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Abstract Background The prevalence of post-surgical lumbar neuropathic radiculopathy is approximately 30%. Poor response to the recommended treatments for neuropathic pain, namely antidepressants and/or gabapentinoids, requires the development of new techniques to prevent chronic pain. One such well-tolerated technique is the administration of autologous plasma enriched in platelets and fibrin (PRF). This approach is largely used in regenerative medicine owing to the anti-inflammatory and analgesic properties of PRF. It could also be an interesting adjuvant to surgery, as it reduces neurogenic inflammation and promotes nerve recovery, thereby reducing the incidence of residual postoperative chronic pain. The aim of the present study is to evaluate the benefit of periradicular intraoperative application of PRF on the residual postsurgical neuropathic pain after disc herniation surgery. Methods A randomized, prospective, interventional, controlled, single-blind study with evaluation by a blind outcome assessor will be performed in Strasbourg University Hospital. We will compare a control group undergoing conventional surgery to an experimental group undergoing surgery and periradicular administration of PRF (30 patients in each arm). The primary outcome is the intensity of postoperative neuropathic radicular pain, measured by a visual analog scale (VAS) at 6 months post-surgery. The secondary outcomes are the characteristics of neuropathic pain (NPSI), the quality of life (SF-12 and PGIC), the presence of anxiety/depression symptoms (HAD), and the consumption of analgesics. We will also carry out transcriptomic analysis of a panel of pro- and anti-inflammatory cytokines in blood samples, before surgery and at 6 months follow-up. These gene expression results will be correlated with clinical data, in particular, with the apparition of postoperative neuropathic pain. Discussion This study is the first randomized controlled trial to assess the efficacy of PRF in the prevention of neuropathic pain following surgery for herniated disc. This study addresses not only a clinical question but will also provide information on the physiopathological mechanisms of neuropathic pain. Trial registration This study is registered at ClinicalTrials.gov: NCT05196503 , February 24, 2022.

Immersive virtual reality (VR) is a promising tool to reduce pain in clinical setting. Digital scripts displayed by VR disposals can be enriched by several analgesic interventions, which are widely used to reduce pain. One of these techniques is hypnosis induced through the VR script (VRH) which is facilitated by immersive environment and particularly efficient even for low hypnotizable patients. The aim of this study is to assess the efficacy of a VRH script on experimentally induced cold pain perception (intensity and unpleasantness) and physiological expression. 41 healthy volunteers had been recruited in this within-subjects study. They received 9 stimulations of 20 s (3 non-nociceptive cold; 3 low nociceptive cold and 3 highly nociceptive cold) during a VRH session of 20 min (VRH condition) or without VRH (noVRH condition). Physiological monitoring during the cold pain stimulation protocol consisted of recording heart rate, heart rate variability and respiratory frequency. Maximum cold pain intensity perception, measured through the visual analog scale (VAS) on 10, was of 3.66 ± 1.84 (VAS score/10) in noVRH condition and 2.46 ± 1.54 in VRH (Wilcoxon, p

BackgroundVirtual reality hypnosis (VRH) is a promising tool to reduce pain. However, the benefits of VRH on pain perception and on the physiological expression of pain require further investigation. ObjectiveIn this study, we characterized the effects of VRH on the heat pain threshold among adult healthy volunteers while monitoring several physiological and autonomic functions. MethodsSixty healthy volunteers were prospectively included to receive nociceptive stimulations. The first set of thermal stimuli consisted of 20 stimulations at 60°C (duration 500 milliseconds) to trigger contact heat evoked potentials (CHEPs). The second set of thermal stimuli consisted of ramps (1°C/second) to determine the heat pain threshold of the participants. Electrocardiogram, skin conductance responses, respiration rate, as well as the analgesia nociception index were also recorded throughout the experiment. ResultsData from 58 participants were analyzed. There was a small but significant increase in pain threshold in VRH (50.19°C, SD 1.98°C) compared to that in the control condition (mean 49.45°C, SD 1.87; P0.5; n=22 and n=52, respectively). During VRH, participants exhibited a clear reduction in their autonomic sympathetic tone, as shown by the lower number of nonspecific skin conductance peak responses (P

