Pain Sensitivity Research Articles

Altered parasympathetic outflow and central sensitization response to continuous pain in cyclic vomiting syndrome: a functional magnetic resonance imaging study.

Cyclic vomiting syndrome (CVS) is a disorder of brain-gut interaction characterized by recurrent episodes of nausea and vomiting interspersed with asymptomatic periods and associated with autonomic nervous system dysfunction. We examined the dysautonomic response to noxious stimuli seen in CVS patients using our previously validated approach to integrate peripheral autonomic outflow metrics, temporal summation of pain, and brain fMRI. BOLD fMRI and ECG were acquired from CVS patients and healthy adults during a rest condition and a sustained cuff pressure pain stimulus at the leg. After the latter scan, participants rated pain for the full 6-minute pain stimulus as well as first, middle, and last two-minutes to calculate temporal summation. During sustained pain, patients (n=13) exhibited greater reduction in heart rate variability within the high-frequency range (HF-HRV) and reduced anticorrelation between HF-HRV and fMRI signal in the anterior insula, pregenual anterior cingulate cortex, and ventrolateral and dorsolateral prefrontal cortex relative to healthy adults (n=13). Compared to healthy adults (n=14), patients (n=14) exhibited increasing pain intensity over the course of sustained cuff pressure. Seed-based functional connectivity analysis revealed for healthy adults (n=13), pain sensitization correlated with pain-induced increases in connectivity between primary somatosensory cortex and regions of interest in both left anterior insula/posterior orbitofrontal cortex and right pre-supplementary motor area, while this correlation was disrupted in CVS (n=10). Our results support altered central coding of nociceptive stimuli and autonomic responsivity of CVS patients in key brain regions implicated in autonomic control and interoception.

Pain chronification risk assessment: advanced phenotyping and scoring for prediction and treatments tailored to individualized patient profile

AbstractAcute pain is a physiologic, protective life-important warning neurological signal indicating multi-level tissue modulations caused by a broad spectrum of health adverse events such as stress overload, mechanical trauma, ischemia–reperfusion, sterile and infection-triggered inflammation, single- and multi-organ damage, acute and chronic wounds, tissue remodeling and degeneration, amongst others. On the other hand, pain chronification results in a pathologic transformation from the protective pain signaling into persistent debilitative medical condition with severe consequences including but not restricted to phenotype-specific behavioral patterns, reduced quality of life, and cognitive and mood disorders. Who is predisposed to an increased vs. decreased pain sensitivity and to the pain chronification? The motivation of personalized medicine that “same size does not fit all” is getting obvious also for an advanced approach in algesiology. Consequently, an in-depth patient stratification is essential for the paradigm change in overall pain management from currently applied reactive medical services to the cost-effective predictive, preventive, and personalized medicine (PPPM/3PM) in primary (reversible damage to health and targeted protection against health-to-disease transition) and secondary (personalized protection against disease progression) care. To this end, specifically innovative concepts of phenotyping elaborated in this study play a crucial role in patient stratification for predicting pain-associated outcomes, evidence-based targeted prevention of the pain chronification, and creation of treatment algorithms tailored to individualized patient profiles.

Epigenetic modifications associated to diabetic peripheral neuropathic pain (Review).

The present review aimed to provide an update on the scientific progress of the role of epigenetic modifications on diabetic peripheral neuropathic pain (DPNP). DPNP is a devastating and troublesome complication of diabetes mellitus (DM), which affects one third of patients with DM and causes severe hyperalgesia and allodynia, leading to challenges in the treatment of these patients. The pathophysiology of DPNP is multifactorial and is not yet fully understood and treatment options for this disease are currently unsatisfactory. The underlying mechanisms and pathophysiology of DPNP have largely been explored in animal models and a mechanism‑derived approach might offer a potential therapeutic‑target for attenuating certain phenotypes of DPNP. Altered gene expression levels within the peripheral or central nervous systems (CNS) are a crucial mechanism of DPNP, however, the transcriptional mechanisms of these genes have not been fully elucidated. Epigenetic modifications, such as DNA methylation and histone modifications (methylation, acetylation, or phosphorylation), can alter gene expression levels via chromatin remodeling. Moreover, it has been reported that altering gene expression via epigenetic modifications within the peripheral or CNS, contributes to the changes in both pain sensitivity and pharmacological efficacy in DPNP. Therefore, the present review summarized the findings of relevant literature on the epigenetic alterations in DPNP and the therapeutic potential for targeting these alterations in the future treatment of this disease.

