Effects of Early Exposure of Isoflurane on Chronic Pain via the Mammalian Target of Rapamycin Signal Pathway

Abstract

Persistent post-surgical pain (PPSP) is a chronic pain condition, often with neuropathic features, that occurs in approximately 20% of children who undergo surgery. The biological basis of PPSP has not been elucidated. Anesthetic drugs can have lasting effects on the developing nervous system, although the clinical impact of this phenomenon is unknown. Here, we used a mouse model to test the hypothesis that early developmental exposure to isoflurane causes cellular and molecular alteration in the pain perception circuitry that causes a predisposition to chronic, neuropathic pain via a pathologic upregulation of the mammalian target of the rapamycin (mTOR) signaling pathway. Mice were exposed to isoflurane at postnatal day 7 and select cohorts were treated with rapamycin, an mTOR pathway inhibitor. Behavioral tests conducted 2 months later showed increased evidence of neuropathic pain, which did not occur in rapamycin-treated animals. Immunohistochemistry showed neuronal activity was chronically increased in the insular cortex, anterior cingulate cortex, and spinal dorsal horn, and activity was attenuated by rapamycin. Immunohistochemistry and western blotting (WB) showed a co-incident chronic, abnormal upregulation in mTOR activity. We conclude that early isoflurane exposure alters the development of pain circuits and has the potential to contribute to PPSP and/or other pain syndromes.

A novel social fear conditioning procedure alters social behavior and mTOR signaling in differentially housed adolescent rats

“…mTOR is a serine/threonine protein kinase that forms the catalytic subunit of two protein complexes, mTOR Complex 1 (mTORC1) and 2 (mTORC2) that regulate distinct cellular processes. Ribosomal protein S6, a downstream target of mTOR, is a component of Complex 1 and phosphorylated (p)S6 has been used as a specific marker of mTORC1 activation (Li, Mathena, Eregha, & Mintz, 2019; Yuskaitis et al., 2018). The mTORC1 cascade triggers mRNA translation and protein synthesis important for neuronal plasticity, while mTORC2 is associated with cell survival and proliferation (Hoeffer and Klann, 2010; Saxton & Sabatini, 2017; von Manteuffel et al., 1997).…”

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

“…All mice, except naïve, underwent SNI-evoked chronic pain. We did not set “Iso only” group in this study because effect of isoflurane exposure on intact animals had been investigated in our previous study [ 29 ].…”

“…Our previous work shows that, in intact newborn mice, isoflurane exposure causes cellular and molecular alteration in the developing pain perception circuitry via a pathologic upregulation of mTOR signaling pathway and enhances sensitivity to painful stimuli [ 29 ]. In this study, we sought to test the overall hypothesis that early postnatal GA exposure alters the development of pain circuitry through effects caused by increased signaling in the mTOR pathway such that mice more are rendered more susceptible to chronic neuropathic pain.…”

mTOR‐mediated autophagy in the hippocampus is involved in perioperative neurocognitive disorders in diabetic rats

“…Similarly, a recent study also reported that rapamycin treatment had a long-lasting effect on reducing the expression of p-mTOR and phospho-s6 even up to 18 days in a rodent model of isoflurane exposure. 47 Future studies are needed to investigate how long the pharmacologic effects of rapamycin can last after multiple consecutive days of injections.…”