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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

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.

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.

Background: Virtual 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.Objective: In this study, we characterized the effects of VRH on the heat pain threshold among adult healthy volunteers while monitoring several physiological and autonomic functions.Methods: Sixty 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.Results: Data 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; P<.001, Wilcoxon matched-pairs signed-rank test; Cohen d=0.38). No significant effect of VRH on CHEPs and heart rate variability parameters was observed (all P>0.5; 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<.001, two-way analysis of variance; n=39) and by an increase in the analgesia nociception index (P<.001, paired t-test; n=40).Conclusions: The results obtained in this study support the idea that VRH administration is effective at increasing heat pain thresholds and impacts autonomic functions among healthy volunteers. As a nonpharmacological intervention, VRH has beneficial action on acute experimental heat pain. This beneficial action will need to be evaluated for the treatment of other types of pain, including chronic pain. [ABSTRACT FROM AUTHOR]

Effective relief of acute and long-term postoperative pain is of utmost importance to patients undergoing surgery. Here, we worked on a controlled procedure of abdominal surgery in the rat inducing persistent postoperative pain symptoms for up to 10 days and tested the efficacy of perioperative care with the local anesthetic ropivacaine. Laparotomy was likewise used to implant radiotelemetric probes by which electrocardiogram, body temperature, and locomotor activity were recorded in freely moving animals. We showed that postoperative pain symptoms (mechanical allodynia) measured in periphery of the scar were associated over time with persistent tachycardia, elevated heart rate variability, and loss of mobility. Furthermore, a single subcutaneous infiltration of the local anesthetic ropivacaine in the periphery of the abdominal incision was sufficient to prevent the appearance of allodynia and the associated cardiac and motor signs of pain, monitored by radiotelemetry. These beneficial effects were observed when the infiltration was performed in the perioperative period, but not later. This study on freely moving animals exhibiting long-lasting postoperative pain symptoms and altered autonomic/motor function illustrates well the importance of the timing of preemptive analgesia care with long-acting local anesthetics. Moreover, it emphasizes the utility of monitoring heart rate variability to quantify spontaneous expression of long-lasting postoperative pain. PERSPECTIVE: Speeding the recovery time after surgery using perioperative ropivacaine care is of significant clinical relevance because it might limit the risk of chronic pain and postoperative complications. In humans, chronobiological analysis of heart rate variability could also help quantify spontaneous pain expression with minimal emotional bias. [ABSTRACT FROM AUTHOR]

Abstract: In animal studies, thermal sensitivity is mostly evaluated on the basis of nociceptive reaction latencies in response to a given thermal aversive stimulus. However, these techniques may be inappropriate to differentiate allodynia from hyperalgesia or to provide information differentiating the activation of nociceptor subtypes. The recent development of dynamic hot and cold plates, allowing computer-controlled ramps of temperature, may be useful for such measures. In this study, we characterized their interest for studying thermal nociception in freely moving mice and rats. We showed that escape behavior (jumps) was the most appropriate parameter in C57Bl/6J mice, whereas nociceptive response was estimated by using the sum of paw lickings and withdrawals in Sprague-Dawley rats. We then demonstrated that this procedure allows the detection of both thermal allodynia and hyperalgesia after peripheral pain sensitization with capsaicin in mice and in rats. In a condition of carrageenan-induced paw inflammation, we observed the previously described thermal hyperalgesia, but we also revealed that rats exhibit a clear thermal allodynia to a cold or a hot stimulus. These results demonstrate the interest of the dynamic hot and cold plate to study thermal nociception, and more particularly to study both thermal allodynia and hyperalgesia within a single paradigm in awake and freely moving rodents. Perspective: Despite its clinical relevance, thermal allodynia is rarely studied by researchers working on animal models. As shown after stimulation of capsaicin-sensitive fibers or during inflammatory pain, the dynamic hot and cold plate validated in the present study provides a useful tool to distinguish between thermal allodynia and thermal hyperalgesia in rodents. [Copyright &y& Elsevier]

