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

Abstract

Patients who have undergone surgery in early life may be at elevated risk for suffering neuropathic pain in later life. The risk factors for this susceptibility are not fully understood. Here, we 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. Mice were exposed to isoflurane at postnatal day 7 (P7) and underwent spared nerve injury at P28 which causes chronic pain. Selected groups were treated with rapamycin, an mTOR inhibitor, for eight weeks. 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. Accompanying upregulation of mTOR and rapamycin-reversible changes in chronic pain-associated markers, including N-cadherin, cAMP response element-binding protein (CREB), purinergic P2Y12 receptor, glial fibrillary acidic protein (GFAP) in DSC; and connexin 43, phospho-extracellular signal-regulated kinase (p-ERK), GFAP, Iba1 in DRG, were observed. We concluded that early GA exposure, at least with isoflurane, alters the development of pain circuits such that mice are subsequently more vulnerable to chronic neuropathic pain states.

Toward a brighter constellation: multiorgan neuroimaging of neural and vascular dynamics in the spinal cord and brain

“… 24 Importantly, exposure to isoflurane has also been reported to affect calcium dynamics in the spinal cord, 8 stimulate peripheral sensory nerves by sensitizing transient receptor potential V1 (Trpv1) receptors, 25 inhibit neuronal CaV3.2 calcium channels, 26 and increase the susceptibility to chronic pain by causing alterations in dorsal spinal cord and dorsal root ganglion. 27 Given these basic challenges, a key requirement for multisite imaging is the design of surgical procedures that minimize duration and that allow awake imaging if possible.…”

Towards a Brighter Constellation: Multi-Organ Neuroimaging of Neural and Vascular Dynamics in the Spinal Cord and Brain

“…31 Importantly, exposure to isoflurane has also been reported to affect calcium dynamics in the spinal cord, 15 stimulate peripheral sensory nerves by sensitizing transient receptor potential V1 (Trpv1) receptors, 32 inhibit neuronal CaV3.2 calcium channels, 33 and increase the susceptibility to chronic pain by causing alterations in dorsal spinal cord and dorsal root ganglion. 34 Given these basic challenges, a key requirement for multi-site imaging is the design of surgical procedures that minimize duration, and that allow awake imaging if possible.…”