Exploring signs of central sensitization in adolescents with hypermobility Spectrum disorder or hypermobile Ehlers-Danlos syndrome.

Hypermobility Spectrum Disorder (HSD) and Hypermobile Ehlers-Danlos Syndrome (hEDS) are two overlapping heritable connective tissue disorders characterized by joint hypermobility, chronic pain, impaired body perception, and musculoskeletal symptoms. Central sensitization has been proposed as a plausible explanation for symptoms like widespread pain, fatigue, mood disorders, and sleep disturbances in patients with HSD/hEDS. The aim of this study was to investigate signs of central sensitization, including exercise-induced hypoalgesia (EIH), and fatigue severity in adolescents with HSD/hEDS. In this prospective, experimental, case-control study, thirty-seven adolescents with HSD/hEDS and 47 healthy adolescents (all aged 13-17 years) were included. Pressure pain thresholds (PPTs) were measured at four muscle groups using a pressure algometer. EIH was evaluated by measuring PPTs on two muscle groups immediately after an exercise test on a bicycle ergometer. Participants also completed questionnaires on fatigue and cognitive/emotional factors. The study demonstrated significantly lower PPTs in four different muscle groups in adolescents with HSD/hEDS compared to the healthy control group. Both groups achieved a significantly higher PPTs after exercise in the muscle involved in the activity. Adolescents with HSD/hEDS reported higher fatigue levels and more cognitive/emotional difficulties than the control group. Adolescents with HSD/hEDS showed generalized hyperalgesia measured through PPTs at different body sites. EIH was partly affected in adolescents with HSD/hEDS, presenting as unchanged pain sensitivity in the remote muscle. Pain should be considered as a phenomenon that is influenced by different biopsychosocial factors, including possible central sensitization, which increase its complexity. This study breaks new ground by showing signs of central sensitization, including diminished EIH, in adolescents with HSD or hEDS. Given that exercise is a key element in pain management, these findings offer valuable insights when developing treatment plans for adolescents with HSD or hEDS.

Temporal summation of pain in sickle cell disease: comparison of adolescents and young adults with chronic vs. infrequent pain.

This study examined the role of central sensitization in the experience of pain among adolescents and young adults with the most severe genotypes of sickle cell disease (SCD). We hypothesized that adolescents and young adults with chronic SCD pain would demonstrate a higher perceptual response to repeated stimulation of identical intensity (i.e., temporal summation of pain, TSP) compared to counterparts with infrequent pain. We also examined psychological risk factors that can impact pain sensitivity. Patients ages 12-21 years, diagnosed with SCD type Hb SS or Hb S Beta0Thalasemia, who reported infrequent pain (≤2 pain days/month; n = 25) or met AAPT criteria for chronic SCD pain (n = 25) were enrolled. Patients were age- and sex-matched, with similar proportions receiving chronic blood transfusion and hydroxyurea. Patients completed static quantitative sensory testing (QST) and dynamic TSP testing to assess pain sensitivity. Patients and a caregiver completed demographic and psychological measures (depression, anxiety, pain interference, pain catastrophizing). Simple slope analysis revealed differentially elevated heat TSP among adolescents and young adults with chronic SCD pain (b = 3.14, p = .002) but not those with infrequent pain (b = 0.45, p = .61). Faster habituation was further observed for those with chronic compared to infrequent pain. Adolescents and young adults with chronic pain reported more frequent depression, anxiety, and pain interference symptoms; however, psychological symptoms and pain catastrophizing were not associated with QST or TSP (ps >.17). Current results demonstrate that a well-established, prognostic, QST risk marker (i.e., TSP) may distinguish chronic from infrequent pain subgroups of adolescents and young adults with SCD.