Devices designed for mechanical pain threshold studies are often difficult to implement. The purpose of this study was to investigate a simple tool based on calibrated forceps to induce quantifiable mechanical stimulation in the rat on a linear scale. The most suitable protocol was tested by determining the effects of 3 repetitive measurements on both hind paws, respectively, during long-term (9 days), mid-term (1 day), and short-term (2 hours). Only threshold increase related to weight gain over long-term was observed, suggesting that moderate rat training can be used. The capacity of the device to reveal hyperalgesia was tested in a model of carrageenan-induced inflammation in the hind paw. The hyperalgesia was maximal 6 hours after carrageenan injection and progressively decreased. Similar, although more variable, responses were observed with von Frey filaments. Morphine-induced analgesia resulted in a dose-dependent increase of paw threshold. Tolerance to morphine administrated on a once daily schedule (10 mg/kg) during 5 days was revealed by a significant decrease in analgesia by day 3. Taken together, these results demonstrated accuracy of this device for easy, fast, and reproducible measure of mechanical pain threshold on rat limbs. Moreover, it allows the performance of rat testing with minimal constraint, which reduces data variability. PERSPECTIVE: The calibrated forceps is an easy to use device well-suited to rapidly test mechanical pain threshold with accuracy. It is well-designed for preclinical behavioral screening of noxious or analgesic properties of molecules. [ABSTRACT FROM AUTHOR]

Abstract: Although the behavioral response to pain is complex and involves supraspinal processes, assessment of pain symptoms in animal models still mainly relies on reflex-based nociceptive tests, which do not account for the affective-motivational nor cognitive components of pain. We introduce a double avoidance place preference paradigm, an integrated testing procedure in freely moving rats that relies on the conflict between the avoidance of a dark compartment in which a thermal ramp is activated, and the escape towards an aversive brightly lit compartment. We were able to differentiate the first nociceptive threshold from the temperature of definitive escape from the dark compartment, conveying information on the adaptive behavior of animals. Measures were repeated after an hour to evaluate the adaptive learning response upon reexposure. In naive animals, there was a significant decrease in the time spent in the dark compartment at all stages of the testing paradigm upon reexposure, leading to a final escape before the flood had reached nociceptive values. This adaptive behavior was blunted by anxiolytic treatment. In animals exhibiting hyperalgesia following intraplantar complete Freund adjuvant injection, escape thresholds were significantly higher than that of control animals, hinting at a maladaptive affective-motivational response to noxious stimulation. However, in cuff animals, we failed to reveal any hot nociceptive hypersensitivity, but animals exhibited a strong adaptive response to cold simulation upon reexposure. Overall, the proposed paradigm allows for an integrated cortical response leading to a proactive avoidance behavior, while fully complying with ethical standards in animal experimentation., (Copyright © 2024 International Association for the Study of Pain.)

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  < 0.0001). Considering pain unpleasantness perception, 3.68 ± 2.06 in noVRH and 2.21 ± 1.63 in VRH (Wilcoxon, p  < 0.0001). Hypnotizability negatively correlated with the decrease in VAS intensity from noVRH to VRH (Spearman r  = -0.45; p  = 0.0038). In our sample, we found that 31/41 volunteers (75.6%) displayed a reduction of more than 10% of their VAS pain intensity and unpleasantness scores. Trait anxiety was the best predictor of the VRH responders, as well as heart rate variability. In addition, respiratory rate was diminished under VRH in every subgroup. VRH is an effective tool to reduced pain intensity and unpleasantness in a vast majority of healthy subjects. We further indicate in this study that heart rate variability parameter RMSSD (root mean square of successive differences) is a good predictor of this effect, as well as anxiety as a personality trait (but not state anxiety). Further studies are expected to determine more precisely to whom it will be the most useful to offer tailored, non-pharmacological pain management solutions to patients., Competing Interests: CC and DG hold a pending patent for the software HypnoVR© used in this study. AD holds a pending patent for the thermal stimulator used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Terzulli, Chauvin, Champagnol Di-Liberti, Faisan, Goffin, Gianesini, Graff, Dufour, Laroche, Salvat and Poisbeau.)

