Calcium buffering tunes intrinsic excitability of spinal dorsal horn parvalbumin-expressing interneurons: A computational model DOI Open Access
Xinyue Ma, Loïs S. Miraucourt,

Haoyi Qiu

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 6, 2023

Abstract Parvalbumin-expressing interneurons (PVINs) play a crucial role within the dorsal horn of spinal cord by preventing touch inputs from activating pain circuits. After nerve injury, their output is decreased via mechanisms that are not fully understood. In this study, we show PVINs nerve-injured mice change firing pattern tonic to adaptive. To examine ionic responsible for output, employed reparametrized Hodgkin-Huxley (HH) type model PVINs, which predicted (1) transition due an increased contribution small conductance calcium-activated potassium (SK) channels, enabled (2) impairment in intracellular calcium buffering systems. Analyzing dynamics HH-type further demonstrated generalized Hopf bifurcation differentiates two types state transitions observed transient PVINs. Importantly, mechanism holds true when embed neuronal circuit horn. experimentally validate hypothesized mechanism, used pharmacological modulators SK channels and naïve become adaptive exposed channel activator, adapting return upon blockade. Our work provides important insights into cellular underlying after injury highlights potential targets new effective treatment approaches neuropathic pain. Significant Statement exert inhibitory control over A β fiber- mediated nociceptive pathways at The loss tone leads symptoms, like mechanical allodynia, This study identifies reduced intrinsic excitability as cause condition. Combining computational experimental approaches, predict calcium-dependent modulates PVINs’ electrical activity following injury: depletion cytosolic buffer allows rapid accumulation through active membranes, turn potentiates impedes spike generation. results therefore pinpoint interesting therapeutic treating symptoms.

Язык: Английский

Parabrachial Calca neurons drive nociplasticity DOI Creative Commons
Logan Condon,

Ying Yu,

Sekun Park

и другие.

Cell Reports, Год журнала: 2024, Номер 43(4), С. 114057 - 114057

Опубликована: Апрель 1, 2024

Pain that persists beyond the time required for tissue healing and pain arises in absence of injury, collectively referred to as nociplastic pain, are poorly understood phenomena mediated by plasticity within central nervous system. The parabrachial nucleus (PBN) is a hub relays aversive sensory information appears play role nociplasticity. Here, preventing PBN Calca neurons from releasing neurotransmitters, we demonstrate activation necessary manifestation maintenance chronic pain. Additionally, directly stimulating neurons, neuron activity sufficient drive Aversive stimuli multiple modalities, such exposure nitroglycerin, cisplatin, or lithium chloride, can nociplasticity Calca-neuron-dependent manner. events form increased excitability; however, neuroplasticity also occur downstream circuitry.

Язык: Английский

Процитировано

14
Nerve injury disrupts temporal processing in the spinal cord dorsal horn through alterations in PV+ interneurons DOI Creative Commons

Genelle Rankin,

Anda M. Chirila,

Alan J. Emanuel

и другие.

Cell Reports, Год журнала: 2024, Номер 43(2), С. 113718 - 113718

Опубликована: Янв. 30, 2024

How mechanical allodynia following nerve injury is encoded in patterns of neural activity the spinal cord dorsal horn (DH) remains incompletely understood. We address this mice using spared model neuropathic pain and vivo electrophysiological recordings. Surprisingly, despite dramatic behavioral over-reactivity to stimuli injury, an overall increase sensitivity or reactivity DH neurons not observed. do, however, observe a marked decrease correlated firing patterns, including synchrony stimulus-evoked firing, across DH. Alterations temporal are recapitulated by silencing parvalbumin+ (PV+) interneurons, previously implicated allodynia, as allodynic pain-like behaviors. These findings reveal decorrelated network activity, driven alterations PV+ prominent feature suggest restoration proper potential therapeutic strategy treat chronic pain.

Язык: Английский

Процитировано

10
The dual role of microglia in neuropathic pain after spinal cord injury: Detrimental and protective effects DOI

Chang Sun,

Junhao Deng, Yifei Ma

и другие.

