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 language | American English |
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Pages (from-to) | 1388-1401 |
Number of pages | 14 |
Journal | Pain |
Volume | 164 |
Issue number | 6 |
DOIs | |
State | Published - 1 Jun 2023 |
Bibliographical note
Funding Information:Support is gratefully acknowledged from the Canadian Institute of Health Research (CIHR), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF) and the Azrieli Foundation—grant agreement 2545/18; Israeli Science Foundation—grant agreement 1470/17; the Deutsch-Israelische Projectkooperation program of the Deutsche Forschungsgemeinschaft (DIP) grant agreement B.I. 1665/1-1ZI1172/12-1 and Sessile and Seymour Alpert Chair in Pain Research.
Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.
Keywords
- AIS
- Hyperalgesia
- Hyperexcitability
- Inflammatory pain
- Inhibitory neurons
- Superficial dorsal spinal cord