Early life adversities influence a nervous system still in development with long-term consequences for later life. These include nociceptive circuit alterations critical to shape an adaptive pain response to protect the organism from potential damage. Adult rats with a history of neonatal maternal separation (NMS) display visceral and somatic nociceptive hypersensitivity and inefficient analgesic responses to stress. In this study, we have characterized the consequences of NMS on wide dynamic range neurons (WDR) in the spinal cord of anaesthetized adult rats during the nociceptive processing of hot and cold noxious information. We found that WDR neurons of NMS rats display an excessive coding of mechanical and thermal information applied at the rat's hindpaws. This nicely explains the hypernociceptive behaviours seen after noxious mechanical, cold and hot peripheral stimulation. A peripheral change in the expression of molecular transducers for these stimuli (i.e., TRPV1, TRPM8 and TRPA1) does not seem to account for this general hyperexcitability. Instead, a decreased chloride-mediated inhibitory tone on WDR neurons may play a role as indicated by the abnormal elevation of the type 1 Na-K-Cl cotransporter transcripts. Altogether, we propose that long-term consequences of NMS are associated with reduced spinal cord inhibition favouring the expression of pain hypersensitivity. We cannot exclude that this phenomenon is also present at supraspinal sites, as other NMS-associated symptoms include excessive anxiety and impaired sociability., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objectives: Clinical studies revealed that early-life adverse events contribute to the development of IBS in adulthood. The aim of our study was to investigate the relationship between prenatal stress (PS), gut microbiota and visceral hypersensitivity with a focus on bacterial lipopeptides containing γ-aminobutyric acid (GABA)., Design: We developed a model of PS in mice and evaluated, in adult offspring, visceral hypersensitivity to colorectal distension (CRD), colon inflammation, barrier function and gut microbiota taxonomy. We quantified the production of lipopeptides containing GABA by mass spectrometry in a specific strain of bacteria decreased in PS, in PS mouse colons, and in faeces of patients with IBS and healthy volunteers (HVs). Finally, we assessed their effect on PS-induced visceral hypersensitivity., Results: Prenatally stressed mice of both sexes presented visceral hypersensitivity, no overt colon inflammation or barrier dysfunction but a gut microbiota dysbiosis. The dysbiosis was distinguished by a decreased abundance of Ligilactobacillus murinus , in both sexes, inversely correlated with visceral hypersensitivity to CRD in mice. An isolate from this bacterial species produced several lipopeptides containing GABA including C14AsnGABA. Interestingly, intracolonic treatment with C14AsnGABA decreased the visceral sensitivity of PS mice to CRD. The concentration of C16LeuGABA, a lipopeptide which inhibited sensory neurons activation, was decreased in faeces of patients with IBS compared with HVs., Conclusion: PS impacts the gut microbiota composition and metabolic function in adulthood. The reduced capacity of the gut microbiota to produce GABA lipopeptides could be one of the mechanisms linking PS and visceral hypersensitivity in adulthood., Competing Interests: Competing interests: PP is a senior fellow of the Institut Universitaire de France. CM has been awarded the UEG Research Award 2020 for her stay at The University of Gothenburg and by the FARE Fellowship of the French Gastroenterology Society in 2015., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Our knowledge about the detailed wiring of neuronal circuits in the spinal dorsal horn (DH), where initial sensory processing takes place, is still very sparse. While a substantial amount of data is available on the somatodendritic morphology of DH neurons, the laminar and segmental distribution patterns and consequential function of individual axons are much less characterized. In the present study, we fully reconstructed the axonal and dendritic processes of 10 projection neurons (PNs) and 15 interneurons (INs) in lamina I of the rat, to reveal quantitative differences in their distribution. We also performed whole-cell patch-clamp recordings to test the predicted function of certain axon collaterals. In line with our earlier qualitative description, we found that lamina I INs in the lateral aspect of the superficial DH send axon collaterals toward the medial part and occupy mostly laminae I-III, providing anatomical basis for a lateromedial flow of information within the DH. Local axon collaterals of PNs were more extensively distributed including dorsal commissural axon collaterals that might refer to those reported earlier linking the lateral aspect of the left and right DHs. PN collaterals dominated the dorsolateral funiculus and laminae IV-VI, suggesting propriospinal and ventral connections. Indeed, patch-clamp recordings confirmed the existence of a dorsoventral excitatory drive upon activation of neurokinin-1 receptors that, although being expressed in various lamina I neurons, are specifically enriched in PNs. In summary, lamina I PNs and INs have almost identical dendritic input fields, while their segmental axon collateral distribution patterns are distinct. INs, whose somata reside in lamina I, establish local connections, may show asymmetry, and contribute to bridging the medial and lateral halves of the DH. PNs, on the other hand, preferably relay their integrated dendritic input to deeper laminae of the spinal gray matter where it might be linked to other ascending pathways or the premotor network, resulting in a putative direct contribution to the nociceptive withdrawal reflex., (© 2022 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals LLC.)

