Quell Opioid Reduction and Pain Relief in Patients With Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Pain,Metastatic Breast Cancer,Colorectal Cancer,Colorectal Neoplasms,Prostate Cancer
PROVIDER: 2218031 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.
2024-09-12 | GSE267265 | GEO
Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.
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Project description:Neural circuit basis of placebo pain relief [10X]
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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.
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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:Neural circuit basis of placebo pain relief [SMART-seq]
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Project description:Post-surgical pain causes significant suffering. Extracts of the human amniotic membrane (AM) may be novel regenerative matrices, but little is known about their use in pain treatment. Locally applying FLO (particulates of AM) in mice acutely attenuated post-surgical pain hypersensitivity and inhibited its transition to a prolonged state after plantar-incision. Mechanistically, this was achieved through direct nociceptive neuronal inhibition via CD44-dependent mechanisms and indirect anti-pain effect by attenuating immune cell recruitment and promoting wound healing. We purified heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) from human AM as a major bioactive matrix component for pain relief, as it mirrored FLO-induced analgesia and nociceptive neuronal inhibition. Strikingly, HC-HA/PTX3 triggered acute cytoskeleton rearrangement to inhibit ion channels on nociceptive neurons, presenting a novel cellular mechanism for pain control. Moreover, long-term drug treatment broadly changed neuronal gene expression. Our study demonstrated the potential and mechanisms of a naturally occurring biologic from human birth tissues as non-opioid treatments for post-surgical pain.
2024-06-25 | GSE242389 | GEO
Project description:Pain is the leading cause of disability in the developed world but remains a poorly treated condition. Specifically, post-surgical pain continues to be a frequent and undermanaged condition. Here, we investigate the analgesic potential of pharmacological NaV1.7 inhibition in a mouse model of acute post-surgical pain, based on incision of the plantar skin and underlying muscle of the hind paw. We demonstrate that local and systemic treatment with the selective NaV1.7 inhibitor μ-theraphotoxin-Pn3a is effectively anti-allodynic in this model and completely reverses mechanical hypersensitivity in the absence of motor adverse effects. In addition, the selective NaV1.7 inhibitors ProTx-II and PF-04856264 as well as the clinical candidate CNV1014802 also reduced mechanical allodynia. Interestingly, co-administration of the opioid receptor antagonist naloxone completely reversed analgesic effects of Pn3a, indicating an involvement of endogenous opioids in the analgesic activity of Pn3a. Additionally, we found super-additive antinociceptive effects of sub-therapeutic Pn3a doses not only with the opioid oxycodone but also with the GABAB receptor agonist baclofen. Transcriptomic analysis of gene expression changes in dorsal root ganglia of mice post-surgery revealed decreased expression of several pro-nociceptive genes including N- and P/Q-type voltage-gated calcium channels important for neurotransmitter release, which suggest a reactive compensatory mechanism to reduce excessive pain similar to the endogenous opioid system. In summary, these findings suggest that pain after surgery can be successfully treated with NaV1.7 inhibitors alone or in combination with baclofen or opioids, which may present a novel and safe treatment strategy for this frequent and poorly managed condition.
2019-05-01 | GSE125076 | GEO
Project description:Distinct microglial transcriptional responses during opioid exposure or neuropathic pain
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Project description:Opioids analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit their use. It has been recently demonstrated that morphine treatment results in significant disruption in gut barrier function leading to increased translocation of gut commensal bacteria. Further study indicated distinct alterations in the gut microbiome and metabolome following morphine treatment, contributing to the negative consequences associated with opioid use. However, it is unclear how opioids modulate gut homeostasis in the context of a hospital acquired bacterial infection. In the current study, a mouse model of C. rodentium infection was used to investigate the role of morphine in the modulation of gut homeostasis in the context of a hospital acquired bacterial infection. Citrobacter rodentium is a natural mouse pathogen that models intestinal infection by enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and causes attaching and effacing lesions and colonic hyperplasia. Morphine treatment resulted in 1) the promotion of C. rodentium systemic dissemination, 2) increase in virulence factors expression with C. rodentium colonization in intestinal contents, 3) altered gut microbiome, 4) damaged integrity of gut epithelial barrier function, 5) inhibition of C. rodentium-induced increase in goblet cells, and 6) dysregulated IL-17A immune response. This is the first study to demonstrate that morphine promotes pathogen dissemination in the context of intestinal C. rodentium infection, indicating morphine modulates virulence factor-mediated adhesion of pathogenic bacteria and induces disruption of mucosal host defense during C. rodentium intestinal infection in mice. This study demonstrates and further validates a positive correlation between opioid drug use/abuse and increased risk of infections, suggesting over-prescription of opioids may increase the risk in the emergence of pathogenic strains and should be used cautiously. Therapeutics directed at maintaining gut homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management.
2020-02-18 | E-MTAB-7503 | biostudies-arrayexpress