Structural plasticity of axon initial segment in spinal cord neurons underlies inflammatory pain

Yaki Caspi, Michael Mazar, Yishai Kushnir, Yoav Mazor, Ben Katz, Shaya Lev, Alexander M. Binshtok*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Physiological or pathology-mediated changes in neuronal activity trigger structural plasticity of the action potential generation site - the axon initial segment (AIS). These changes affect intrinsic neuronal excitability, thus tuning neuronal and overall network output. Using behavioral, immunohistochemical, electrophysiological, and computational approaches, we characterized inflammation-related AIS plasticity in rat's superficial (lamina II) spinal cord dorsal horn (SDH) neurons and established how AIS plasticity regulates the activity of SDH neurons, thus contributing to pain hypersensitivity. We show that in naive conditions, AIS in SDH inhibitory neurons is located closer to the soma than in excitatory neurons. Shortly after inducing inflammation, when the inflammatory hyperalgesia is at its peak, AIS in inhibitory neurons is shifted distally away from the soma. The shift in AIS location is accompanied by the decrease in excitability of SDH inhibitory neurons. These AIS location and excitability changes are selective for inhibitory neurons and reversible. We show that AIS shift back close to the soma, and SDH inhibitory neurons' excitability increases to baseline levels following recovery from inflammatory hyperalgesia. The computational model of SDH inhibitory neurons predicts that the distal shift of AIS is sufficient to decrease the intrinsic excitability of these neurons. Our results provide evidence of inflammatory pain-mediated AIS plasticity in the central nervous system, which differentially affects the excitability of inhibitory SDH neurons and contributes to inflammatory hyperalgesia.

Original languageAmerican English
Pages (from-to)1388-1401
Number of pages14
JournalPain
Volume164
Issue number6
DOIs
StatePublished - 1 Jun 2023

Bibliographical note

Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.

Keywords

  • AIS
  • Hyperalgesia
  • Hyperexcitability
  • Inflammatory pain
  • Inhibitory neurons
  • Superficial dorsal spinal cord

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