Mimicking opioid analgesia in cortical pain circuits
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE308301 | GEO | 2026/01/09
REPOSITORIES: GEO
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Project description:Chronic pain is a persistent unpleasant sensation that produces pathological synaptic plasticity in the central nervous system. Some of the studies demonstrate that the anterior cingulate cortex (ACC) is a critical area for nociceptive and chronic pain processing. Our previous study revealed that animal models of chronic pain alter excitatory and inhibitory synaptic transmission in the ACC. However, it is not clear what molecules are involved in the alterations of synaptic plasticity in the ACC of chronic pain models. To identify genes with altered expression in the ACC of a chronic pain model, whole transcriptome analysis were performed. In addition to the ACC, whole transcriptome analysis was also performed in the hippocampus, a brain region that has not been reported to be associated with chronic pain. Complete freund's adjuvant (CFA, Sigma-Aldrich, #F5881) into the left hind paw was used for induce chronic inflammatory pain in this study.
2021-04-01 | GSE147216 | GEO
Project description:The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus co-treated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone anti-nociception in all models by 52.3%-628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP and naltrindole, and D24M had a mild transient effect in the Rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced anti-nociception using small molecule inhibitors (KN93, Src-I1). Together these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs via the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.
2023-03-10 | PXD022106 | Pride
Project description:Chronic pain affects 20-30% of the population and imposes a significant socio-economic burden as it is often accompanied by substantial emotional comorbidities such as anxiety and depression. Yet, the mechanisms underlying the interactions between the sensory and emotional aspects of chronic pain remain poorly understood. Here, we investigated the role of FKBP51, a regulator of the stress response, in mediating both sensory and emotional symptoms of chronic pain. Inhibition of FKBP51, via genetic deletion or pharmacological blockade, in persistent joint pain reduced fast-onset sensory, functional and activity-related symptoms, as well as late anxio-depressive comorbidities. FKBP51 inhibition after the establishment of the hypersensitive state provided only temporary symptoms relief, while acute inhibition at disease onset protected from the full development of sensory and anxio-depressive symptoms for up to 6 months. Our results also indicated that early pain symptoms could predict the late sensory and emotional outcomes of chronic pain. RNA sequencing of spinal cord tissue revealed that late FKBP51 inhibition transiently altered nociceptive genes associated with mechanical hypersensitivity. In contrast, early inhibition persistently downregulated the Naaa gene, a key regulator of the transition to chronic pain, and reorganized spinal cilia. Our results indicate that early FKBP51 inhibition after injury can persistently reduce chronic pain and prevent the onset of associated emotional comorbidities by modulating critical spinal neurobiological pathways that play pivotal roles in the transition to chronic pain.
2025-10-14 | GSE293520 | GEO
Project description:Current treatments for chronic pain rely largely on opioids despite their significant side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Towards this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells, and then by the lumbar intrathecal route delivered both epigenome-engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain and BzATP-induced pain. Our results demonstrate: i) effective repression of NaV1.7 in lumbar dorsal root ganglia; ii) reduced thermal hyperalgesia in the inflammatory state; iii) decreased tactile allodynia in the neuropathic state; and iv) no changes in normal motor function. We anticipate this genomically scarless and non-addictive pain prevention and amelioration approach enabling Long-lasting Analgesia via Targeted in vivo Epigenetic Repression of NaV1.7, a methodology we dub pain LATER, will have significant therapeutic potential in management of persistent pain states.
2022-01-01 | GSE159818 | GEO
Project description:In settings of heightened pain sensitivity, such as following peripheral nerve injury (PNI) or opioid-induced hyperalgesia (OIH), microglia take on an activated phenotype. Functional studies have suggested that microglia activated by PNI or chronic opioids then engage common mechanisms to facilitate pain. Here we conducted RNA sequencing of acutely isolated spinal cord microglia to comprehensively interrogate commonality between PNI and OIH. By combining our results with meta-analysis of published datasets, we identify transcriptional signatures of microglial reactivity that differ between PNI models over time, opioid exposure, or CNS pathology, despite similar histological outcomes. Collectively, these results reveal a discrepancy between histological markers of activation and transcriptional response, and provide a resource of pain-associated microglial transcriptomes that caution against a universal signature of microglia activation.