Synergistic Epistasis and Systems Biology Approaches to Uncover a Pharmacogenomic Map Linked to Pain, Anti-Inflammatory and Immunomodulating Agents (PAIma) in a Healthy Cohort

The global public health addiction crisis has been stark, with over 932,400 deaths in the USA and Canada from opioid overdose since 1999–2020, surpassing the mortality rates at the top of the HIV/AIDS epidemic. Both nations exhibit opioid consumption rates significantly above the norm for developed countries. Analgesic type of opioids present both therapeutic benefits and substantial health risks, necessitating balanced drug regulation, careful prescribing, and dedicated opioid stewardship. The role of the cytochrome P450 2D6 (CYP2D6) system (Enzymatic functions) in metabolizing opioids highlights the potential of genotype-guided analgesia. By integrating Pharmacogenomics (PGx), this approach aims to optimize pain management, enhance safety, and reduce addiction risks. This understanding prompted the utilization of multifactor dimensionality reduction (MDR) to explore a range of phenotypes including PGx and gene–gene interactions (GGI) in a healthy cohort, thereby personalizing pain management strategies. The study sampled 100 unrelated healthy Western Iranians and 100 individuals from the 1000 Genome Project. Pre-testing involved searching for PGx annotations (variants associated with drug-gene-diseases) related to pain sensitivity and inflammation using the PharmGKB database, which identified 128 relevant genes. A questionnaire helped select 100 participants who had never used potent opioids but also other psychoactive agents (e.g., nicotine, amphetamines, etc.) and disease-related drugs. Whole-exome sequencing (WES) was then employed to analyze these genes in an Iranian cohort. Further analyses included MDR for identifying synergistic gene annotations and GGI for exploring complex gene interactions through the Visualization of Statistical Epistasis Networks (ViSEN). The study identified a Pain, Anti-Inflammatory, and Immunomodulating agents (PAIma) panel from the 128 genes, resulting in 55,590 annotations across 21 curated pathways. After filtering, 54 significant structural or regulatory variants were identified. This research also highlighted novel gene relationships involving the CYP3A5 gene, hsa-miR-355-5p, Paliperidone, and CYP2D6, which warrant further investigation. This study offers a novel pharmacogenetic framework that could potentially transform opioid prescribing practices to mitigate misuse and enhance personalized pain management. Further validation of these findings from multi countries and ethnic groups could guide clinicians in implementing DNA-based opioid prescribing, aligning treatment more closely with individual genetic profiles.Graphical abstract

Chronic post-surgical pain after total knee arthroplasty: a narrative review.

Total knee arthroplasty (TKA) is an efficacious treatment for end-stage knee osteoarthritis, often accompanied by severe postoperative pain. In certain patients, this pain can persist for over 3months and is referred to as chronic post-surgical pain (CPSP). Postoperative persistent pain has emerged as a significant and noteworthy issue impacting patient quality of life following TKA. The etiology of CPSP after TKA is multifaceted. Peripheral or central sensitizations resulting from inflammatory reactions, nerve injury, and neurobiological mechanisms are the primary mechanisms contributing to chronic persistent pain after TKA. Preoperative, intraoperative, and postoperative factors can induce pain sensitization. Once CPSP occurs after TKA, it significantly hampers patient recovery with challenging treatment options. Currently, among the preventive and therapeutic strategies for chronic pain after TKA, it is widely believed that early comprehensive preventive treatment to prevent acute to chronic pain transition can substantially reduce the incidence of CPSP following TKA. In recent years, studies have investigated perioperative strategies aimed at reducing the occurrence of persistent pain after TKA. This article provides an overview of advancements in understanding the pathogenesis, high-risk factors, and preventive measures for chronic pain following TKA. We hope that this review will guide future research directions on CPSP after TKA while contributing to clinical perioperative pain management.

The exploration of active components of 701 Dieda Zhentong patch and analgesic properties on chronic constriction injury rats.

