PAIN®最新文献

Abstract: Neuropathic pain is a complex chronic condition with a multifactorial etiology that includes genetic susceptibility. However, the genetic basis of neuropathic pain remains poorly understood. We aimed to investigate genetic variants associated with the presence and intensity of neuropathic pain using genome-wide association analyses in the GeNeuP cohort, comprised of 1146 deeply phenotyped individuals with peripheral neuropathy from Norway. Genotyping was performed using the Illumina Global Screening Array, and analyses were conducted to test associations with the presence and intensity of neuropathic pain. No significant associations were detected at the genome-wide significance level ( P < 5 × 10 -8 ) for either the presence or intensity of neuropathic pain. However, at the subthreshold level ( P < 10 -6 ), 3 single nucleotide polymorphisms (annotated to the CHRDL1 and MCF2L gene and a long non-coding RNA) were associated with intensity of neuropathic pain. A targeted candidate gene analysis of 163 genes previously implicated in neuropathic pain and neuropathy did not yield significant associations. These results highlight the complexity of the genetic architecture underlying neuropathic pain and the challenges in identifying common variants with detectable effects. The identification of subthreshold associations of genes involved in synaptic plasticity is intriguing and merits further investigation. Larger studies with refined phenotyping will be essential to validate these signals and to advance understanding of the genetic contributors to neuropathic pain.

Abstract: Pain is a common debilitating symptom reported in people with endometriosis. Yet, we do not have a good understanding of factors that may contribute to higher pain and worse psychosocial outcomes in this population. One key construct linked to higher pain and distress in people with endometriosis is Fear of disease Recurrence or Progression (FORP). Accordingly, in the context of endometriosis, we aimed to identify the prevalence of severe FORP; test whether theoretical constructs from models of fear of cancer recurrence (interpretation bias, metacognitive beliefs, existential concerns) relate to FORP; and better understand the nature of relationships between FORP, theoretical and emotional distress, and pain-related constructs. Participants with a confirmed (n = 274) or provisional (n = 43) diagnosis of endometriosis were recruited through Endometriosis Australia. Participants completed a cross-sectional online survey assessing relevant constructs. We conducted bivariate correlations and network analyses to test for relationships between key constructs. Nearly 85% of participants reported severe levels of FORP. We found that people with greater existential concerns and more unhelpful metacognitive beliefs but not stronger interpretation bias reported greater FORP. However, only existential concerns contributed independent variance in FORP. We also found that individuals with heightened FORP reported greater physical pain and poorer overall well-being. These results suggest that FORP is common and important. Furthermore, metacognitive beliefs and existential concerns were identified as important factors. Testing whether these factors are potentially modifiable intervention targets through longitudinal and intervention studies could ultimately lead to reductions in the impact of endometriosis-associated pain.

Abstract: Increased afferent sensitivity is a key pathophysiological mechanism of overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome. Gi-DREADDs-based chemogenetic offers a novel approach for silencing neuronal activity. This study investigates the translational potential of Gi-DREADDs in suppressing OAB and pain by selectively silencing bladder primary sensory neurons. All mice were female. The transduction efficiency and specificity of 3 adeno-associated virus (AAV) serotypes (AAV9, PHP.S, and AAV-retro) delivered via bladder injection or intrathecal injection were compared. Bladder-injected AAV-retro demonstrated the highest specificity, transducing 70% of dorsal root ganglion (DRG) neurons labeled with retrograde tracer DiI. It did not transduce DRG neurons innervating organs outside bladder, the autonomic neurons in major pelvic ganglion and the motor neurons in spinal cord. Unexpectedly, bladder-injected PHP.S failed to transduce bladder sensory neurons. Using AAV-retro to deliver hM4D(Gi) to bladder DRG neurons, and activation with clozapine-N-oxide (CNO), significantly inhibited DRG neuron responses to high K+ and capsaicin in vitro. In vivo, activation of AAV-retro-mediated hM4D(Gi) with CNO significantly alleviated OAB and pain behaviors in both acute (capsaicin) and chronic (cyclophosphamide) pain models without affecting voiding pressure or causing urinary retention. These findings indicate that selectively silencing bladder sensory neurons with chemogenetic has translational potential for treatment of OAB or chronic bladder pain.

