Thalamocortical Circuit Controls Neuropathic Pain via Up-regulation of HCN2 in the Ventral Posterolateral Thalamus

Yan, Yi; Zhu, Mengye; Cao, Xuezhong; Xú, Gang; Shen, Wei; Li, Fan; Zhang, Jinjin; Luo, Lingyun; Zhang, Xuexue; Zhang, Daying; Liu, Tao

doi:10.1007/s12264-022-00989-5

Cited by 8 publications

(6 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One week later, pain and anxiodepressive‐like behaviors were evaluated followed by the local infusion of either NS or ZD7288 (10 μg/kg, 200 nL on each side) into the LHb of SNI and Sham mice (Figure 8B ). 39 Results showed that compared with the NS‐infused group, the mechanical pain thresholds were significantly increased after the infusion of ZD7288 into the LHb at both 60 and 90 min in SNI 6w mice (Figure 8C ). Furthermore, the application of ZD7288 produced evident antidepressant effects in both FST and TST (Figure 8D,E ) and did not affect the motor activity of mice, as evaluated by the OFT (Figure 8F,G ).…”

Section: Resultsmentioning

confidence: 93%

“…A double dummy cannula with a 0.5 mm extension beyond the tip of the guide cannula—secured with a dust cap—was inserted into the guide cannula to avoid clogging during the recovery period. 38 After a recovery period of at least 7 days, ZD7288 (10 μg/kg, Sigma) 31 , 39 dissolved in 0.9% saline (NS) was infused into each side of the LHb using a Hamilton micro‐syringe connected to a double injector cannula that was via a polyethylene pipe filled with mineral oil. A total volume of 200 nL of ZD7288 was infused at a rate of 100 nL/min.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

HCN channels in the lateral habenula regulate pain and comorbid depressive‐like behaviors in mice

Cao,

Zhu,

et al. 2024

CNS Neurosci Ther

Self Cite

View full text Add to dashboard Cite

AimsComorbid anxiodepressive‐like symptoms (CADS) in chronic pain are closely related to the overactivation of the lateral habenula (LHb). Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels have been implicated to play a key role in regulating neuronal excitability. However, the role of HCN channels in the LHb during CADS has not yet been characterized. This study aimed to investigate the effect of HCN channels in the LHb on CADS during chronic pain.MethodsAfter chronic neuropathic pain induction by spared nerve injury (SNI), mice underwent a sucrose preference test, forced swimming test, tail suspension test, open‐field test, and elevated plus maze test to evaluate their anxiodepressive‐like behaviors. Electrophysiological recordings, immunohistochemistry, Western blotting, pharmacological experiments, and virus knockdown strategies were used to investigate the underlying mechanisms.ResultsEvident anxiodepressive‐like behaviors were observed 6w after the SNI surgery, accompanied by increased neuronal excitability, enhanced HCN channel function, and increased expression of HCN2 isoforms in the LHb. Either pharmacological inhibition or virus knockdown of HCN2 channels significantly reduced LHb neuronal excitability and ameliorated both pain and depressive‐like behaviors.ConclusionOur results indicated that the LHb neurons were hyperactive under CADS in chronic pain, and this hyperactivation possibly resulted from the enhanced function of HCN channels and up‐regulation of HCN2 isoforms.

show abstract

Section: Resultsmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

HCN channels in the lateral habenula regulate pain and comorbid depressive‐like behaviors in mice

Cao,

Zhu,

et al. 2024

CNS Neurosci Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…Importantly, the lateral thalamus has been strongly implicated in chronic pain processing 126 , and exhibits plasticity following nerve injury 127 . Therefore, neuroplasticity in the VPL during pathological conditions [127][128][129] may alter how incoming tactile information is processed, which may aberrantly contribute to tactile-evoked pain perception. Further studies on how DCN input to the VPL is interpreted during naive and chronic pain conditions are required.…”

Section: Redundancymentioning

confidence: 99%

The Dorsal Column Nuclei Scale Mechanical Sensitivity in Naive and Neuropathic Pain States

