Abnormal activity in injured nerve fibers triggers spinal microglial reactivity, a critical step in the development of chronic postoperative pain. It remains unclear whether spinal microglia respond to inputs from nociceptive fibers alone or require combined activity from nociceptors and nonnociceptors. Using electrical and optogenetic approaches, we selectively activated different fiber subtypes without causing neuronal injury. Our findings demonstrate that only simultaneous activation of both nociceptive and nonnociceptive fibers induces sustained hypersensitivity and a spinal microglia response. This response is characterized by increased cell proliferation, altered electrophysiological profile with hyperpolarized membrane potential, increased potassium currents, and a less ramified morphology. In contrast, activation of nociceptive or nonnociceptive fibers alone does not induce these changes. In addition, inhibiting spinal microglia with minocycline prevents those changes. Overall, our study suggests that both types of peripheral sensory input are necessary to elicit microglial reactivity in the spinal cord and the subsequent development of sustained pain-related behavior.

Hyperexcitability of peripheral sensory neurons plays a critical role in the development and maintenance of chronic pain. Pharmacological analgesics used in clinics reduce neuronal activity. They often come with non‐negligible side effects. Optogenetic approaches can modulate neuronal activity and are attracting growing interest for therapeutic uses, but the delivery of light in different parts of the body requires the development of specific optoelectronic interfaces. We designed and produced a microfabricated optoelectronic implant to deliver yellow light (559 nm) onto the sciatic nerve. We have surgically implanted the device in transgenic mice expressing the yellow light‐sensitive inhibitory archaerhodopsin (ArchT) in nociceptive neurons. Yellow light induced a significant reduction in the responses of the nociceptive neurons and curbed the behavioral responses to noxious mechanical and thermal stimuli. Remarkably, the yellow light‐related inhibition did not alter the behavioral responses evoked by innocuous mechanical stimulation or by intense inflammation. The optoelectronic implants showed reliable and reproducible opto‐electrical performance. For stimulation parameters used in vivo (3.3 V, 60–80 mW/mm 2 , 20 s train pulses, 1 Hz, 80% duty‐cycle, and an inter‐train interval of 1 s), limited temperature increase was measured in an environment mimicking neural tissue surrounded by muscle and fat. Similarly, the basal sensitivity of the implanted mice remains comparable to non‐implanted mice, suggesting a safe integration of the soft electronic device. Our study confirmed that optoelectronic implants tailored to the sciatic nerve can provide specific light spectra and intensities at adequate levels for the optogenetic actuator to trigger significant electrophysiological and behavioral responses in pain perception.

Microglia, resident immune cells in the central nervous system, play a role in neuroinflammation and the development of neuropathic pain. We found that the stimulator of interferon genes (STING) is predominantly expressed in spinal microglia and upregulated after peripheral nerve injury. However, mechanical allodynia, as a marker of neuropathic pain following peripheral nerve injury, did not require microglial STING expression. In contrast, STING activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated neuropathic pain in male mice, but not female mice. STING activation in female mice leads to increase in proinflammatory cytokines that may counteract the analgesic effect of ADU-S100. Microglial STING expression and type I interferon-ss (IFNss) signaling were required for the analgesic effects of STING agonists in male mice. Mechanistically, downstream activation of TANK-binding kinase 1 (TBK1) and the production of IFN-ss, may partly account for the analgesic effect observed. These findings suggest that STING activation in spinal microglia could be a potential therapeutic intervention for neuropathic pain, particularly in males.

BACKGROUND:Only few previous cohort studies examined simultaneously predictors of chronic pain (CP) onset and recovery. Furthermore, these studies used various sociodemographic and pain-related characteristics, without standardized measures of sleep and depression. The present study aimed at expanding and strengthening these findings in a large Swiss population. METHODS:We analysed data from a longitudinal cohort (n = 4602) collected at two time points separated by 5 years in Lausanne, Switzerland. We studied through two independent multivariable logistic regression models, the predictors of CP onset and recovery, including socio-demographic data as well as standardized measures of sleep and mood. RESULTS:Chronic pain was reported by 43.1% and 44.4% of participants, with 11.6% at the second follow-up reporting moderate or intense pain. Neuropathic pain, regardless of intensity, had a more negative impact on quality of life. An inferential model (n = 1331) identified the male sex as predictive for recovering from CP. Older age, being overweight or obese (compared to normal weight), higher depression scores and pain medication intake were predictive for sustained pain at the second follow-up. A second model (n = 1886) identified being overweight or obese (compared to normal weight), low quality of sleep and being a former smoker (compared to a non-smoker) as predictive for developing CP, while the male sex was lowering the risk. CONCLUSIONS:While sex and weight are associated with both recovery and new CP onset, separate variables also need to be considered in these processes, underlining specific factors to be addressed, depending on the context, whether preventive or therapeutic. SIGNIFICANCE STATEMENT:Multivariable models in a Swiss cohort (N = 4602) associate male sex, not taking pain medication, normal weight, lower depression scores and younger age with recovery from chronic pain, while females, obese or overweight, having worse sleep and former smokers are associated with onset of new chronic pain. These common and separate factors need to be considered in treatment and prevention efforts.