An increasing number of traditional Chinese medicine(TCM) have been confirmed to possess analgesic bioactivity. 701 Dieda Zhentong patch(701-DZP) which includes 14 kinds of TCMs exhibited excellent efficacy in alleviating back or leg pain after a soft-tissue injury. In this study, UPLC/MS was used to construct the fingerprint of 701-DZP and excavate the potential bioactive ingredients of it. 21 compounds were detected and identified in the fingerprint including 12 compounds that pass through the skin and 6 compounds observed in the plasma. Then, the role of 701-DZP in neuropathic pain(NPP) was assessed by network pharmacology and CCI rats. 701-DZP inhibited pain sensitization(MWT and TWL) and the release of inflammation mediators(IL-1β and IL-6) in CCI rats which were in keeping with the core targets of the PPI network. The results of IHC and Western blot showed that the expression of the P2X3 receptor in the DRG and SC of CCI rats was significantly reduced after the treatment with 701-DZP. Moreover, the 701-DZP down-regulated the level of phosphorylation of ERK1/2 MAPK instead of P38 MAPK in the DRG of CCI rats. In conclusion, this study has clarified 6 potential analgesic active compounds of 701-DZP and explored the analgesic properties, which may inhibit the expression of the P2X3 receptor to reduce the release of inflammatory mediators based on the ERK1/2 MAPK pathway to alleviate the NPP.

The Role of Pain Medications in Modulating Peripheral Nerve Injury Recovery.

Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non-steroidal anti-inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma-aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI-related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti-inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage-gated Ca2+ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery.

Effect of individualized anesthesia and analgesia on postoperative pain in patients stratified for pain sensitivity: A study protocol for the PeriOPerative individualization trial randomized controlled trial.

Despite advancements in surgical and anesthesia techniques, acute and persistent postoperative pain are still a common challenge. Postoperative pain has direct effects on individual patient care and outcome, as well as putting strain on limited health care resources. Several prediction methods for postoperative pain have been described. One such method is the assessment of pain during peripheral venous cannulation (VCP). It is not known if different approaches to anesthesia and analgesia, depending on the evaluation of risk for postoperative pain, can improve outcome. The aim of this study is to evaluate if individualized anesthesia and analgesia can affect postoperative pain and recovery after surgery, in patients stratified by VCP. Adult patients scheduled for laparoscopic surgery undergo pain-sensitivity stratification using VCP on the day of surgery. Patients scoring VCP ≥2.0 on the visual analogue scale (pain-sensitive) are randomized to multimodal anaesthesia and analgesia with opioids or standard of care. Patients scoring VCP ≤1.9 (pain-tolerant) are randomized to opioid-free anaesthesia or standard of care. The primary outcome is acute postoperative pain measured with numeric rating scale in the postoperative care unit. Secondary outcomes include analysis of pain after 24 h, persistent postoperative pain and quality of recovery. Individualized perioperative pain management has the potential to improve patient care. This study will examine the impact of different anesthesia and analgesia regimes, in patients with differing pain sensitivity, on postoperative pain. Prospectively posted at ClinicalTrials.gov, identifier NCT04751812.

Labor epidural analgesia among Han and Uyghur parturients: a prospective observational study in China