Experimental Neurology, Год журнала: 2023, Номер 370, С. 114570 - 114570

Опубликована: Окт. 16, 2023

Язык: Английский

Процитировано

18
Modulation of SK Channels via Calcium Buffering Tunes Intrinsic Excitability of Parvalbumin Interneurons in Neuropathic Pain: A Computational and Experimental Investigation DOI Creative Commons
Xinyue Ma, Loïs S. Miraucourt,

Haoyi Qiu

и другие.

Journal of Neuroscience, Год журнала: 2023, Номер 43(31), С. 5608 - 5622

Опубликована: Июль 14, 2023

Parvalbumin-expressing interneurons (PVINs) play a crucial role within the dorsal horn of spinal cord by preventing touch inputs from activating pain circuits. In both male and female mice, nerve injury decreases PVINs' output via mechanisms that are not fully understood. this study, we show PVINs nerve-injured mice change their firing pattern tonic to adaptive. To examine ionic responsible for decreased output, used reparametrized Hodgkin-Huxley type model PVINs, which predicted (1) transition is because an increased contribution small conductance calcium-activated potassium (SK) channels, enabled (2) impairment in intracellular calcium buffering systems. Analyzing dynamics further demonstrated generalized Hopf bifurcation differentiates two types state transitions observed transient PVINs. Importantly, mechanism holds true when embed PVIN neuronal circuit horn. experimentally validate hypothesized mechanism, pharmacological modulators SK channels naive become adaptive exposed channel activator, adapting return on blockade. Our work provides important insights into cellular underlying after highlights potential targets new effective treatment approaches neuropathic pain.

Язык: Английский

Процитировано

17
Retinoic acid-mediated homeostatic plasticity in the nucleus accumbens core contributes to incubation of cocaine craving DOI
Amanda M. Wunsch,

Eun-Kyung Hwang,

Jonathan R. Funke

и другие.

Psychopharmacology, Год журнала: 2024, Номер 241(10), С. 1983 - 2001

Опубликована: Июнь 27, 2024

Язык: Английский

Процитировано

5
Parabrachial neurons promote nociplastic pain DOI Creative Commons
Richard D. Palmiter

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

Процитировано

4
Blockade of spinal dopamine D1/D2 receptor heteromers by levo-Corydalmine suppressed calcium signaling cascade in spinal neurons to alleviate bone cancer pain in rats DOI Creative Commons
Xiaonan Ma,

Chang-Heng Yao,

Yujie Yang

и другие.

Journal of Cancer, Год журнала: 2024, Номер 15(4), С. 1041 - 1052

Опубликована: Янв. 1, 2024

Background: Dopamine receptors have been reported to be involved in pain, while the exact effects and mechanism bone cancer pain not fully explored.Methods: Bone model was created by implanting walker 256 mammary gland carcinoma into right tibia cavity.Primary cultured spinal neurons were used for vitro evaluation.FLIPR, western-blot, immunofluorescence, Co-IP detect cell signaling pathway.Results: Our results indicated that dopamine D1 receptor (D1DR) D2 (D2DR) could form heteromers TCI rats, antagonizing D1DR D2DR reduced formation alleviated TCI-induced pain.Further or antagonist induced antinociception rats reversed D1DR, D2DR, D1/D2DR heteromer agonists.And Gq, IP3, PLC inhibitors also attenuated pain.In decreased Ca 2+ oscillations upregulated agonists activated primary neurons.Moreover, inhibition of partially mediated CaMKII MAPKs pathway.In addition, a natural compound levo-Corydalmine (l-CDL), inhibit attenuate pain.Results: Inhibition via l-CDL decreases excitability neurons, which might present new therapeutic strategy pain.

Язык: Английский

Процитировано

3
Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia DOI Creative Commons
Hiroyuki Neyama,

Yuping Wu,

Yuka Nakaya

и другие.

Science Advances, Год журнала: 2025, Номер 11(3)

Опубликована: Янв. 15, 2025

Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in medial prefrontal cortex (mPFC) activate descending pain inhibitory system to initiate placebo neuropathic rats. Chemogenetic manipulation demonstrated specific activation of receptor–positive (MOR + ) neurons mPFC or suppression mPFC–ventrolateral periaqueductal gray (vlPAG) circuit inhibited MOR are monosynaptically connected and directly inhibit layer V pyramidal project vlPAG via GABA A receptors. Thus, intrinsic opioid signaling disinhibits excitatory outflow suppressing neurons, leading initiates analgesia. Our results shed light on fundamental mechanism effect maximizes therapeutic efficacy reduces adverse drug effects medical practice.