Satellite glial cells (SGCs), enveloping primary sensory neurons’ somas in the dorsal root ganglion (DRG), contribute to neuropathic pain upon nerve injury. Glial fibrillary acidic protein (GFAP) serves as an SGC activation marker, though its DRG satellite cell specificity is debated. We employed the hGFAP-CFP transgenic mouse line, designed for astrocyte studies, to explore its expression within the peripheral nervous system (PNS) after spared nerve injury (SNI). We used diverse immunostaining techniques, Western blot analysis, and electrophysiology to evaluate GFAP+ cell changes. Post-SNI, GFAP+ cell numbers increased without proliferation, and were found near injured ATF3+ neurons. GFAP+ FABP7+ SGCs increased, yet 75.5% of DRG GFAP+ cells lacked FABP7 expression. This suggests a significant subset of GFAP+ cells are non-myelinating Schwann cells (nmSC), indicated by their presence in the dorsal root but not in the ventral root which lacks unmyelinated fibres. Additionally, patch clamp recordings from GFAP+ FABP7−cells lacked SGC-specific Kir4.1 currents, instead displaying outward Kv currents expressing Kv1.1 and Kv1.6 channels specific to nmSCs. In conclusion, this study demonstrates increased GFAP expression in two DRG glial cell subpopulations post-SNI: GFAP+ FABP7+ SGCs and GFAP+ FABP7− nmSCs, shedding light on GFAP’s specificity as an SGC marker after SNI.

This data pertain to the manuscript titled "Kir2.1 modulation in macrophages sensitises dorsal root ganglion neurons through TNF secretion after nerve injury", currently in preprint on BioRxiv (https://doi.org/10.1101/2023.06.21.545843). The name of the data files correspond to the for each figure in the study. The data file in .csv format are organized so that they can easily be opened in R or other analysis language. To understand them and how they are labelled, it is advised to open the figure next to them and find the appropriate panel. Here are included: Example images of section of mouse dorsal root ganglion (DRG) after spared nerve injury (SNI), labelled for CX3CR1+ cells, Ki67 and MHC class II by immunohistochemistry. LC-MS-MS proteomic data set of CX3CR1+ cells from DRG of mice after SNI. Voltage clamp data of CX3CR1+ cells from DRG of mice after SNI Electrophysiological data sets (multi-electrode array, current clamp and voltage clamp) of dissociated DRG neurons treated with medium conditioned by CX3CR1+ or GFAP+ cells sorted from ipsilateral or contralateral DRG from mice after SNI. In addition, pharmacological treatments were added to the conditioned medium (CM).

Macrophages and satellite glial cells are found between injured and uninjured neurons in the lumbar dorsal root ganglia (DRG). We explored the mechanism of neuro-immune and neuron-glia crosstalk leading to hyperexcitability of DRG neurons. After spared nerve injury (SNI), CX3CR1+ resident macrophages became activated, proliferated, and increased inward-rectifying potassium channel Kir 2.1 currents. Conditioned medium (CM) by macrophages, obtained from DRG of SNI mice, sensitized small DRG neurons from naïve mice. However, treatment with CM from GFAP+ glial cells did not affect neuronal excitability. When subjected to this macrophage-derived CM, DRG neurons had increased spontaneous activity, current-evoked responses and voltage-gated NaV 1.7 and NaV 1.8 currents. Silencing Kir 2.1 in macrophages after SNI prevented the induction of neuronal hyperexcitability from their CM. Blocking vesicular exocytosis or soluble tumor necrosis factor in CM or interfering with the downstream intracellular p38 pathway in neurons, also prevented neuronal hyperexcitability. Blocking protein trafficking in neurons reduced the effect of CM, suggesting that the hyperexcitable state resulted from changes in NaV channel trafficking. These results suggest that DRG macrophages, primed by peripheral nerve injury, contribute to neuron-glia crosstalk, NaV channel dysregulation and neuronal hyperexcitability implicated in the development of neuropathic pain.