BackgroundDisparities in pain sensitivity and tolerance have been described, however, little is known about variability in the experience of labor pain and childbirth in China. MethodsThis prospective observational study was conducted at a tertiary hospital in Xinjiang, China with two major ethnic groups: Han and Uyghur women. Women with a vaginal delivery with labor epidural analgesia were enrolled. The primary outcome was cervical dilation at labor epidural analgesia request, and multivariable linear regression analysis was performed to determine associated variables. Secondary outcomes were pain score at epidural request and epidural analgesics use. Data presented as mean ± standard deviation. ResultsCervical dilatation at labor epidural analgesia request was significantly lower (1.2 ± 0.7 vs. 0.8 ± 0.6 cm; p=0.0095), and pain score (numerical pain scale 0-10) was significantly higher (0.8 ± 1.0 vs. 4.2 ± 1.2; p=0.0002) among Uyghur compared to Han women. In the multivariate model, Uyghur women had a lower cervical dilation (p=0.0392) and a higher pain score (p<0.0001) at epidural request. During the labor process, a larger proportion of Uyghur women used the patient-controlled epidural analgesia (PCEA) pump (77.8% vs 53.6%, p=0.0011). They pressed the pump in a significantly shorter time (61.3±41.2 vs 104.0±105.2min, p=0.0015) and for more times (1.9±1.7 vs 1.2±1.4, p=0.0022), contributing to significantly more epidural analgesic use (sufentanil: 0.06±0.02 vs 0.07±0.03 μg/kg/h, p=0.0150, ropivacaine: 0.11±0.04 vs 0.14±0.06 mg/kg/h, p=0.0003, respectively). ConclusionsOur findings suggest that Uyghur women experience labor pain with higher levels of pain with a higher use of epidural analgesics than Han women. Further studies are needed to evaluate whether these differences are clinically relevant.FundingThis study was funded by the National Natural Science Foundation of China (No. 72074162).Ethics and Trial registration: Ethical approval was obtained (www.chictr.org.cn Identifier: ChiCTR2200062630).

The association between neuropathic pain features and central sensitization with acute headache associated to a whiplash injury

BackgroundHeadache is one of the most common symptoms after a whiplash injury, although the pathophysiology remains under discussion. This study aimed to evaluate differences in neuropathic pain and central sensitization features between those who present with whiplash-associated headache (WAH) soon after a whiplash injury and those who do not. MethodsThis case-control study evaluated differences on the self-administered Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), Pain Detect Questionnaire (PDQ) and the Central Sensitization Inventory (CSI) between those who present with WAH in the acute phase after a whiplash injury (n = 46) and those who do not (n = 36). Moreover, the association of these variables in addition to neck pain intensity and the Neck Disability Index (NDI) score, with the presence of WAH was examined through logistic regression. ResultsWhile differences between groups were found for both neuropathic and central sensitization features, only the presence of neuropathic pain features was associated with the presence of headache, with 27 scores for the S-LANSS and 23 for the PDQ from 46 people with headache (58.6% and 50.0%, respectively). The NDI and the S-LANSS partially explained (R2 = 0.68) the presence of WAH according to a logistic regression model. ConclusionSignificant differences were found between people with whiplash with and without WAH when the S-LANSS, the PDQ and the CSI were assessed. S-LANSS and NDI were the variables most associated with the presence of WAH. These findings suggest that neuropathic pain features may be associated with the presence of acute WAH.

Topical capsaicin modulates the two-point discrimination threshold-Modulation depends on stimulation modality and intensity.

Spatial acuity concerns the ability to localize and discriminate sensory input and is often tested using the two-point discrimination threshold (2PDT). Sensitization of the pain system can affect the spatial acuity, but it is unclear how 2PDTs of different testing modalities are affected. The aim was to investigate if the 2PDTs for mechanical and heat stimulation at different intensities were modulated by topical capsaicin sensitization. 30 healthy subjects were divided into either a capsaicin or a placebo group. The 2PDT was tested using two different modalities, mechanical and thermal (laser) delivered at innocuous and noxious intensities. The 2PDT were determined at baseline and re-assessed 48 h later. In the follow-up session, the subjects either had a capsaicin patch (8%) or placebo patch placed in the testing area for 30 min before re-testing the 2PDT. The 2PDT was highly dependent on stimulation modality and intensity. The lowest 2PDT was found for innocuous mechanical stimuli (40.0 mm, 95% CI 38.1-41.9 mm), and the highest 2PDT was found for innocuous thermal stimuli (81.7 mm, 95% CI 73.9-89.5 mm). Topical capsaicin generally increased the 2PDT, but this was only significant for innocuous mechanical stimuli. The perceived intensity of the stimuli was increased following capsaicin and was generally higher for noxious stimuli than for innocuous stimuli (ANOVA, p < 0.001). This study showed that capsaicin provoked pain sensitization increased the 2PDT. The 2PDT tested using innocuous mechanical stimuli showed less variable results indicating that this test is most suitable to detect this aspect of spatial acuity. This study investigated how the two-point discrimination threshold (2PDT) can be modulated by topical capsaicin. The 2PDT was assessed for two different modalities (thermal and mechanical) and for two different intensities (innocuous and noxious) before and after capsaicin. The results showed that the 2PDT was generally impaired following capsaicin, but this was only significant for mechanical innocuous stimuli. Furthermore, it was shown that mechanical innocuous stimuli assessed the 2PDT with lower variability than other combinations.

