Written by Ding Xu

Editor in charge ︱ Wang Sizhen

Editor︱Yang Binwei

Pain experience in the neonatal period, leading to an exacerbated pain response to reinjury later in life

The persistent effects of neonatal injury on pain pathways illustrate the urgent need for preventive strategies

As a continuation of previous work, in July 2022, Ding Xu's team from Beijing Children's Hospital affiliated to Capital Medical University and National Children's Medical Center published online in the journal "Brain, Behavior, and Immunity" entitled "Sciatic nerve block downregulates the BDNF pathway to alleviate The neonatal incision-induced exaggeration of incisional pain via decreasing microglial activation” research paper

The present study found that sciatic nerve block attenuated mechanical and thermal hyperalgesia in neonatal incision and adult reincision rats and attenuated microglia activation in the dorsal horn of the spinal cord (Figure 1)

Figure 1 Sciatic nerve block reduces allodynia and spinal microglial activation in neonatal and adult incision rats

(Source: Ding Xu et al.

Figure 2 Chemical activation of spinal microglia attenuates the effect of sciatic nerve block on pain behavior

(Source: Ding Xu et al.
, Brain Behav Immun, 2022)

The team's previous research found that in neonatal and adult incision rats, BDNF increased in microglia in the dorsal horn of the spinal cord, which was involved in long-term potentiation and facilitation of synaptic transmission, and that surgical incision in the neonatal period caused postoperative pain in adulthood.
Sensitization [9]
.

In particular, intrathecal injection of a microglia inhibitor alleviated the increase in BDNF caused by incision in the neonatal period and in adulthood
.

In addition, SHP2 in synaptosomes in the dorsal horn of the spinal cord is involved in the above-mentioned postoperative pain sensitization through phosphatidylinositol 3-kinase [10, 11]
.

Studies have shown that BDNF up-regulates SHP2 in the development of neuropathic pain[12]
.

BDNF increases the phosphorylation of GluA1 and the membrane transport of AMPA receptors containing the GluA1 subunit [13]
.

In adult animals, GluA1 in the spinal dorsal horn plays an important role in postoperative pain and is involved in postoperative pain sensitization experienced in adulthood [14]
.

Activation of SHP2 upregulates the phosphorylation and transport of GluA1 [15]
.

However, the role of BDNF derived from spinal microglia, and its downstream SHP2 and GluA1, in the relief of pain sensitization after sciatic nerve block is unknown
.

Figure 3 The role of the AMPA receptor GluA1 subunit in the spinal dorsal horn in incision-induced incision pain sensitization in the neonatal period
.

(Source: Ding Xu et al.
, Brain Behav Immun, 2022)

The present study found that GluA1 phosphorylation was increased, and GluA1 subunit-containing AMPA receptor membrane transport was increased
.

Intrathecal injection of AMPA receptor inhibitors or agonists relieved or simulated postoperative pain sensitization, respectively (Figure 3)
.

Inhibition of BDNF or SHP2 blocked the up-regulation of downstream molecules caused by incision in neonatal and adulthood
.

Knockdown of SHP2 in adult rats with only surgical incision in the neonatal period attenuated the increase in GluA1 induced by administration of exogenous BDNF (Fig.
4)
.

Inhibition of spinal microglia using chemogenetic tools in neonatal and adult incised rats attenuates upregulation of BDNF, SHP2, and GluA1
.

Knockout of BDNF gene in microglia suppressed SHP2 and GluA1, which were up-regulated by Notch during neonatal and adulthood (Fig.
5)
.

Figure 4.
BDNF in the spinal dorsal horn increases GluA1 through SHP2, and then participates in incision pain sensitization
.

(Source: Ding Xu et al.
, Brain Behav Immun, 2022)

Figure 5 Inhibition of spinal microglia alleviates the up-regulation of BDNF, SHP2 and GluA1
.

(Source: Ding Xu et al.
, Brain Behav Immun, 2022)

In addition, sciatic nerve block normalized the expression of BDNF, SHP2 and GluA1 (Figure 6)
.

Up-regulation of BDNF, SHP2 or AMPA receptors reduced the alleviation effect of sciatic nerve block on downstream molecules and pain behavior (Figure 7)
.

Spinal microglia activation using chemogenetic tools inhibited sciatic nerve block-induced trimolecular reduction (Fig.
8)
.

Figure 6 Sciatic nerve block down-regulates trimolecules
.

(Image source: Ding Xu et al.
, Brain Behav Immun, 2022)

Figure 7: Administration of BDNF, overexpression of SHP2, or activation of AMPA receptors down-regulates the effect of sciatic nerve blockade
.

(Source: Ding Xu et al.
, Brain Behav Immun, 2022)

Figure 8 Activation of microglia inhibits the alleviating effect of sciatic nerve block on trimolecular upregulation
.

(Source: Ding Xu et al.
, Brain Behav Immun, 2022)

Conclusions and Discussion, Inspirations and Prospects In conclusion, this study demonstrates the long-term effect of reduced spinal microglia activation, involved in sciatic nerve block, on incision-induced incision pain sensitization in the neonatal period
.

In addition, BDNF in the spinal dorsal horn is at least partially dependent on microglia to increase phosphorylation of SHP2, upregulate phosphorylation of the AMPA receptor GluA1 subunit and membrane trafficking, which in turn sensitizes incision pain
.

Conversely, sciatic nerve blockade downregulates the BDNF/SHP2/AMPA receptor-containing GluA1 subunit signaling pathway, resulting in sustained relief of incisional pain hypersensitivity
.

Repeated general anesthesia in the neonatal period is associated with poor outcomes, so multimodal perioperative analgesia regimens have been recommended for children, but the appropriate combination has not been established
.

Consistent with previous reports [4-6], this study suggests that in the clinical practice of neonatal surgery, sciatic nerve block and general anesthesia or other methods may be combined to prevent persistent effects on pain sensitivity
.

Of course, the side effects of sciatic nerve block require further preclinical and clinical studies
.

Original link: https://doi.
org/10.
1016/j.
bbi.
2022.
07.
010

This research was supported by the National Natural Science Foundation of China (81500942)
.

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End of this article