BACKGROUND:The expression of chronic pain remains a delicate matter for those older persons who suffer from this condition. If many studies highlight the difficulties of putting pain into words, scarce are those that take into account how given social networks can facilitate or prevent its expression. Based on a qualitative study that explores the communication about chronic pain in older persons' social network, this article reports on this key issue of talking about health in later life within family settings and provides clinicians with information about the way older persons with chronic conditions perceive their everyday realities and social relations.METHODS:A multidisciplinary research team (medicine, linguistics and psychology) interviewed 49 persons with chronic pain, all from the French-speaking part of Switzerland, aged 75 and older, without any major cognitive or auditory impairments. After transcription, the interviews were analyzed by combining content and discourse analysis with social network theories.RESULTS:Communication about chronic pain depends significantly on the position of the interlocutors within the family structure, with a preference for direct relatives or individuals with similar difficulties. In social networks, the ability to communicate about chronic pain is both a resource (by allowing older persons to get help or by strengthening interpersonal relations) and a challenge (by threatening their autonomy, social relations or self-esteem).CONCLUSIONS:The study shows the predominance of the nuclear family (partner, children) in communication relating specifically to the everyday management of chronic pain. This state of affairs is, nevertheless, balanced by issues of (loss of) autonomy. These findings, in line with current trends in geriatrics, could benefit future reflections on the scope and limits of including relatives in the care of older patients with chronic conditions.

SignificanceClinical evidence suggests that adolescents engage in dangerous activities despite understanding the risks involved, questioning the theory of decreased top-down control of the immature prefrontal cortex promoting adolescent disinhibited behaviors. In the present study, we report that adolescent rats show a much higher degree of inflexible behavior when making decisions under conflict compared to adults. Unexpectedly, we identified a lower excitability of layer 5 pyramidal neurons in the anterior insular cortex (AIC) of adolescent rats and smaller synaptic glutamatergic inputs to these cells but no difference in layer 5 prefrontal cortex pyramidal neurons. Chemogenetic activation of AIC neurons reduced persistent reward-seeking despite punishment, suggesting that the delayed maturation of the insula may promote inflexible reward-related behaviors in adolescent rats.

BACKGROUND:This article focuses on how older persons perceive their friends' role in their daily experience of chronic pain. It reports part of the results of a study in which we interviewed 49 participants, aged 75 and older, about the way they communicate about chronic pain within their social network.METHODOLOGY:Using discourse and content analysis, we first examine older persons' definition of friendship, and then identify the various dimensions of friendship that are engaged in the communication about chronic pain.RESULTS:Participants define close friends as people with whom they share intimacy and social proximity (same gender, age and experience of pain). These dimensions allow older persons to talk freely about their pain without the fear of being judged or rejected, particularly when it is related to a dynamic of reciprocity.CONCLUSIONS:This article shows that the contribution of friends to the everyday life of older persons with chronic pain is mainly that of providing emotional support.

Chronic pain patients frequently suffer from sleep disturbances. Improvement of sleep quality alleviates pain, but neurophysiological mechanisms underlying sleep disturbances require clarification to advance therapeutic strategies. Chronic pain causes high-frequency electrical activity in pain-processing cortical areas that could disrupt the normal process of low-frequency sleep rhythm generation. We found that the spared-nerve-injury (SNI) mouse model, mimicking human neuropathic pain, had preserved sleep-wake behavior. However, when we probed spontaneous arousability based on infraslow continuity-fragility dynamics of non-rapid-eye-movement sleep (NREMS), we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices of SNI mice. Closed-loop mechanovibrational stimulation revealed higher sensory arousability in SNI. Sleep in chronic pain thus looked preserved in conventional measures but showed elevated spontaneous and evoked arousability. Our findings develop a novel moment-to-moment probing of NREMS fragility and propose that chronic pain-induced sleep complaints arise from perturbed arousability.

Frequent nightly arousals typical for sleep disorders cause daytime fatigue and present health risks. As such arousals are often short, partial, or occur locally within the brain, reliable characterization in rodent models of sleep disorders and in human patients is challenging. We found that the EEG spectral composition of non-rapid eye movement sleep (NREMS) in healthy mice shows an infraslow (~50 s) interval over which microarousals appear preferentially. NREMS could hence be vulnerable to abnormal arousals on this time scale. Chronic pain is well-known to disrupt sleep. In the spared nerve injury (SNI) mouse model of chronic neuropathic pain, we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices, although sleep macroarchitecture appeared unaltered. Closed-loop mechanovibrational stimulation further revealed higher sensory arousability. Chronic pain thus preserved conventional sleep measures but resulted in elevated spontaneous and evoked arousability. We develop a novel moment-to-moment probing of NREMS vulnerability and propose that chronic pain-induced sleep complaints arise from perturbed arousability.