Язык: Английский

Процитировано

0
Differential Neuronal Activation of Nociceptive Pathways in Neuropathic Pain After Spinal Cord Injury DOI Creative Commons
Ziyu He, Jun Zhang, Jia Xu

и другие.

Cellular and Molecular Neurobiology, Год журнала: 2025, Номер 45(1)

Опубликована: Янв. 30, 2025

Neuropathic pain, a prevalent complication following spinal cord injury (SCI), severely impairs the life quality of patients. No ideal treatment exists due to incomplete knowledge on underlying neural processes. To explore SCI-induced effect nociceptive circuits, protein expression c-Fos was analyzed as an indicator neuronal activation in rat contusion model exhibiting below-level pain. Additional stimuli were delivered mimic different peripheral sensory inputs daily life. Following noxious rather than innocuous or no stimulation, greater number dorsal horn (DH) neurons activated after SCI, mainly deep DH. SCI facilitated excitatory but not inhibitory DH neurons. Moreover, interneurons expressing kinase C gamma (PKCγ) laminae II–III, which are known play role mechanical allodynia nerve injury, responded larger amounts both and stimulation SCI. Accordingly, more projection lamina I activated. Within supraspinal nuclei processing differentially enhanced response detected with significant increase locus coeruleus medial thalamus, slight periaqueductal gray raphe, change lateral parabrachial nucleus primary cortex. These findings indicated differential hyperexcitability along neuroaxis particular emphasis involvement specific neuron subtypes, such PKCγ noradrenergic neurons, may serve crucial targets for potential therapies. Rats pain like behavior showed increased engagement subtypes activity nuclei. The figure created using Figdraw 2.0.

Язык: Английский

Процитировано

0
Electroacupuncture Neural Stimulation Mitigates Bladder Dysfunction and Mechanical Allodynia in Cyclophosphamide Induced Cystitis through Downregulation of the BDNF-TrkB Signaling Pathway DOI Creative Commons
Ying Hua Su, Fei Yang,

Juncong Xie

и другие.

eNeuro, Год журнала: 2025, Номер 12(3), С. ENEURO.0329 - 24.2025

Опубликована: Март 1, 2025

Central sensitization plays a critical role in bladder pain syndrome/interstitial cystitis (BPS/IC). Electroacupuncture (EA) nerve stimulation therapy has been broadly acknowledged as an effective means of alleviating chronic pathological pain. However, it remains to be explored whether EA is mitigating pain-sensitive symptoms BPS/IC and the mechanisms involved. This study aims investigate analgesic effect mechanism therapy. To achieve this goal, we employed several techniques: mechanical threshold tests assess sensitivity, urodynamic studies evaluate function, Western blotting (WB) for protein analysis, immunofluorescence visualizing, transcriptomics. A rat model was established through systemic intraperitoneal injection with cyclophosphamide (CYP). executed by stimulating deep part hypochondriac point, where 2nd-4th sacral nerves traverse. treatment observed effectively reduce allodynia, enhance urinary suppress activation microglial cells, alleviate neuroinflammation. Additionally, demonstrated capability downregulate BDNF-TrkB signal transduction spinal dorsal horn. Transcriptome sequencing indicated that potentially inhibits excitatory neural transmission modulates pathways related longevity. Furthermore, shown efficacy treating conditions such Huntington's disease, amyotrophic lateral sclerosis, prion diseases. In conclusion, regulating signaling, can dysfunction allodynia cyclophosphamide-induced model. Our research elucidates underlying offers new theoretical insights addressing painful BPS.Significance Statement major factor (BPS/IC), making management crucial. explores potential electroacupuncture therapeutic approach improve function induced cyclophosphamide. findings demonstrate significantly reduces enhances decreases neuroinflammation modulating signaling The highlights EA's inhibit provide relief conditions. These results offer into therapy, improving strategies similar syndromes.

Язык: Английский

Процитировано

0