Targeted therapy: P2X3 receptor silencing in bone cancer pain relief.

Bone cancer pain remains a significant clinical challenge, often refractory to conventional treatments. The upregulation of the P2X3 receptor in the dorsal root ganglia has been implicated in the pathogenesis of bone cancer pain. This study aimed to elucidate the role of the P2X3 receptor in this context and assess the therapeutic potential of receptor silencing. Utilizing a rat model with Walker 256 cells to simulate bone cancer pain, researchers conducted molecular analyses, including semi-quantitative RT-PCR and Western Blot, to investigate P2X3 receptor expression in the dorsal root ganglia. Results demonstrated a marked increase in P2X3 receptor levels in the dorsal root ganglia of the bone cancer pain model. Targeted silencing of the P2X3 receptor using specific shRNA delivered via lentiviral vectors significantly reduced pain sensitivity, underscoring the receptor's potential as a valuable therapeutic target. In addition, a comprehensive gene expression analysis leveraging the GEO data set GSE249443 was performed to explore the underlying biological pathways linked to bone cancer pain. This analysis provided insights into the intricate interplay between bone cancer pain and associated biological processes, offering a deeper understanding of the mechanisms involved in pain modulation and progression. In conclusion, this research identifies the P2X3 receptor as a critical molecular target for mitigating bone cancer pain. The selective silencing of the P2X3 receptor emerges as a promising and innovative therapeutic strategy, presenting novel avenues for managing bone cancer pain and potentially revolutionizing treatment approaches in this challenging domain.

Transcranial Direct Current Stimulation Reduces Pressure Pain Sensitivity in Patients With Noncancer Chronic Pain.

Noncancer chronic pain is a clinical challenge because pharmacological treatment often fails to relieve pain. Transcranial direct current stimulation (tDCS) is a treatment that could have the potential for pain relief and improvement in quality of life. However, there is a lack of clinical trials evaluating the effects of tDCS on the pain system. The aim of the present study was to evaluate the effect of 5 days of anodal tDCS treatment on the pain system in patients with chronic noncancer pain using quantitative sensory testing and quality of life questionnaires: (1) Brief Pain Inventory-short form, (2) European Organization for Research and Treatment of Life Questionnaire-C30, and (3) Hospital Anxiety Depression Scale. Eleven patients with noncancer chronic pain (51 ± 13.6 y old, 5M) participated in the study. Anodal tDCS was applied for 5 consecutive days, followed by sham stimulation after a washout period of at least 2 weeks. Pressure pain thresholds and pain tolerance thresholds (PTT) were assessed in different body regions on days 1 and 5. Anodal tDCS appeared to maintain PTT at C5 (clavicle) on day 5, but sham stimulation decreased PTT ( P = 0.007). In addition, anodal tDCS increased PTT compared with sham at day 5 at Th10 ventral dermatomes ( P = 0.014). Both anodal and sham tDCS decreased the Brief Pain Inventory-short form total and interference scores, and the European Organization for Research and Treatment of Life Questionnaire-C30 fatigue score, but no interaction effect was observed. This study adds to the evidence in the literature that tDCS may be a potential therapeutic tool for the management of noncancer chronic pain.