Aims: The authors evaluated the impact of the first COVID-19 pandemic wave on French chronic pain structures (CPS). Methods: An online survey assessed CPS resource allocation, workflow and perceived impact on patient care. Results: All CPS workflow was severely impacted by the reallocation of 42% of specialists. In-person appointments were cancelled by 72% of participants. Follow-up was maintained in 91% of participants (telemedicine). Skills in end-of-life decision-making/counseling were rarely solicited. The perceived impact of the crisis on the experience of patients was high (eight out of ten), with a significant increase in access-to-care delay. Conclusion: CPS maintained patient follow-up. Special features of CPS specialists were rarely solicited by COVID-19 teams experiencing a high workload. Recommendations on optimal CPS resource reallocations have to be standardized in crisis conditions.

For a long time, the capacity of the newborn infant to feel pain was denied. Today it is clear that the nociceptive system, even if still immature, is functional enough in the newborn infant to elicit pain responses. Unfortunately, pain is often present in the neonatal period, in particular in the case of premature infants which are subjected to a high number of painful procedures during care. These are accompanied by a variety of environmental stressors, which could impact the maturation of the nociceptive system. Therefore, the question of the long-term consequences of early life stress is a critical question. Early stressful experience, both painful and non-painful, can imprint the nociceptive system and induce long-term alteration in brain function and nociceptive behavior, often leading to an increase sensitivity and higher susceptibility to chronic pain. Different animal models have been developed to understand the mechanisms underlying the long-term effects of different early life stressful procedures, including pain and maternal separation. This review will focus on the clinical and preclinical data about early life stress and its consequence on the nociceptive system., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

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., Competing Interests: The authors have no conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

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.

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., Competing Interests: PP received financial support from Biocodex laboratories to investigate the molecular mechanisms of action of etifoxine. The financial support by Biocodex laboratories does not alter adherence to PLOS ONE policies on sharing data and materials. In good agreement, data could be filed in an open source depository. Moreover, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background: Early life stress is known to affect the development of the nervous system and its function at a later age. It increases the risk to develop psychiatric disorders as well as chronic pain and its associated affective comorbidities across the lifespan. GABAergic inhibition is important for the regulation of central function and related behaviors, including nociception, anxiety or social interactions, and requires low intracellular chloride levels. Of particular interest, the oxytocinergic (OTergic) system exerts potent anxiolytic, analgesic and pro-social properties and is known to be involved in the regulation of chloride homeostasis and to be impaired following early life stress., Methods: We used behavioral measures to evaluate anxiety, social interactions and pain responses in a rat model of neonatal maternal separation (NMS). Using quantitative PCR, we investigated whether NMS was associated with alterations in the expression of chloride transporters in the cerebrum and spinal cord. Finally, we evaluated the contribution of OTergic signaling and neuro-inflammatory processes in the observed phenotype., Results: NMS animals displayed a long-lasting upregulation of chloride importer Na-K-Cl cotransporter type 1 (NKCC1) expression in the cerebrum and spinal cord. Neonatal administration of the NKCC1 inhibitor bumetanide or oxytocin successfully normalized the anxiety-like symptoms and the lack of social preference observed in NMS animals. Phenotypic alterations were associated with a pro-inflammatory state which could contribute to NKCC1 upregulation., Conclusions: This work suggests that an impaired chloride homeostasis, linked to oxytocin signaling dysfunction and to neuro-inflammatory processes, could contribute to the sensori-affective phenotype following NMS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neuropathic pain is frequently associated with anxiety and major depressive disorders, which considerably impact the overall patient experience. Favoring GABAergic inhibition through the pain matrix has emerged as a promising strategy to restore proper processing of nociceptive and affective information in neuropathic pain states. In this context, the non-benzodiazepine anxiolytic etifoxine (EFX), known to amplify GABAergic inhibition through positive modulation of GABA A receptors and neurosteroidogenesis, presents several advantages. Therefore, we sought to investigate the preclinical therapeutic potential of EFX on the somatosensory and affective components of neuropathic pain. Here, we used a murine model in which neuropathic pain was induced by the implantation of a compressive cuff around the sciatic nerve (mononeuropathy). We showed that the intraperitoneal EFX treatment for five consecutive days (50 mg/kg) relieved mechanical allodynia in a sustained manner. Besides its effect on evoked mechanical hypersensitivity, EFX also alleviated aversiveness of ongoing pain as well as anxiodepressive-like consequences of neuropathic pain following cuff-induced mononeuropathy. This effect was also seen 12 weeks after induction of the neuropathy when allodynia was no longer present. Analgesic and neuroprotective actions of EFX were also seen by the absence of neuropathic pain symptoms if a second sciatic nerve constriction injury was applied to the contralateral hindpaw. Mass spectrometry analysis revealed a normalization of brainstem serotonin levels in EFX-treated animals and an increase in norepinephrine. This study suggests that EFX presents promising therapeutic potential for the relief of both somatosensory and affective consequences of neuropathic pain, a beneficial effect that is likely to involve monoamine descending controls., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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.

