Central neuropathic pain

Nature Reviews Disease Primers, Journal Year: 2023, Volume and Issue: 9(1)

Published: Dec. 21, 2023

Language: Английский

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Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(19)

Published: April 29, 2024

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous human de novo variants two high-confidence genes, CELSR3 WWC1 . Mice Celsr3 Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur both male female TD models. show reduced inhibition only females. Repetitive motor behaviors, common more pronounced females, include vertical rearing grooming. deficits are attenuated aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes spontaneous behavior less predictable patterns movement. Continuous fixed-ratio reinforcement shows that have enhanced responding reward learning. Electrically evoked striatal release, tested one model, greater. Brain development otherwise grossly normal without signs interneuron loss. Altogether, expressing genes face validity. Reduced repetitive behaviors core responsive aripiprazole. Enhanced alongside greater release. Phenotypes can also vary sex stronger affection an unexpected finding considering males frequently affected

Language: Английский

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Pain persists in mice lacking both Substance P and CGRPα signaling

eLife, Journal Year: 2025, Volume and Issue: 13

Published: March 18, 2025

The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides their receptors are expressed at high levels in pain-responsive neurons from the periphery to brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve clinical trials. Since extensively co-expressed, we hypothesized that simultaneous inhibition would be required effective analgesia. We therefore generated Tac1 Calca double knockout (DKO) mice assessed behavior using a wide range of pain-relevant assays. As expected, were undetectable throughout nervous system DKO mice. To our surprise, animals displayed largely intact responses mechanical, thermal, chemical, visceral stimuli, as well itch. Moreover, chronic inflammatory neurogenic inflammation unaffected by loss two peptides. Finally, neuropathic evoked nerve injury or chemotherapy treatment was also preserved peptide-deficient Thus, results demonstrate even combination, transmission acute pain.

Language: Английский

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Development of PainFace software to simplify, standardize, and scale up mouse grimace analyses

Pain, Journal Year: 2024, Volume and Issue: 165(8), P. 1793 - 1805

Published: Feb. 12, 2024

Abstract Facial grimacing is used to quantify spontaneous pain in mice and other mammals, but scoring relies on humans with different levels of proficiency. Here, we developed a cloud-based software platform called PainFace (http://painface.net) that uses machine learning detect 4 facial action units the mouse grimace scale (orbitals, nose, ears, whiskers) score grimaces black-coated C57BL/6 male female 0 8 scale. Platform accuracy was validated 2 laboratories, 3 conditions evoke grimacing—laparotomy surgery, bilateral hindpaw injection carrageenan, intraplantar formalin. can generate up 1 per second from standard 30 frames/s video, making it possible over time, operates at speed scales computing power. By analyzing frequency distribution scores, found spent 7x more time “high grimace” state following laparotomy surgery relative sham controls. Our study shows reproducibly quantifies indicative nonevoked enables laboratories standardize scale-up analyses.

Language: Английский

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Digging deeper into pain: an ethological behavior assay correlating well-being in mice with human pain experience

Pain, Journal Year: 2024, Volume and Issue: 165(8), P. 1761 - 1773

Published: March 5, 2024

Abstract The pressing need for safer, more efficacious analgesics is felt worldwide. Preclinical tests in animal models of painful conditions represent one the earliest checkpoints novel therapeutics must negotiate before consideration human use. Traditionally, pain status laboratory animals has been inferred from evoked nociceptive assays that measure their responses to noxious stimuli. disconnect between how tested and it experienced by humans may part explain shortcomings current medications highlights a refinement. Here, we survey patients with chronic who assert everyday aspects life, such as cleaning leaving house, are affected ongoing level pain. Accordingly, test impact on an ethological behavior mice, digging. Stable digging was observed over time naive mice both sexes. By contrast, deficits were seen after acute knee inflammation. analgesia conferred meloxicam gabapentin compared monosodium iodoacetate osteoarthritis model, effectively ameliorating deficits, line finding effective. Finally, visceral decrease correlated extent disease. Ultimately, make case adopting assays, digging, studies animals, which believe be representative experience thus valuable assessing clinical potential animals.

