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  4. Effects of Early Exposure to Isoflurane on Susceptibility to Chronic Pain Are Mediated by Increased Neural Activity Due to Actions of the Mammalian Target of the Rapamycin Pathway

Effects of Early Exposure to Isoflurane on Susceptibility to Chronic Pain Are Mediated by Increased Neural Activity Due to Actions of the Mammalian Target of the Rapamycin Pathway

Int. J. Mol. Sci., 2023 · DOI: 10.3390/ijms241813760 · Published: September 6, 2023

AnesthesiologyNeurologyPain Management

Simple Explanation

Early-life surgery may increase the risk of neuropathic pain later in life. This study used mice to investigate whether early exposure to the general anesthetic Isoflurane could increase the risk of neuropathic pain. Isoflurane exposure enhanced susceptibility to chronic pain, and rapamycin treatment improved outcomes. The study found that early isoflurane exposure enhanced sensitivity for mechanical and thermal stimuli in a chronic pain model. Isoflurane exposure increases mTOR expression and neural activity in DSC and DRG, which are key elements of the pain-processing circuitry. The results suggest that early postnatal exposure to isoflurane renders mice susceptible to worsened outcomes in the SNI model of chronic neuropathic pain. The mTOR signaling pathway and related molecules in pain circuitry are involved in this alteration.

Study Duration
8 weeks
Participants
64 immature C57BL/6 mice
Evidence Level
Not specified

Key Findings

  • 1
    Early isoflurane exposure enhances sensitivity for mechanical and thermal stimuli in a chronic pain model caused by SNI.
  • 2
    Isoflurane exposure increases mTOR expression and neural activity in DSC and DRG, which are key elements of the pain-processing circuitry.
  • 3
    Inhibition of the mTOR signal pathway with rapamycin treatment substantially ameliorates the susceptibility to pain stimuli and reverses the effects on neural activity.

Research Summary

This study used a mouse chronic pain model to test the hypothesis that early exposure to the general anesthetic (GA) Isoflurane causes cellular and molecular alterations in dorsal spinal cord (DSC) and dorsal root ganglion (DRG) that produces a predisposition to neuropathic pain via an upregulation of the mammalian target of the rapamycin (mTOR) signaling pathway. Behavioral tests showed that early isoflurane exposure enhanced susceptibility to chronic pain, and rapamycin treatment improved outcomes. Immunohistochemistry, Western blotting, and q-PCR indicated that isoflurane upregulated mTOR expression and neural activity in DSC and DRG. The mTOR signaling pathway and related molecules in pain circuitry are involved in this alteration. These data suggest very interesting future directions to investigate potential mechanisms by which isoflurane and other anesthetics could increase the risk of chronic pain in children who undergo GA exposure.

Practical Implications

Modifications in anesthetic technique

Prospective studies in patients undergoing early life anesthesia to test whether modifications in anesthetic technique can affect chronic pain outcomes.

Preventative strategies

Prospective studies in patients undergoing early life anesthesia to test whether preventative strategies to mitigate the hypothesized anesthetic effect can affect chronic pain outcomes.

Further mechanistic investigation

Further mechanistic investigation of the anesthetic effects on the development of pain circuitry are independently interesting in uncovering potential mechanisms to prevent chronic pain.

Study Limitations

  • 1
    Rapa could be acting via off target effects
  • 2
    Effects we observed in DSC and DRG might be indirectly caused by mTOR
  • 3
    Our data did not really distinguish between effects mediated by mTORC1 and mTORC2

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