The document presents a new issue of the journal "Pain and Analgesia" featuring articles on pain related to Covid-19, non-specific low back pain, the management of neuropathic pain with dronabinol, and the evaluation of the risk of post-surgical chronic pain. The 50th annual IASP congress in Amsterdam was marked by historic conferences and discussions on inequality in pain management and central sensitization. The next World Pain Congress will take place in Bangkok in two years. [Extracted from the article]

Abstract. Introduction:. Early neuronal processing of thermal noxious information relies mostly on molecular detectors of the transient receptor potential family expressed by specific subpopulation of sensory neurons. This information may converge to second-order wide-dynamic-range (WDR) neurons located in the deep layer of the dorsal horn of the spinal cord. Method:. Using a micro-Peltier thermode thermal contact stimulator II delivering various cold and hot noxious stimulations, we have characterized the extracellular electrophysiological responses of mechanosensitive WDR neurons in anesthetized adult male and female Wistar rats. Results:. Most of the WDR neurons were activated after hot and cold noxious stimulations, at mean temperature thresholds corresponding to 43 and 20°C, respectively. If the production of action potential was not different in frequency between the 2 thermal modalities, the latency to observe the first action potential was significantly different (cold: 212 ms; hot: 490 ms, unpaired Student t-test: t = 8.041; df = 32; P < 0.0001), suggesting that different fiber types and circuits were involved. The temporal summation was also different because no facilitation was seen for cold noxious stimulations contrary to hot noxious ones. Conclusion:. Altogether, this study helps better understand how short-lasting and long-lasting hot or cold noxious stimuli are integrated by mechanosensitive WDR neurons. In our experimental conditions, we found WDR neurons to be nociceptive specific for C-fiber–mediated hot stimuli. We also found that cold nonnoxious and noxious information, triggered at glabrous skin areas, are likely taken in charge by A-type sensory neurons. This study will be helpful to establish working hypothesis explaining the thermal pain symptoms displayed by animal models and patients in a translational extent.

More than 450 million people worldwide suffer from diabetes, or 1 in 11 people. Chronic hyperglycemia degrades patients’ quality of life and the development of neuropathic pain contributes to the burden of this disease. In this study, we used the mouse model of streptozocin-induced diabetic type 1 neuropathy to assess the analgesic potential of etifoxine. Etifoxine is a prescribed anxiolytic that increases GABAAA receptor function through a direct positive allosteric modulation effect and, indirectly, by stimulating the production of endogenous GABAA receptor positive modulators such as allopregnanolone-type neurosteroids. We show that a post-symptomatic or preventive treatment strongly and durably reduces mechanical hyperalgesia and anxiety in diabetic neuropathic mice. This analgesic and neuroprotective effect on painful symptoms and emotional comorbidities is promising and should now be clinically evaluated.

Abstract Background- Mice deficient for the stable tubule only peptide (STOP) display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission. Results- In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p.) produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg) was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg) was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice. Conclusions- Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.

Noise and high light illumination in the neonatal intensive care unit (NICU) are recognized as stressors that could alter the well-being and development of vulnerable preterm infants. This prospective observational study evaluated the pain behaviours of very preterm infants (VPIs) to sound peaks (SPs) and light levels variations (LLVs) in the NICU. We measured spontaneously occurring SPs and LLVs in the incubators of 26 VPIs over 10 h. Their behavioural responses were analysed through video recordings using the “Douleur Aigue du Nouveau-né” (DAN) scale. We compared the maximum DAN scores before and after environmental stimuli and the percentage of VPIs with a score ≥ 3 according to the type of stimuli. A total of 591 SPs and 278 LLVs were analysed. SPs of 5 to 15 dBA and LLVs significantly increased the maximum DAN scores compared to baseline. The occurrence of DAN scores ≥ 3 increased with both stressors, with a total of 16% of SPs and 8% of LLVs leading to quantifiable pain behaviour. Altogether, this study shows that VPIs are sensitive to SPs and LLVs, with a slighter higher sensitivity to SPs. The mechanisms leading to pain behaviours induced by noise and light changes should be evaluated further in the context of VPIs brain development. Our results provide further arguments to optimize the NICU sensory environment of neonatal units and to adapt it to the expectations and sensory abilities of VPIs.

