAergic anesthetics in the mesopontine tegmentum that enable pain-free surgery DOI Open Access
Mark S. Baron,

Kristina Vaso,

Angham Ibraheem

et al.

Pain, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 31, 2024

Abstract The mesopontine tegmental anesthesia area (MPTA) is a focal brainstem locus which, when exposed to GABAergic agents, induces brain-state transitioning from wakefulness unconsciousness. Correspondingly, MPTA lesions render animals relatively insensitive anesthetics delivered systemically. Using chemogenetics, we recently identified neuronal subpopulation within the whose excitation this same pro-anesthetic effect. However, very few of these “effector-neurons” express synaptic γ 2 -containing GABA A receptor isoforms and none extrasynaptic δ -subunit containing receptors, suggesting that they are not direct cellular target agents. Here used pharmacological tools in rats define molecular target(s) GABAergics MPTA. microinjected into at nanomolar concentrations, selective for -Rs, proved be as was blocking reuptake. Likewise, low-concentration gaboxadol/THIP, also effective, whereas benzodiazepines zolpidem, which selectively were not. pentobarbital propofol applied low concentrations present brain after systemic dosing. Glycinergic agonists inhibitory, but infective on other non-GABAergic tested, most only marginally effective. We conclude -Rs primary Immunolabeling revealed -R isoform expressed exclusively by distinct “δ-cells” reside close apposition effector neurons. This suggests during wakefulness, δ-cells serve inhibitory interneurons silenced disinhibit (excite) effector-neurons, triggering transition

Language: Английский

Citations

0