Dose-dependent dorsal column activation drives analgesic effects of spinal cord stimulation in a rat model of neuropathic pain

Eline M Versantvoort; Kimberley Ladner; Dave Mugan; Darayus Nanavati; Daniel Parker; Quoc C Vuong; Birte E Dietz; Ilona Obara

doi:10.1136/rapm-2026-107607

Dose-dependent dorsal column activation drives analgesic effects of spinal cord stimulation in a rat model of neuropathic pain

Reg Anesth Pain Med. 2026 Apr 29:rapm-2026-107607. doi: 10.1136/rapm-2026-107607. Online ahead of print.

Authors

Eline M Versantvoort¹, Kimberley Ladner¹, Dave Mugan^{1

2}, Darayus Nanavati², Daniel Parker², Quoc C Vuong³, Birte E Dietz^{1

2}, Ilona Obara⁴

Affiliations

¹ School of Pharmacy and Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
² Saluda Medical Pty Ltd, Artarmon, New South Wales, Australia.
³ School of Psychology and Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
⁴ School of Pharmacy and Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK ilona.obara@ncl.ac.uk.

PMID: 42055600
DOI: 10.1136/rapm-2026-107607

Abstract

Background: Spinal cord stimulation (SCS) is typically dosed to the perception threshold, defined as the onset of stimulation-induced sensations. The evoked compound action potential threshold (ECAPT) is an objective marker of dorsal column fiber activation onset. It approximates the perception threshold, and ECAPT-guided dosing improves clinical outcomes. Preclinical models are valuable for investigating the mechanisms of SCS, yet dosing strategies in animal studies commonly rely on motor threshold-based stimulation intensities, with limited translational relevance. Here, we establish a causal relationship between ECAPT, dorsal column activation, and analgesic efficacy, demonstrating for the first time that ECAPT provides a clinically comparable marker to guide preclinical SCS dosing based on neural activation.

Methods: Adult male Sprague-Dawley rats with spared nerve injury (SNI)-induced neuropathic pain (n=25) were implanted epidurally with an eight-contact lead covering T12-L2. SCS (50 Hz, 100 µs) was delivered at individualized doses of 0×ECAPT, 0.5×ECAPT (open loop), or 1.1-1.4×ECAPT (closed loop). Additional SNI and sham controls (n=6 each) received no lead implantation or stimulation. Analgesic efficacy was assessed by paw withdrawal responses to mechanical (von Frey filaments) and cold (acetone) stimuli.

Results: ECAPT-based SCS doses of 1.2-1.3×ECAPT achieved the most sustained reduction in mechanical and cold hypersensitivity, whereas 1.1×ECAPT was less effective and 1.4×ECAPT provided no additional benefit. Subthreshold doses (0-0.5×ECAPT) were ineffective.

Conclusions: These findings validate ECAP as a translationally relevant measure of neural activation and demonstrate that dorsal column fiber recruitment is a key driver of SCS-induced analgesia, supporting ECAPT-guided dosing to enhance the clinical relevance and standardization of preclinical stimulation protocols.

Keywords: Analgesia; Animal Experimentation; CHRONIC PAIN; Peripheral Nerve Injuries; Spinal Cord Stimulation.