Biology subjects

Treede, R.-D.

Publications and source records attributed to Treede, R.-D..

4 recordsLinked to original sources

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↗

bioRxiv2021

Long-term sensitization of rat spinal neurons induced by adolescent psychophysical stress is further enhanced by a mild-nociceptive lumbar input

BackgroundNon-specific low back pain (LBP) is one of the most common chronic pain conditions and adverse childhood experiences (ACEs) are known mediators for chronicity of LBP. Sensitization of dorsal horn neurons (DHNs) is a significant element that contributes to chronic LBP. Repeated restraint stress in adult animals is known to cause manifest DHN sensitization when combined with a short-lasting nociceptive input. ObjectiveIn this study, we investigated whether repeated restraint stress in early adolescence leads to a long-term sensitization of DHNs and if an additional mild-nociceptive input by intramuscular nerve growth factor (NGF) leads to further sensitization. MethodsAdolescent Wistar rats were stressed repeatedly in a narrow plastic restrainer, 1 hour per day for 12 consecutive days. Control animals were handled but not restrained. In adulthood, rats were treated with intramuscular injections of saline or NGF (short-lasting mild-nociceptive input) into the lumbar multifidus muscle (L5). Behavioral tests for pain sensitivity were performed before, after stress and inconjunction with intramuscular injections. Rats were transcardially perfused and immunohistochemistry was performed on lumbar (L2) spinal segments. ResultsAdolescent restraint stress significantly lowered the low back pressure pain threshold (PPT) immediately after the stress (p<0.0001) and was maintained throughout adulthood (p<0.05). Additionally, paw withdrawal threshold (PWT) was significantly lowered by stress (p<0.0001) but normalized towards adulthood. An NGF injection in adulthood in previously stressed animals lowered the PPT (Cohens d=0.87) and increased microglia marker (Iba-1) immunoreactive area in the superficial DHN (p<0.01) with a trend in increased ferets diameter of the immunoreactive cell (p=0.05). ConclusionsOur adolescence stress model induced behavioral signs of sensitization and enhanced sensitivity to further sensitization and dorsal horn microglia activation by subsequent mild nociceptive input (NGF injection). These findings help to understand certain aspects of how adolescent stress might predispose to exacerbation of pain with an additional insult.

neuroscience↗

bioRxiv2019

Neural network-based alterations during repeated heat pain stimulation in major depression

The current study aimed to identify alterations in brain activation and connectivity related to nociceptive processing and pain sensitization in major depressive disorder (MDD), using repeated heat pain stimulation during functional magnetic resonance imaging (fMRI) in 37 MDD patients and 33 healthy controls. Regional activation did not differ between groups, but functional connectivity was significantly decreased in MDD in a neural network connecting frontal, temporal and occipital areas (family-wise error (FWE)-corrected pFWE = 0.045). Supplemental analyses suggested a significant association between network connectivity and trait neuroticism (p = 0.007) but not with the clinical state or familiar risk of MDD (all p values > 0.13). Our data relate a network-based phenotype for altered pain processing and antinociceptive control to MDD and encourage future studies on the shared intermediate neural psychological risk architecture of MDD and chronic pain.

neuroscience↗