When thinking about pain contributes to suffering: the example of pain catastrophizing

Abstract The extensive literature on the potent role negative thoughts about pain have on the experience of pain and pain-related suffering has documented associations with important neurobiological processes involved in amplifying nociceptive signals. We focus this review on pain catastrophizing (pCAT)— appraisals of pain as threatening, overwhelming, and unmanageable— and review the evidence that these thoughts are learned in childhood through experience and observation of others, particularly caretakers and parents. For children who have learned pCAT, repeated exposures to pain over time activate pCAT and likely contribute to further amplification of pain through changes in the neurobiological pain regulatory systems, which overlap with those regulating the stress response. We propose that repeated pain and stress exposures throughout childhood, adolescence, and into adulthood alter the neurobiology of pain via a repetitive positive feedback loop that increases risk for heightened pain sensitivity over time with repeated exposures. At some point, often precipitated by an acute episode of pain and possibly influenced by allostatic load, pCAT contributes to persistence of episodic or acute pain and exacerbates pain-related suffering. This developmental trajectory is not inevitable, as the impact of pCAT on pain and pain-related suffering can be influenced by various factors. We also present future directions for work in this area.

Sex specific gut-microbiota signatures of resilient and comorbid gut-brain phenotypes induced by early life stress

BackgroundAlterations in gut-brain axis communication pathways and the gut microbiota ecosystem caused by early life stress have been extensively described as critical players in the pathophysiology of stress-induced disorders. However, the extent to which stress-induced gut microbiota alterations manifest in early life and contribute to the sex-specific susceptibility to distinct gut-brain phenotypes in adulthood has yet to be defined. MethodsMale and female Sprague-Dawley rat offspring underwent maternal separation (3h/day from postnatal day 2 to 12). Faecal samples were collected before weaning for gut microbiota 16S rRNA sequencing and metabolomic analysis. Visceral pain sensitivity and negative valence behaviours were assessed in adulthood using colorectal distension and the forced swim test respectively. Behavioural data were processed in a two-step cluster analysis to identify groupings within the dataset. Multi-omics analysis was carried out to investigate if the microbial signatures following early life stress were already defined according to the membership of the adult behavioural phenotypes. ResultsMaternal separation resulted in increased visceral hypersensitivity while showing a trend for a sex- dependent increase in negative valence behaviour in adulthood. The cluster analysis revealed four clusters within the dataset representing distinct pathophysiological domains reminiscent of the behavioural consequences of early-life stress: 1. resilient, 2. pain, 3. immobile and 4. comorbid. The early life gut microbiota of each of these clusters show distinct alterations in terms of diversity, genus level differential abundance, and functional modules. Multi-omic integrations points towards a role for different metabolic pathways underlying each cluster-specific phenotype. ConclusionOur study is the first to identify distinct phenotypes defined by susceptibility or resilience to gut-brain dysfunction induced by early life stress. The gut microbiota in early life shows sex-dependent alterations in each cluster that precede specific behavioural phenotypes in adulthood. Future research is warranted to determine the causal relationship between early-life stress-induced changes in the gut microbiota and to understand the trajectory leading to the manifestation of different behavioural phenotypes in adulthood.

Microglia-Dependent Peripheral Neuropathic Pain in Adulthood Following Adolescent Exposure to Morphine in Male Rats

Persistent effects of adolescent morphine exposure on neurobiological processes and behaviors in adulthood have been partially identified. Hypersensitivity following adolescent exposure to morphine is a complex and multifaceted phenomenon whose underlying mechanisms remain largely unknown. This study aimed to investigate the involvement of microglia in neuropathic pain sensitivity following adolescent morphine exposure, focused on hippocampal genes expression and plasticity. To achieve this, adolescent male Wistar rats received morphine, along with minocycline, to inhibit microglial activity. The allodynia and hyperalgesia of adult rats were evaluated using von-Frey filaments and the Hargreaves plantar test in both baseline and neuropathic pain conditions. Hippocampal genes expression was analyzed following the behavioral tests. The plasticity of the Schaffer-CA1 hippocampal synapses was also assessed using field potential recording following neuropathy. Results showed that adolescent morphine exposure exacerbated the allodynia and hyperalgesia in both baseline and neuropathic pain states in adult rats, which was significantly reduced by the co-administration of minocycline during adolescence. Neuropathy in adult rats was found to increase hippocampal expression of inflammatory mediators, but adolescent morphine prevented this effect. Additionally, we observed a reduction in the baseline synaptic transmission and long-term potentiation (LTP) at the Schaffer-CA1 hippocampal synapses after neuropathy in adult rats following adolescent exposure to morphine. The reduction of synaptic activity was not altered by the co-administration of minocycline with morphine during adolescence. It is concluded that microglia play an important role in mediating hypersensitivity induced by adolescent morphine exposure, although hippocampal microglia may not be directly involved in this process.

