Spinal somatosensory evoked potentials as a translational biomarker for analgesic target engagement

Abstract

The high failure rate in the development of novel analgesics for chronic and neuropathic pain conditions has highlighted the need for more objective measures of analgesic target engagement, to facilitate the transition of preclinical analgesic success into clinical efficacy. The development of translational biomarkers based on existing electrophysiological and neuroimaging techniques could accelerate the development of novel and effective analgesics, but it is unknown if such measures can be back-translated into preclinical models or be modulated by analgesic drugs. The experiments in this thesis will assay the sensitivity of spinal somatosensory potentials (SEPs) to three standard-of-care analgesics, lacosamide, pregabalin and tapentadol, as a translational biomarker for pain and investigate the neuronal correlates of their generators and the mechanism underpinning their modulation.
All experiments were performed in naïve, anaesthetised, male Wistar rats using surface electrode, tungsten electrode and multielectrode recording techniques to characterise the generators of spinal SEPs evoked by innocuous and noxious electrical stimulation, and to develop an assay to test their sensitivity to analgesic action. The primary negative component (N1) of spinal SEPs was significantly reduced by lacosamide, in a manner that reflected its mechanism of action as a non-selective voltage-gated sodium channel antagonist, indicating a peripheral site of inhibition. The N1 peak of spinal SEPs was unaffected by pregabalin, an antagonist of the voltage gated calcium channel α2δ-subunit, in response to innocuous or noxious electrical stimulation. The N1 peak evoked by innocuous and noxious electrical stimulation was significantly inhibited by tapentadol, a µ-opioid receptor (MOR) agonist and noradrenaline-reuptake inhibitor (NRI), indicating a centrally-mediated site of action.
To unpick the MOR-mediated and NRI-mediated inhibition of spinal SEPs by tapentadol, spike sorting of multielectrode data from SEP recordings into single unit clusters enabled the classification of functional populations of spinal neurons. Wide dynamic range (WDR) neurons and low-threshold mechanoreceptive (LTMR) neurons were activated by Aβ-fibres during the generation of the N1 peak, but only WDR neurons were inhibited by tapentadol. The inhibition of WDR neurons by tapentadol was fully reversed by the MOR-antagonist naloxone, but only weakly reversed by the noradrenaline-transport antagonist atipamezole, indicating a predominant MOR-mediated effect of inhibition in naïve rats. The inhibition and recovery of WDR neuronal activity reflected the inhibition and recovery of the spinal SEPs by naloxone and atipamezole, indicating WDR neurons as their likely neuronal generator.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Anthony Edward Pickering (Supervisor) & Jim Dunham (Supervisor)