Science literature interpretation: reverse assist, endogenous analgesic failure promotes the formation of pathological pain

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Core ideas

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Analysis of the results of the study

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To clarify the role

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Subsequently, the authors further identified the spinal cord microcircuits involved in this analgesia

To determine whether optogenetic stimulation activates inhibitory interneurons in DHSCs, the authors performed cFos/Pax2 immunostaining

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In the body electrophysiological recordings show that these mechanical and thermal anaphylaxises are associated with an increase in the responsiveness of DHSC neurons, A significant increase in the response of WDR neurons to c-fiber afferents in peripheral stimulation during optogenetic activation of the 5-HT fiber endings of the spinal cord
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These results strongly suggest that a chloride imbalance in spinal cord neurons may alter the control
of pain by converting the downward inhibition of RMg 5-HT fibers to downward ease.

To validate this possibility, the authors used CLP290 to pharmacologically enhance the KCC2 chloride transporter
in SNI mice.
The authors observed that CLP290 was able to significantly induce an increase
in KCC2 levels on the cell membranes of DHSC neurons.
The authors then assessed the pain behavior of SNI mice treated with CLP290 in optogenetic stimulation, and optogenetic stimulation of 5-HT fibers significantly alleviated mechanical pain and heat pain allergies
in SNI mice.
Using the electrophysiological recordings in vitro, the authors also found that after CLP290 treatment, mouse WDR neurons were less
responsive to peripheral stimuli during light stimulation of RMg 5-HT fibers.
These results show that KCC2-mediated chlorine balance can control the downside effect of RMg 5-HT: normal chlorine balance can effectively maintain the inhibition of RMg 5-HT downward projection, while KCC2 function is low after nerve injury, causing chlorine imbalance disorder, resulting in downward inhibition of RMg 5-HT becoming prone to downward mobility
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Salvage KCC2 Function Recovery SSRI-Mediated Analgesia
The above mechanism may explain why SSRIs do not relieve pain in patients with chronic pain
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To test this hypothesis, the authors combined
SSRI treatment with the KCC2 enhancer.
The authors observed that in SNI mice, SSRI fluoxetine alone was shown to cause mild mechanical pain and heat pain allergies, and CLP290 was able to slightly but significantly reduce mechanical pain and heat pain allergies
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In contrast, the combination of fluoxetine and CLP290 provides strong relief from mechanical pain and hypertherapetic allergies, analgesic effects that persist
24 hours after a single injection.
Finally, the authors further confirmed this analgesic effect using conditional position preference experiments, and during the test, SNI mice were clearly inclined to stay in the box where fluoxetine + CLP290 was given during training, indicating that fluoxetine combined with CLP290 significantly improved the pain status of
SNI mice.

 

summary

The results of the study show that the descending 5-HT nerve fibers in RMg create a gated effect
on mechanical and thermal stimulation by forming synaptic connections with inhibitory interneurons in DHSC.
In addition, the downregulation of KCC2 is the basis for the change of 5-HT descending fibers affecting pain transmission signals, and the transition
from pain suppression to pain susceptibility in the pathological state.
These results suggest that the balance between downward excitation and inhibition depends on local changes at the spinal cord level, contrary
to previous beliefs.
In particular, the same 5-HT loops can be excitatory and/or inhibitory, depending on the excitability
of the target region.

Research Method Highlights

This work elucidates the mechanism of action of endogenous serotonin-derived pain modulation instability
.
Experimental techniques
such as brain stereotactic injection, optogenetics, in vivo electrophysiological recording, behavioral assessment, and immunohistochemistry were used.
In the field of life science research for 20 years, Reward has been committed to providing customers with reliable solutions and services, in this research, Reward provided a self-developed brain stereoposition injection system to ensure that the relevant experimental operations can be completed
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In addition, Rewards provides a complete solution
for the study's experiments on optogenetics, in vitro electrophysiology recording, behavioral evaluation, and immunohistochemistry.
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