Krajewski, J. | bioRxiv Science

bioRxiv2026

Contribution of Wide Dynamic Range neuronal activation to somatosensory evoked potentials supports use as biomarker of spinal nociceptive processing

Identifying objective translational biomarkers of spinal nociceptive processing is important to accelerate analgesic development. The primary negative component (N1) of spinal somatosensory evoked potentials (SEPs) has been proposed as such a biomarker. However, the cellular substrates of the N1 potential (evoked by innocuous electrical stimulation) and their relevance to nociceptive processing have not been directly demonstrated. Here, we employed a 64-channel multielectrode recording approach in the dorsal horn of anaesthetised Wistar rats to functionally characterise the neuronal populations activated during the generation of spinal SEPs and determine how their activity is modulated by tapentadol. Single units were classified based on their responses to mechanical stimulation of the hindpaw, and their electrically evoked responses to sciatic nerve stimulation. Of 59 well-isolated units, 47 (80%) were classified as wide dynamic range (WDR) neurons and 12 (20%) as low-threshold mechanoreceptive (LTMR) neurons, spatially distributed across spinal laminae III-V. Tapentadol (10 mg/kg, intraperitoneal (i.p)) selectively attenuated the mechanically- and electrically-evoked activity of WDR neurons without affecting LTMR responses. This WDR-inhibition was largely reversed by naloxone (0.25 mg/kg, i.p) but not by atipamezole (1 mg/kg, i.p), identifying a predominant opioid receptor-mediated mechanism of inhibition in the naive state. The magnitude of WDR inhibition by tapentadol correlated with the degree of reduction of the N1 amplitude. These findings establish activity in WDR neurons as a core component of the N1 potential, supporting the use of spinal SEPs as a translational biomarker of analgesic target engagement within the dorsal horn. SummaryMultielectrode recordings identify inhibition of WDR neurons as the mechanism by which tapentadol modulates spinal SEPs, supporting use as a biomarker of spinal nociceptive processing.

neuroscience↗

bioRxiv2025

Preclinical assay of the effects of lacosamide, pregabalin and tapentadol on the rat N1 spinal somatosensory evoked potential.

The high failure rate in translating novel analgesics into the clinic has highlighted the need for more translatable biomarkers of analgesic efficacy. The N13 component of spinal somatosensory evoked potential (SEP) has been proposed as a biomarker of spinal nociceptive processing in humans, but it is not known whether this can be back translated into rodents. Tapentadol, lacosamide and pregabalin were used as pharmacological probes to assess the sensitivity of spinal SEPs to drug action. In anaesthetised, naive rats (n=44), a multielectrode silicon probe was inserted into the L4 spinal cord to record SEPs from the dorsal horn following electrical stimulation of the sciatic nerve. At baseline, the N1 component (rodent equivalent of the human N13) had an amplitude of 1.33 {+/-} 0.07mV at a latency of 4.6 {+/-} 0.2ms following low-intensity stimulation, with an intensity-dependent amplitude increase into the noxious range. The N1 amplitude was significantly reduced by 10mg/Kg tapentadol (40.2 {+/-} 12.5 % vs vehicle 96.2 {+/-} 8.0 %) and 30mg/Kg lacosamide (46.3 {+/-} 20.9 % lacosamide vs vehicle 115 {+/-} 5.9 %) at 60 minutes after intraperitoneal administration. Tapentadol also reduced the N1 amplitude in the noxious range. Lacosamide increased the stimulus current required to evoke the half maximal N1 response (EC50), without reducing the maximum N1 amplitude in the noxious range. Pregabalin (at any dose up to 30mg/kg) did not modulate the N1 amplitude. These results show the spinal N1 is differentially modulated in a way that reflects distinct mechanisms of drug action consistent with it being a translatable biomarker of analgesic efficacy.

neuroscience↗