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.
Highlights
Persistent post-surgical pain (PPSP) is defined as pain that continues for at least 3 months following a surgical intervention that either was not present prior to surgery or that is completely distinct in character from pre-operative pain at the surgical site [1,2]
It is difficult to investigate the character of pain in children, two studies indicate that neuropathic pain symptoms are likely predominant in PPSP on the basis of questions posed to the child and parent [7,8], and, interestingly, a study of PSPP after hernia repair showed hyperalgesia to pin-prick [9]
We focused on two cortical regions that are involved in pain transduction and modulation—the insular cortex (IC) and anterior cingulate cortex (ACC)—and on the spinal cord dorsal horn (SDH)
Summary
Persistent post-surgical pain (PPSP) is defined as pain that continues for at least 3 months following a surgical intervention that either was not present prior to surgery or that is completely distinct in character from pre-operative pain at the surgical site [1,2]. The mechanisms by which anesthetics act on the developing nervous system to effect lasting change have not been elucidated, but alterations in synapse number, distribution, and function have been identified as likely contributors [17,18,19,20] Given the role of synaptic plasticity in the onset of chronic pain [21], there exists the intriguing possibility that exposure to certain anesthetics might constitute a biological risk factor for PPSP. We employed a mouse model to test the overall hypothesis that early developmental exposure to isoflurane, one of the most commonly used general anesthetic agents, can cause an increase in the risk of chronic pain, with a goal of understanding whether anesthetic technique may be an important factor in PPSP. Activity in the mTOR pathway has been implicated in chronic pain generally and in neuropathic pain [33,34,35,36], and we further explored the possibility that early developmental isoflurane exposure may lead to a lasting effect on pain pathways via an action on the mTOR pathway
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