Inflammatory processes are critical promoting factors of chronic pain states, mostly by inducing peripheral and central sensitization of the nociceptive system. These processes are associated with a massive increase in glutamatergic transmission, sometimes facilitated by spinal disinhibition. In this study, we used etifoxine, a non-benzodiazepine anxiolytic known to amplify inhibition mediated by gamma-aminobutyric acid type A (GABA A ) receptors in pain processing regions, either directly (through allosteric modulation) or indirectly (through the synthesis of endogenous neurosteroids). We used different models of local inflammation to evaluate the possible direct action of etifoxine on analgesia and edema. Pain symptom and edema measurements were performed after intraplantar carrageenan injection or after topical ear inflammation. We found that etifoxine treatment was associated with reduced plantar surface temperature 24 h after intraplantar carrageenan injection. In this model, etifoxine also alleviated thermal hot and mechanical hyperalgesia. A similar finding was observed while analyzing pain symptoms in the late phase of the formalin test. In a model of ear inflammation, etifoxine appeared to have a moderate anti-edemic effect after topical application. This slight action of etifoxine on the limitation of inflammatory processes could be mediated in part by cyclo-oxygenase 1 activity inhibition. Etifoxine appears as a promising therapeutic tool contributing to the limitation of inflammatory pain symptoms. Since etifoxine is already prescribed as an anxiolytic in several countries, it could be a good candidate for the prevention of inflammatory-driven edema and hyperalgesia, although the precise mechanism of action relative to its anti-inflammatory potential remains to be elucidated., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Oxytocin (OT), known for its neurohormonal effects around birth, has recently been suggested for being a critical determinant in neurodevelopmental disorders. This hypothalamic neuropeptide exerts a potent analgesic effect through an action on the nociceptive system. This endogenous control of pain has an important adaptive value but might be altered by early life stress, possibly contributing to its long-term consequences on pain responses and associated comorbidities. We tested this hypothesis using a rat model of neonatal maternal separation (NMS) known to induce long-term consequences on several brain functions including chronic stress, anxiety, altered social behavior, and visceral hypersensitivity. We found that adult rats with a history of NMS were hypersensitive to noxious mechanical/thermal hot stimuli and to inflammatory pain. We failed to observe OT receptor-mediated stress-induced analgesia and OT antihyperalgesia after carrageenan inflammation. These alterations were partially rescued if NMS pups were treated by intraperitoneal daily injection during NMS with OT or its downstream second messenger allopregnanolone. The involvement of epigenetic changes in these alterations was confirmed since neonatal treatment with the histone deacetylase inhibitor SAHA, not only normalized nociceptive sensitivities but also restored OT receptor-mediated stress-induced analgesia and the endogenous antihyperalgesia in inflamed NMS rats. There is growing evidence in the literature that early life stress might impair the nociceptive system ontogeny and function. This study suggests that these alterations might be restored while stimulating OT receptor signaling or histone deacetylase inhibitors, using molecules that are currently available or part of clinical trials for other pathologies.