The Relationship Between the Elastic Properties and Pain Pressure Threshold in Cesarean Scar Tissue-An Observational Study.

Cesarean section (C-section) scars can lead to chronic pain due to changes in tissue properties. Combining elastography and algometry can assess these scars comprehensively by identifying areas of increased rigidity and quantifying pain sensitivity. This study aims to evaluate the efficacy of using elastography and algometry together to assess cesarean scar tissue, correlating tissue stiffness with pain thresholds for targeted pain management. Thirty-one non-pregnant women who had undergone a C-section between six months and two years prior participated. Elastography measured tissue stiffness, while algometry provided quantitative measures of pain sensitivity on and around the scar. The correlation between tissue stiffness and pain thresholds was analyzed. Elastography identified areas of increased rigidity within the scar tissue, which corresponded with lower pain thresholds measured by algometry, indicating higher pain sensitivity. A significant correlation was found between increased tissue stiffness and reduced pain thresholds (p < 0.05). Combining elastography and algometry offers a powerful diagnostic tool for evaluating C-section scars. This approach identifies areas that may benefit from targeted pain management interventions, enhancing understanding and treatment of pain associated with cesarean scars. Incorporating these techniques into clinical practice could improve patient outcomes and quality of life.

The participation of monoamines in the realization of vasopressin analgesic effects during electrical stimulation of paws in rats

BACKGROUND: Arginine vasopressin has been implicated in the modulation of stress and pain. The influence of a synthetic analogue of arginine vasopressin, 1-deamino-8-D-arginine-vasopressin, оn pain sensitivity, stress reactivity, levels of monoamines and brain neurotrophic factor in a model of paw electrical stimulation in rats has not been studied. AIM: The aim was to evaluate the effect of a synthetic vasopressin analog, 1-deamino-8-D-arginine-vasopressin, on pain sensitivity and the content of norepinephrine, serotonin, dopamine, brain neurotrophic factor in the parietal cortex and spinal cord in electrocutaneous paw stimulation test in rats. MATERIALS AND METHODS: The study was conducted on male Wistar rats who were injected with 1-deamino-8-D-arginine-vasopressin intranasally once a day for 5 days in small (single 20 ng, course 100 ng) and large doses (single 2 ug, course 10 ug). The content of brain neurotrophic factor in the parietal cortex and spinal cord, and corticosterone in blood serum were determined using enzyme immunoassay. The levels of norepinephrine, serotonin, dopamine and their metabolites in the brain were evaluated using high-performance liquid chromatography. RESULTS: 1-Deamino-8-D-arginine-vasopressin in different doses reduced pain sensitivity in rats, more pronounced when administered in large doses. The peptide in small doses in the parietal cortex increased the content of dopamine and reduced the levels of 5-hydroxyindolacetic acid, a metabolite of serotonin; in the spinal cord, it reduced the content of 5-hydroxyindolacetic acid. 1-Deamino-8-D-arginine-vasopressin in high doses in the parietal cortex increased the content of dopamine and reduced the levels of 5-hydroxyindolacetic acid; in the spinal cord ― reduced the content of serotonin and 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine; increased the levels of norepinephrine and homovanilic acid, a metabolite of dopamine. The peptide had no effect on corticosterone levels in the blood and brain neurotrophic factor levels in the brain in rats. CONCLUSIONS: The analgesic effects of 1-deamino-8-D-arginine-vasopressin were revealed with intranasal administration in different subendocrine doses. Regardless of the administered doses, dopamine and serotonin at the supraspinal level were involved in peptide-induced anesthesia; serotonin at the spinal cord level. More pronounced analgesia with the administration of 1-deamino-8-D-arginine-vasopressin in high doses was due to the additional involvement of dopamine and norepinephrine at the spinal cord level.