2022-01-03 | GSE117320 | GEO
Project description:In settings of heightened pain sensitivity, such as following peripheral nerve injury (PNI) or opioid-induced hyperalgesia (OIH), microglia take on an activated phenotype. Functional studies have suggested that microglia activated by PNI or chronic opioids then engage common mechanisms to facilitate pain. Here we conducted RNA sequencing of acutely isolated spinal cord microglia to comprehensively interrogate commonality between PNI and OIH. By combining our results with meta-analysis of published datasets, we identify transcriptional signatures of microglial reactivity that differ between PNI models over time, opioid exposure, or CNS pathology, despite similar histological outcomes. Collectively, these results reveal a discrepancy between histological markers of activation and transcriptional response, and provide a resource of pain-associated microglial transcriptomes that caution against a universal signature of microglia activation.
2022-01-03 | GSE117319 | GEO
Project description:Neuropathic pain is a troublesome pathological condition without suitable treatments. In this study, we performed RNA sequencing (RNA-seq) analysis to reveal transcriptomic profiles of Anterior Cingulate Cortex (ACC) from chronic constriction injury (CCI) rats. We found 1628 differentially expressed genes (DEGs) were mainly involved in the inflammatory and immune process. Besides, cytokine signaling and other cell-defense related pathways mainly contribute to the occurrence and development of neuropathic pain. Then we classified the DEGs based on the time trend. Our results suggested that chemokines played a vital role in pain, and moreover, CCL5, CXCL9 and CXCL13, compared with CCL2, CCL3, CCL4, CCL6 and CCL7 had different time-dependent manners. In a word, targeting chemokines is of great significance to explore specific mechanisms and develop suitable drugs for neuropathic pain.
2022-04-05 | GSE172133 | GEO
Project description:The goal was to identify actively translated sequences in Dorsal spinal cord from Mice 2hours after Hind-Paw 20% formalin injection. Ipsi and Contralateral sides were compared to identify transcriptional changes after acute pain. Tissue was collected and ribosomes were pulled-down in the presence of CHX, RNA was purified and sequenced afterwards.
2024-01-30 | E-MTAB-13734 | biostudies-arrayexpress
Project description:BackgroundThis is an updated version of the original Cochrane review published in Issue 4, 2006. Patients may control postoperative pain by self administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne et al found a strong patient preference for PCA over non-patient controlled analgesia, but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, a 2001 review by Walder et al did not find statistically significant differences in pain intensity or pain relief between PCA and groups treated with non-patient controlled analgesia.ObjectivesTo evaluate the efficacy and safety of patient controlled intravenous opioid analgesia (termed PCA in this review) versus non-patient controlled opioid analgesia of as-needed opioid analgesia for postoperative pain relief.Search methodsWe ran the search for the previous review in November 2004. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 12), MEDLINE (1966 to 28 January 2015), and EMBASE (1980 to 28 January 2015) for randomized controlled trials (RCTs) in any language, and reference lists of reviews and retrieved articles.Selection criteriaWe selected RCTs that assessed pain intensity as a primary or secondary outcome. These studies compared PCA without a continuous background infusion with non-patient controlled opioid analgesic regimens. We excluded studies that explicitly stated they involved patients with chronic pain.Data collection and analysisTwo review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. We performed meta-analysis of outcomes that included pain intensity assessed by a 0 to 100 visual analog scale (VAS), opioid consumption, patient satisfaction, length of stay, and adverse events.Main resultsForty-nine studies with 1725 participants receiving PCA and 1687 participants assigned to a control group met the inclusion criteria. The original review included 55 studies with 2023 patients receiving PCA and 1838 patients assigned to a control group. There were fewer included studies in our updated review due to the revised exclusion criteria. For the primary outcome, participants receiving PCA had lower VAS pain intensity scores versus non-patient controlled analgesia over most time intervals, e.g., scores over 0 to 24 hours were nine points lower (95% confidence interval (CI) -13 to -5, moderate quality evidence) and over 0 to 48 hours were 10 points lower (95% CI -12 to -7, low quality evidence). Among the secondary outcomes, participants were more satisfied with PCA (81% versus 61%, P value = 0.002) and consumed higher amounts of opioids than controls (0 to 24 hours, 7 mg more of intravenous morphine equivalents, 95% CI 1 mg to 13 mg). Those receiving PCA had a higher incidence of pruritus (15% versus 8%, P value = 0.01) but had a similar incidence of other adverse events. There was no difference in the length of hospital stay.Authors' conclusionsSince the last version of this review, we have found new studies providing additional information. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia for postoperative pain control.
| S-EPMC7387354 | biostudies-literature
Project description:A Transcriptomic Analysis of Neuropathic Pain in the Anterior Cingulate Cortex after Nerve Injury
| PRJNA722201 | ENA