Oxytocin (OT) orchestrates social and emotional behaviors through modulation of neural circuits. In the central amygdala, the release of OT modulates inhibitory circuits and, thereby, suppresses fear responses and decreases anxiety levels. Using astrocyte-specific gain and loss of function and pharmacological approaches, we demonstrate that a morphologically distinct subpopulation of astrocytes expresses OT receptors and mediates anxiolytic and positive reinforcement effects of OT in the central amygdala of mice and rats. The involvement of astrocytes in OT signaling challenges the long-held dogma that OT acts exclusively on neurons and highlights astrocytes as essential components for modulation of emotional states under normal and chronic pain conditions.

A lack of social relations appears to impact on health and life expectancy among the older persons. The quality and diversity of social relations are correlated with good health and well-being in later life. Chronic pain is a crucial issue in aging population. Effective communication between the older persons with chronic pain, their relatives and the actors of the healthcare system facilitates the management of this condition. Studies on communication in later life generally do not consider the older persons' social network as a whole, focusing only a specific segment (e.g., family or medical staff). This lack of scientific data prevents the actors of the healthcare system from offering solutions to bridge clinically relevant communication gaps. As a consequence, our study has three objectives: (1) to identify how the older persons perceive communication about chronic pain with their social network; (2) to identify their unmet communication needs; (3) to develop recommendations that improve communication about chronic pain in later life. The study will be divided into two phases. The first phase will meet objectives 1 and 2. It will involve individual interviews with about 50 people over 75 years old suffering from chronic pain and without major cognitive or auditory troubles. In this phase, we will apply a multi-layered analysis. We will map the older persons' personal network and identify their communication practices and needs, by combining content and discourse analysis with social network theories. The second phase of the study will aim at recommendations based on the results of the first phase (objective 3). It will require focus groups with different sets of stakeholders (older persons, relative caregivers, health professionals, decision-makers). In the second phase, we will use content analysis to pinpoint the concerns and suggestions for action. The results will be disseminated on three levels: (1) to the scientific world (specialists in the field of health and aging and health communication); (2) to health practitioners working with older persons; (3) to society at large, with a focus on institutions and groups directly concerned by the issue.

Oxytocin orchestrates social and emotional behaviors through modulation of neural circuits in brain structures such as the central amygdala (CeA). The long-standing dogma is that oxytocin signaling in the central nervous system occurs exclusively via direct actions on neurons. However, several findings over the last decades showed that astrocytes actively participate in the modulation of neuronal circuits. Here, we investigate the degree of astrocytes’ involvement in oxytocin functions. Using astrocyte’ specific gain and loss of function approaches, we demonstrate that CeA astrocytes not only directly respond to oxytocin, but are actually necessary for its effects on neuronal circuits and ultimately behavior. Our work identifies astrocytes as a crucial cellular substrate underlying the promotion of a positive emotional state by oxytocin. These results further corroborate that astrocytes are key regulators of neuronal circuits activity by responding to specific neuropeptidergic inputs, and opens up new perspectives to understand how neuromodulators gate brain functions.

Side effects are frequent in pharmacological pain management, potentially preceding analgesia and limiting drug tolerability. Discussing side effects is part of informed consent, yet can favor nocebo effects. This study aimed to test whether a positive suggestion regarding side effects, which could act as reminders of the medication having been absorbed, might favor analgesia in a clinical interaction model. Sixty-six healthy males participated in a study "to validate pupillometry as an objective measure of analgesia". Participants were unknowingly randomized double-blind to positive vs control information about side effects embedded in a video regarding the study drugs. Sequences of moderately painful heat stimuli applied before and after treatment with diclofenac and atropine served to evaluate analgesia. Atropine was deceptively presented as a co-analgesic, but used to induce side effects. Adverse events (AE) were collected with the General Assessment of Side Effects (GASE) questionnaire prior to the second induced pain sequence. Debriefing fully informed participants regarding the purpose of the study and showed them the two videos. The combination of medication led to significant analgesia, without a between-group difference. Positive information about side effects increased the attribution of AE to the treatment compared to the control information. The total GASE score was correlated with analgesia, i.e., the more AEs reported, the stronger the analgesia. Interestingly, there was a significant between-groups difference on this correlation: the GASE score and analgesia correlated only in the positive information group. This provides evidence for a selective link between AEs and pain relief in the group who received the suggestion that AEs could be taken as a sign "that help was on the way". During debriefing, 65% of participants said they would prefer to receive the positive message in a clinical context. Although the present results cannot be translated immediately to clinical pain conditions, they do indicate the importance of testing this type of modulation in a clinical context.