Abstract: Conditioned pain modulation (CPM), the change in pain evoked by a test stimulus at 1 body site by a conditioning stimulus at another site, varies across individuals, ranging from inhibition (pain decreases) to no CPM to facilitation (pain increases). Given the role of alpha oscillations in pain, we examined the relationship between CPM and peak alpha frequency (PAF) and power in the dynamic pain connectome (DPC). In 68 healthy individuals who underwent resting-state magnetoencephalography and a heat-based CPM evaluation, 32% had inhibitory CPM, 49% had facilitatory CPM, and 19% had no CPM. The facilitatory subgroup had lower alpha power in the medial prefrontal cortex (mPFC) compared with the inhibitory subgroup and across the DPC (mPFC, right thalamus, bilateral dorsolateral prefrontal cortex [dlPFC]) compared with the noCPM subgroup. Peak alpha frequency in the thalamus bilaterally was strongly correlated with inhibitory CPM (higher PAF with stronger inhibitory CPM). The subgenual anterior cingulate cortex (sgACC) PAF was correlated with inhibitory CPM in males and females in opposite directions, but not at the whole subgroup level. The pressure-based CPM evoked inhibitory CPM in 87% of the 45 individuals tested; the relationship with PAF in the right dlPFC and sgACC had medium-strong effect sizes driven by males (higher PAF with weaker inhibitory CPM). This study indicates that the role of alpha oscillations in CPM is paradigm- and sex-dependent. Our findings that healthy individuals exhibit an alpha-CPM relationship, particularly in the prefrontal regions and sgACC, provide insight into the potential therapeutic use of targeted neuromodulation for pain.

Abstract: Sickle cell disease (SCD) is a genetic disorder caused by a mutation in the beta hemoglobin gene, resulting in red blood cell (RBC) distortion, hemolysis, and severe pain episodes. Despite advancements in understanding acute crisis pain that is caused by vaso-occlusion, the neurobiological mechanisms underlying chronic pain in SCD remain poorly studied. Hemorphins, atypical endogenous opioid peptides derived from the hemoglobin beta chain in RBCs have analgesic effects and may contribute to SCD-related pain mechanisms, as their formation occurs when hemoglobin in RBCs is exposed to proteases in plasma. In this study, we investigated the levels of hemorphins in both plasma and nervous system of humanized transgenic SCD mice using liquid chromatography mass spectrometry. Our results show a significant elevation of hemorphins in SCD mice compared with wild-type controls, with a strong correlation with individual pain levels. These findings suggest that altered hemorphin processing in SCD may contribute to chronic pain by modulating the opioid signaling pathways, offering insights into the neurobiology of pain in SCD.

Abstract: Transcutaneous high-frequency electrical stimulation (HFS) elicits pain and produces prolonged mechanical pinprick hypersensitivity. This study investigated whether acute stress, induced by the Mannheim Multicomponent Stress Test (MMST), elevates HFS-related pain and pinprick hypersensitivity in healthy women. Two between-subject experiments were conducted. In experiment 1 (N = 66), the MMST or a control task was applied before HFS to assess whether stress enhances pain during HFS and contributes to subsequent pinprick hypersensitivity. In experiment 2 (N = 60), stress was induced 20 minutes after HFS to evaluate its effect on already established pinprick hypersensitivity. Unlike the control task, the MMST significantly increased subjective stress in both experiments. In experiment 1, the average pain ratings across all 5 HFS trains did not differ significantly between groups. However, exploratory analysis showed that pain ratings for the first HFS train were 10 points higher (on a 0-100 scale) in the MMST group, although this effect diminished over subsequent trains. Pinprick hypersensitivity developed similarly in both groups, suggesting that stress before HFS may elevate HFS pain but does not influence the development of hypersensitivity. In experiment 2, pinprick hypersensitivity significantly increased after the MMST compared to the control task, although the absolute effect size was relatively small (5 points on a 0-100 scale). Collectively, these findings indicate that acute stress before HFS may elevate HFS pain without influencing the development of subsequent pinprick hypersensitivity. Conversely, when acute stress is induced after HFS, when pinprick hypersensitivity has already been established, it increases hypersensitivity.

Abstract: Neuropathic pain is a common and debilitating symptom with limited treatment options. Genetic studies, which can provide vital evidence for drug development, have identified only 3 genome-wide significant signals for neuropathic pain traits. To address this, we performed the largest genome-wide association study (GWAS) to date of all-cause neuropathic pain and neuropathic pain subtypes. We defined all-cause neuropathic pain and 33 neuropathic pain subtypes using DeepPheWAS software in the UK Biobank, taking advantage of the longitudinal drug prescription data alongside clinical and self-reported records. We performed a GWAS of all-cause neuropathic pain (33,278 cases, 140,134 controls) as our primary analysis and GWASs of neuropathic pain subtypes as secondary analyses. We used 8 variant-to-gene criteria to identify putative causal genes. We identified 7 independent novel genome-wide associations for neuropathic pain phenotypes, which mapped to 22 novel putative causal genes. NCAM1 was the only gene identified from the primary analysis of all-cause neuropathic pain and met the most variant-to-gene criteria (4) of any identified gene. Of the 21 other genes, ASCC1, CHST3, C4A/C4B , and KCNN2 had the most compelling evidence for mechanistic involvement in neuropathic pain. We have performed the largest GWAS to date of all-cause neuropathic pain and more than doubled the number of genome-wide significant associations for neuropathic pain traits, identifying putative causal genes. There is strong evidence for the involvement of NCAM1 in neuropathic pain, which merits for further study for drug development.