Biology subjects

Dunham, J. P.

Publications and source records attributed to Dunham, J. P..

4 recordsLinked to original sources

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↗

bioRxiv2021

Trial by trial, machine learning approach identifies temporally discrete Aδ- and C-fibre mediated laser evoked potentials that predict pain behaviour in rats.

Laser evoked potentials (LEPs) - the EEG response to temporally-discrete thermal stimuli - are commonly used in experimental pain studies in humans. Such stimuli selectively activate nociceptors and produce EEG features which correlate with pain intensity. The rodent LEP has been proposed to be a translational biomarker of nociception and pain, however its validity has been questioned because of reported differences in the classes of nociceptive fibres mediating the response. Here we use a machine learning, trial by trial analysis approach on wavelet-denoised LEPs generated by stimulation of the plantar hindpaw of rats. The LEP amplitude was more strongly related to behavioural response than to laser stimulus energy. A simple decision tree classifier using LEP features was able to predict behavioural responses with 73% accuracy. An examination of the features used by the classifier showed that mutually exclusive short and long latency LEP peaks were clearly seen in single-trial data, yet were not evident in grand average data pooled from multiple trials. This bimodal distribution of LEP latencies was mirrored in the paw withdrawal latencies which were preceded and predicted by the LEP responses. The proportion of short latency events was increased after intradermal application of high dose capsaicin (to defunctionalise TRPV1 expressing nociceptors), suggesting they were mediated by A{delta}-fibres (specifically AMH-I). These findings demonstrate that both C- and A{delta}-fibres contribute to rodent LEPs and concomitant behavioural responses, providing a real-time assay of specific fibre function in conscious animals. Single-trial analysis approaches can improve the utility of LEPs as a translatable biomarker of pain.

neuroscience↗

bioRxiv2019

Tracking somatic drift reveals small effective population size of stem cells and high somatic mutation rate in asexual planaria

Planarian flatworms have emerged as highly promising models of body regeneration due to the many stem cells scattered through their bodies. Currently, there is no consensus as to the number of stem cells active in each cycle of regeneration or the equality of their relative contributions. We approached this problem with a population genetic model of somatic genetic drift. We modeled the fissiparous life cycle of asexual planarians as an asexual population of cells that goes through repeated events of splitting into two subpopulations followed by population growth to restore the original size. We sampled a pedigree of obligate asexual clones of Girardia cf. tigrina at multiple time points encompassing 14 generations. Effective population size of stem cells was inferred from the magnitude of temporal fluctuations in the frequency of somatic variants and under most of the examined scenarios was estimated to be in the range of a few hundreds. Average genomic nucleotide diversity was 0.00398. Assuming neutral evolution and mutation-drift equilibrium, the somatic mutation rate was estimated in the 10-5 - 10-7 range. Alternatively, we estimated Ne and somatic from temporal changes in nucleotide diversity{pi} without the assumption of equilibrium. This second method suggested even smaller Ne and larger . A key unknown parameter in our model on which estimates of Ne and depend is g, the ratio of cellular to organismal generations determined by tissue turnover rate. Small effective number of propagating stem cells might contribute to reducing reproductive conflicts in clonal organisms.

genetics↗