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Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8 T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8 T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8 T cells, Ramp1 CD8 T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8 T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8 T cells.
Learn More >To establish a new rat model of craniofacial myalgia, and to clarify which central nervous system pathways are activated in the model.
Learn More >Perioperative neurocognitive disorders (PND) is a common complication that occurs among elderly patients in the perioperative course. Current clinical evidence has shown that isoflurane exposure could cause cognitive decline but the exact molecular mechanisms remain unclear. As both NMDARs-dependent synaptic plasticity and histone acetylation play vital roles in processing learning and memory, we postulated that these alternations might occur in the isoflurane-associated PND. Here, we found that isoflurane impaired fear memory in aged mice, decreased GluN2B-containing NMDA receptors phosphorylation and trafficking, as well as the expression of EphB2, a key regulator of synaptic localization of NMDA receptors. We also identified that isoflurane could increase the expression of HDAC2, which was significantly enriched at the ephb2 gene promoter and regulated the transcription of ephb2. Furthermore, we showed that Suberoylanilide hydroxamic acid (SAHA), a non-selective HDAC inhibitor or knocking-down HDAC2 rescued the cognitive dysfunction in isoflurane-treated aged mice via increasing acetylation of H3Ac, expression of EphB2 and promoting NMDA receptor trafficking. Collectively, our study highlighted the crucial role of histone posttranslational modifications for EphB2-GluN2B signals in isoflurane-associated PND and modulating HDAC2 might be a new therapeutic strategy for isoflurane-associated PND.
Learn More >Ketamine, an -methyl-D-aspartate receptor antagonist, is effective at relieving adult cancer pain, although there have been very few reports to date regarding its use in children and in adolescents and young adults (AYA). This study assessed the efficacy, safety and opioid-sparing effects of low doses of ketamine added to opioid analgesics to alleviate persistent cancer pain.
Learn More >Morphine is one of the preferred drugs for the clinical treatment of pain. Both clinical and preclinical studies have reported sexual dimorphism in morphine analgesia. Different circulating levels of estrogen could be involved in sex differences in response to morphine analgesia. In our previous research, we found that capsaicin injection into the cervix of rats caused acute visceral pain that could be relieved by morphine. The role of estrogen in morphine analgesia in rats under uterine cervix pain and its underlying mechanisms remain to be explored.
Learn More >Intervertebral disc (IVD) degeneration is suggested as a major cause of chronic low back pain (LBP). Intradiscal delivery of growth factors has been proposed as a promising strategy for IVD repair and regeneration. Previously, BMP-4 was shown to be more potent in promoting extracellular matrix (ECM) production than other BMPs and TGF-β in human nucleus pulposus (NP) cells, suggesting its applicability for disc regeneration.
Learn More >To evaluate efficacy and satisfaction of dextromethorphan as a non-narcotic adjuvant to current analgesic regimens for medication abortion.
Learn More >Given the severity of the ongoing opioid epidemic, it is essential to understand the mechanisms of risk for development and maintenance of opioid use disorder (OUD). The aim of the current large-scale psychophysiological investigation was to test whether patients with OUD had lower resting-state high-frequency heart rate variability (HF-HRV) than those without OUD, controlling for sociodemographic and clinical confounds. Additionally, we tested whether HF-HRV was associated with opioid craving in this population. Participants in this cross-sectional study were 490 chronic pain patients (50.4% female) treated with long-term opioid therapy. OUD diagnosis was determined by psychiatric interview. HF-HRV was measured at resting baseline. We computed the association between OUD and resting-state HF-HRV, controlling for age, gender, race, pain severity, emotional distress and opioid dose. Opioid craving was measured with visual analogue scales to assess whether HF-HRV was associated with craving. Results showed that resting HF-HRV was significantly lower for patients with OUD than for those without OUD (p < 0.001, d = 0.36), indicating deficits in autonomic flexibility. OUD diagnosis (p = 0.002) and OUD severity (p = 0.03) were associated with lower HF-HRV in regression models accounting for a range of confounders. Additionally, lower HF-HRV was significantly (but weakly) correlated with heightened opioid craving (r = -0.166, p < 0.001). Overall, findings suggest that resting-state HF-HRV may serve as a valid biomarker of addiction among people on long-term opioid therapy.
Learn More >P2X receptors are ATP-gated ion channels which play a role in many pathophysiological conditions. They are considered as novel drug targets, particularly in the fields of pain, (neuro) inflammation, and cancer. Due to difficulties in developing drug-like orthosteric ligands that bind to the highly polar ATP binding site, the design of positive and negative allosteric modulators (PAMs and NAMs) is a promising strategy. The P2X4 receptor was proposed as a novel target for neuropathic and inflammatory pain (antagonists), and for the treatment of alcoholism (PAMs). So far, little is known about the allosteric binding site(s) of P2X4 receptors. The aim of this study is to identify the binding site (s) of the macrocyclic natural product ivermectin, the urea derivative BX430, and the antidepressant drug paroxetine that act as allosteric modulators of P2X4 receptors.
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