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Preterm infants (PTI) typically experience many painful and stressful procedures or events during their first weeks of life in a neonatal intensive care unit, and these can profoundly impact subsequent brain development and function. Several protective interventions during this sensitive period stimulate the oxytocin system, reduce pain and stress, and improve brain development. This review provides an overview of the environmental risk factors experienced by PTI during hospitalization, with a focus on the effects of pain, and early maternal separation. We also describe the long-term adverse effects of the simultaneous experiences of pain and maternal separation, and the potential beneficial effects of maternal vocalizations, parental contact, and several related processes, which appear to be mediated by the oxytocin system.

Abstract Background- Mice deficient for the stable tubule only peptide (STOP) display altered dopaminergic neurotransmission associated with severe behavioural defects including disorganized locomotor activity. Endogenous morphine, which is present in nervous tissues and synthesized from dopamine, may contribute to these behavioral alterations since it is thought to play a role in normal and pathological neurotransmission. Results- In this study, we showed that STOP null brain structures, including cortex, hippocampus, cerebellum and spinal cord, contain high endogenous morphine amounts. The presence of elevated levels of morphine was associated with the presence of a higher density of mu opioid receptor with a higher affinity for morphine in STOP null brains. Interestingly, STOP null mice exhibited significantly lower nociceptive thresholds to thermal and mechanical stimulations. They also had abnormal behavioural responses to the administration of exogenous morphine and naloxone. Low dose of morphine (1 mg/kg, i.p.) produced a significant mechanical antinociception in STOP null mice whereas it has no effect on wild-type mice. High concentration of naloxone (1 mg/kg) was pronociceptive for both mice strain, a lower concentration (0.1 mg/kg) was found to increase the mean mechanical nociceptive threshold only in the case of STOP null mice. Conclusions- Together, our data show that STOP null mice displayed elevated levels of endogenous morphine, as well as an increase of morphine receptor affinity and density in brain. This was correlated with hypernociception and impaired pharmacological sensitivity to mu opioid receptor ligands.

Abstract Background Growing evidence in the literature shows that oxytocin (OT) has a strong spinal anti-nociceptive action. Oxytocinergic axons originating from a subpopulation of paraventricular hypothalamic neurons establish synaptic contacts with lamina II interneurons but little is known about the functional role of OT with respect to neuronal firing and excitability. Results Using the patch-clamp technique, we have recorded lamina II interneurons in acute transverse lumbar spinal cord slices of rats (15 to 30 days old) and analyzed the OT effects on action potential firing ability. In the current clamp mode, we found that bath application of a selective OT-receptor agonist (TGOT) reduced firing in the majority of lamina II interneurons exhibiting a bursting firing profile, but never in those exhibiting a single spike discharge upon depolarization. Interestingly, OT-induced reduction in spike frequency and increase of firing threshold were often observed, leading to a conversion of the firing profile from repetitive and delayed profiles into phasic ones and sometimes further into single spike profile. The observed effects following OT-receptor activation were completely abolished when the OT-receptor agonist was co-applied with a selective OT-receptor antagonist. In current and voltage clamp modes, we show that these changes in firing are strongly controlled by voltage-gated potassium currents. More precisely, transient IA currents and delayed-rectifier currents were reduced in amplitude and transient IA current was predominantly inactivated after OT bath application. Conclusion This effect of OT on the firing profile of lamina II neurons is in good agreement with the antinociceptive and analgesic properties of OT described in vivo.

Abstract Background Recent evidence suggests that oxytocin (OT), secreted in the superficial spinal cord dorsal horn by descending axons of paraventricular hypothalamic nucleus (PVN) neurons, produces antinociception and analgesia. The spinal mechanism of OT is, however, still unclear and requires further investigation. We have used patch clamp recording of lamina II neurons in spinal cord slices and immunocytochemistry in order to identify PVN-activated neurons in the superficial layers of the spinal cord and attempted to determine how this neuronal population may lead to OT-mediated antinociception. Results We show that OT released during PVN stimulation specifically activates a subpopulation of lamina II glutamatergic interneurons which are localized in the most superficial layers of the dorsal horn of the spinal cord (lamina I-II). This OT-specific stimulation of glutamatergic neurons allows the recruitment of all GABAergic interneurons in lamina II which produces a generalized elevation of local inhibition, a phenomenon which might explain the reduction of incoming Aδ and C primary afferent-mediated sensory messages. Conclusion Our results obtained in lamina II of the spinal cord provide the first clear evidence of a specific local neuronal network that is activated by OT release to induce antinociception. This OT-specific pathway might represent a novel and interesting therapeutic target for the management of neuropathic and inflammatory pain.