Upadhyay,

Gradwell,

Vajtay

et al. 2024

Preprint

View full text Add to dashboard Cite

SUMMARYTactile perception relies on reliable transmission and modulation of low-threshold information as it travels from the periphery to the brain. During pathological conditions, tactile stimuli can aberrantly engage nociceptive pathways leading to the perception of touch as pain, known as mechanical allodynia. Two main drivers of peripheral tactile information, low-threshold mechanoreceptors (LTMRs) and postsynaptic dorsal column neurons (PSDCs), terminate in the brainstem dorsal column nuclei (DCN). Activity within the DRG, spinal cord, and DCN have all been implicated in mediating allodynia, yet the DCN remains understudied at the cellular, circuit, and functional levels compared to the other two. Here, we show that the gracile nucleus (Gr) of the DCN mediates tactile sensitivity for low-threshold stimuli and contributes to mechanical allodynia during neuropathic pain. We found that the Gr contains local inhibitory interneurons in addition to VPL-projecting neurons, which are differentially innervated by primary afferents and spinal inputs. Functional manipulations of these distinct Gr neuronal populations resulted in bidirectional changes to tactile sensitivity, but did not affect noxious mechanical or thermal sensitivity. During neuropathic pain, silencing Gr projection neurons or activating Gr inhibitory neurons was able to reduce tactile hypersensitivity, and enhancing inhibition was able to ameliorate paw withdrawal signatures of neuropathic pain, like shaking. Collectively, these results suggest that the Gr plays a specific role in mediating hypersensitivity to low-threshold, innocuous mechanical stimuli during neuropathic pain, and that Gr activity contributes to affective, pain-associated phenotypes of mechanical allodynia. Therefore, these brainstem circuits work in tandem with traditional spinal circuits underlying allodynia, resulting in enhanced signaling of tactile stimuli in the brain during neuropathic pain.

show abstract

“…There are several parallels between injury-induced cellular changes in higher centres and those seen in the periphery or spinal cord. For example, peripheral neuropathy induces HCN channel dysfunction in medial prefrontal cortex ( 502 ) and thalamus ( 503 , 504 ) and Na v 1.3 function is altered in thalamic neurons ( 505 , 506 ). Both channel types are similarly affected by peripheral nerve injury ( 208 ).…”

Section: Role Of Supra-spinal Structures In Pain Etiologymentioning

confidence: 99%

Neuropathic pain; what we know and what we should do about it

Smith

2023

Front. Pain Res.

View full text Add to dashboard Cite

Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve injury promotes Schwann cell activation and invasion of immunocompetent cells into the site of injury, spinal cord and higher sensory structures such as thalamus and cingulate and sensory cortices. Various cytokines, chemokines, growth factors, monoamines and neuropeptides effect two-way signalling between neurons, glia and immune cells. This promotes sustained hyperexcitability and spontaneous activity in primary afferents that is crucial for onset and persistence of pain as well as misprocessing of sensory information in the spinal cord and supraspinal structures. Much of the current understanding of pain aetiology and identification of drug targets derives from studies of the consequences of peripheral nerve injury in rodent models. Although a vast amount of information has been forthcoming, the translation of this information into the clinical arena has been minimal. Few, if any, major therapeutic approaches have appeared since the mid 1990's. This may reflect failure to recognise differences in pain processing in males vs. females, differences in cellular responses to different types of injury and differences in pain processing in humans vs. animals. Basic science and clinical approaches which seek to bridge this knowledge gap include better assessment of pain in animal models, use of pain models which better emulate human disease, and stratification of human pain phenotypes according to quantitative assessment of signs and symptoms of disease. This can lead to more personalized and effective treatments for individual patients. Significance statement: There is an urgent need to find new treatments for neuropathic pain. Although classical animal models have revealed essential features of pain aetiology such as peripheral and central sensitization and some of the molecular and cellular mechanisms involved, they do not adequately model the multiplicity of disease states or injuries that may bring forth neuropathic pain in the clinic. This review seeks to integrate information from the multiplicity of disciplines that seek to understand neuropathic pain; including immunology, cell biology, electrophysiology and biophysics, anatomy, cell biology, neurology, molecular biology, pharmacology and behavioral science. Beyond this, it underlines ongoing refinements in basic science and clinical practice that will engender improved approaches to pain management.

show abstract

Thalamocortical Circuit Controls Neuropathic Pain via Up-regulation of HCN2 in the Ventral Posterolateral Thalamus

Cited by 8 publications

References 55 publications

HCN channels in the lateral habenula regulate pain and comorbid depressive‐like behaviors in mice

HCN channels in the lateral habenula regulate pain and comorbid depressive‐like behaviors in mice

The Dorsal Column Nuclei Scale Mechanical Sensitivity in Naive and Neuropathic Pain States

Neuropathic pain; what we know and what we should do about it

Contact Info

Product

Resources

About