Background and Purpose: Chronic administration of medication can significantly affect metabolic enzymes leading to physiological adaptations. Morphine metabolism in the liver has been extensively studied following acute morphine treatment, but such metabolic processes in the CNS are poorly characterized. Long-term morphine treatment is limited by the development of tolerance, resulting in a decrease of its analgesic effect. Whether or not morphine analgesic tolerance affects in vivo brain morphine metabolism and blood-brain barrier (BBB) permeability remains a major question. Here, we have attempted to characterize the in vivo metabolism and BBB permeability of morphine after long-term treatment, at both central and peripheral levels., Experimental Approach: Male C57BL/6 mice were injected with morphine or saline solution for eight consecutive days in order to induce morphine analgesic tolerance. On the ninth day, both groups received a final injection of morphine (85%) and d3-morphine (morphine bearing three 2 H; 15%, w/w). Mice were then killed and blood, urine, brain and liver samples were collected. LC-MS/MS was used to quantify morphine, its metabolite morphine-3-glucuronide (M3G) and their respective d3-labelled forms., Key Results: We found no significant differences in morphine CNS uptake and metabolism between control and tolerant mice. Interestingly, d3-morphine metabolism was decreased compared to morphine without any interference with our study., Conclusions and Implications: Our data suggests that tolerance to the analgesic effects of morphine is not linked to increased glucuronidation to M3G or to altered global BBB permeability of morphine., (© 2018 The British Pharmacological Society.)

Originally confined to the initiation of parturition and milk ejection after birth, the hypothalamic nonapeptide oxytocin (OT) is now recognized as a critical determinant of social behavior and emotional processing. It accounts for the modulation of sensory processing and pain perception as OT displays a potent analgesic effect mediated by OT receptors (OTRs) expressed in the peripheral and central nervous systems. In our chapter, we will first systemically analyze known efferent and afferent OT neuron projections, which form the anatomical basis for OT modulation of somatosensory and pain processing. Next, we will focus on the synergy of distinct types of OT neurons (e.g., magno- and parvocellular OT neurons) which efficiently control acute inflammatory pain perception. Finally, we will describe how OT signaling mechanisms in the spinal cord control nociception, as well as how OT is able to modulate emotional pain processing within the central amygdala. In the conclusions at the end of the chapter, we will formulate perspectives in the study of OT effects on pain anticipation and pain memory, as well as propose some reasons for the application of exogenous OT for the treatment of certain types of pain in human patients.

Background Lithium is widely used to treat bipolar disorders and displays mood stabilizing properties. In addition, lithium relieves painful cluster headaches and has a strong analgesic effect in neuropathic pain rat models. Objectives To investigate the analgesic effect of lithium on the cuff model of neuropathic pain. Methods We used behavioral and pharmacological approaches to study the analgesic effect of a single injection of lithium in wild-type and mu opioid receptor (MOR) null cuffed neuropathic mice. Mass spectrometry and enzyme-linked immunosorbent assay allowed to measure the levels of endogenous MOR agonist beta-endorphin as well as monoamines in brain and plasma samples 4 h after lithium administration. Results A single injection of lithium chloride (100 mg/kg, ip) alleviated mechanical allodynia for 24 h, and this effect was absent in MOR null neuropathic mice. Biochemical analyses highlight a significant increase in beta-endorphin levels by 30% in the brain of lithium-treated mice compared to controls. No variation of beta-endorphin was detected in the blood. Conclusions Together, our results provide evidence that lithium induces a long-lasting analgesia in neuropathic mice presumably through elevated brain levels of beta-endorphin and the activation of MORs.

Objectives: Anxiety and adjustment disorders are among the most prevalent mental health conditions. This review focuses on γ-aminobutyric acid receptor type A (GABA A R)-mediated anxiolysis, describing the action of both endogenous and exogenous modulators of GABA A R. Future directions and innovative strategies to alleviate anxiety symptoms are discussed, with a particular emphasis on etifoxine., Methods: We used available data from the recent literature to update the mode of action of anxiolytics. We focussed our search on anxiolytics acting at GABA A Rs, as well as on the pharmacological properties of formerly and currently prescribed anxiolytics., Results: Considering the adverse effects of current treatments aimed at increasing inhibitory controls, optimisation of existing pharmacotherapies is of crucial importance. Among the alternative compounds targeting the GABAergic system, translocator protein (TSPO) ligands, such as etifoxine (EFX), which promote endogenous neurosteroidogenesis, are emerging as promising candidates for anxiety relief. In several papers comparing the efficacy of benzodiazepines and EFX, EFX showed interesting properties with limited side effects. Indeed, neurosteroids are potent GABA A R modulators with highly underrated anxiolytic properties., Conclusions: Novel therapeutic strategies have been emerging following the recognition of neurosteroids as potent anxiolytics. Featured at the top of the list for well-tolerated anxiety relief, TSPO ligands such as etifoxine appear promising.