Language: Английский

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A humanized chemogenetic system inhibits murine pain-related behavior and hyperactivity in human sensory neurons

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(716)

Published: Oct. 4, 2023

Hyperexcitability in sensory neurons is known to underlie many of the maladaptive changes associated with persistent pain. Chemogenetics has shown promise as a means suppress such excitability, yet chemogenetic approaches suitable for human applications are needed. PSAM 4 -GlyR modular system based on α7 nicotinic acetylcholine and glycine receptors, which responds inert chemical ligands clinically approved drug varenicline. Here, we demonstrated efficacy this channel silencing both mouse by activation large shunting conductances after agonist administration. Virally mediated expression produced behavioral hyposensitivity upon administration, was recovered washout. Stable led similar reversible suppression pain-related behavior even 10 months viral delivery. Mechanical spontaneous pain readouts were also ameliorated acute joint inflammation models. Furthermore, mechanical hypersensitivity generated spared nerve injury model neuropathic observed channel. Effective reproduced hyperexcitability clinical pain: decreased excitability human-induced pluripotent stem cell–derived activity due gain-of-function Na V 1.7 mutation causing inherited erythromelalgia. Our results demonstrate contribution neuron translational potential an effective, stable, humanized treatment

Language: Английский

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Reproducible and fully automated testing of nocifensive behavior in mice

Cell Reports Methods, Journal Year: 2023, Volume and Issue: 3(12), P. 100650 - 100650

Published: Dec. 1, 2023

Language: Английский

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Mimicking opioid analgesia in cortical pain circuits

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 29, 2024

The anterior cingulate cortex plays a pivotal role in the cognitive and affective aspects of pain perception. Both endogenous exogenous opioid signaling within mitigate cortical nociception, reducing unpleasantness. However, specific functional molecular identities cells mediating analgesia remain elusive. Given complexity as sensory emotional experience, richness ethological pain-related behaviors, we developed standardized, deep-learning platform for deconstructing behavior dynamics associated with component mice-LUPE (Light aUtomated Pain Evaluator). LUPE removes human bias quantification accelerated analysis from weeks to hours, which leveraged discover that morphine altered attentional motivational behaviors akin humans. Through activity-dependent genetics single-nuclei RNA sequencing, identified ensembles nociceptive neuron-types expressing mu-opioid receptors. Tuning receptor expression these bidirectionally modulated analgesia. Moreover, employed synthetic promoter-driven approach cell-type optical chemical genetic viral therapies mimic morphine's pain-relieving effects cingulate, without reinforcement. This offers novel strategy precision management by targeting key circuit on-demand, non-addictive, effective

Language: Английский

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Hierarchical behavioral analysis framework as a platform for standardized quantitative identification of behaviors

Cell Reports, Journal Year: 2025, Volume and Issue: 44(2), P. 115239 - 115239

Published: Feb. 1, 2025

Language: Английский

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Pain persists in mice lacking both Substance P and CGRPα signaling

Published: Feb. 3, 2025

The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides their receptors are expressed at high levels in pain-responsive neurons from the periphery to brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve clinical trials. Since extensively co-expressed we hypothesized that simultaneous inhibition would be required effective analgesia. We therefore generated Tac1 Calca double knockout (DKO) mice assessed behavior using a wide range of pain-relevant assays. As expected, were undetectable throughout nervous system DKO mice. To our surprise, animals displayed largely intact responses mechanical, thermal, chemical, visceral stimuli, as well itch. Moreover, chronic inflammatory neurogenic inflammation unaffected by loss two peptides. Finally, neuropathic evoked nerve injury or chemotherapy treatment was also preserved peptide-deficient Thus, results demonstrate even combination, transmission acute pain.

Language: Английский

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