Chemokine CCL2 prevents opioid-induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn

Heles, Mario; Mrózková, Petra; Sulcova, Dominika; Adámek, Pavel; Spicarova, Diana; Paleček, J.

doi:10.1186/s12974-021-02335-4

Cited by 8 publications

(9 citation statements)

References 44 publications

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“…Kaminski et al provided evidence for a molecular interaction because inhibition of opioid receptors led to a downregulation of CCL2 (50). On the other hand, high levels of CCL2 can inhibit the activation of opioid receptors, thus attenuating analgesia (51,52). This suggests that the high CCL2 levels might be a compensatory effect from the opioid treatment.…”

Section: Discussionmentioning

confidence: 99%

Systemic inflammatory markers in patients with polyneuropathies

et al. 2023

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IntroductionIn patients with peripheral neuropathies (PNP), neuropathic pain is present in 50% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation.MethodsTo test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls.ResultsWhile we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction.ConclusionIn patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies.

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Section: Discussionmentioning

confidence: 99%

Systemic inflammatory markers in patients with polyneuropathies

et al. 2023

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“…Enkephalin can enhance the release of pro-inflammatory cytokines like IL6 [50]. The cross-talk can take place between cytokines as CCL2 and opioid peptides and alter nociceptive synaptic transmission [51]. Thus, more work is required to test whether the enkephalin peptide identified here as a ligand of N may increase pain and immune disorders in the context of COVID-19, despite its physiological pain release function.…”

Section: N Implication In Immunity With Possible Long-term Neurologic...mentioning

confidence: 95%

Neuropeptides, New Ligands of SARS-CoV-2 Nucleoprotein, a Potential Link between Replication, Inflammation and Neurotransmission

et al. 2022

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This work identifies new ligands of the nucleoprotein N of SARS-CoV-2 by in silico screening, which used a new model of N, built from an Alphafold model refined by molecular dynamic simulations. The ligands were neuropeptides, such as substance P (1-7) and enkephalin, bound at a large site of the C-terminal or associated with the N-terminal β−sheet. The BA4 and BA5 Omicron variants of N also exhibited a large site as in wt N, and an increased flexibility of the BA5 variant, enabling substance P binding. The binding sites of some ligands deduced from modeling in wt N were assessed by mutation studies in surface plasmon resonance experiments. Dynamic light scattering showed that the ligands impeded RNA binding to N, which likely inhibited replication. We suggest that the physiological role of these neuropeptides in neurotransmission, pain and vasodilation for cholecystokinin and substance P could be altered by binding to N. We speculate that N may link between viral replication and multiple pathways leading to long COVID-19 symptoms. Therefore, N may constitute a “danger hub” that needs to be inhibited, even at high cost for the host. Antivirals targeted to N may therefore reduce the risk of brain fog and stroke, and improve patients’ health.

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“… 31 , 32 In addition, either genetic deletion or pharmacological inhibition of TRPA1 mitigated pain responses. 33 , 34 However, unlike that of TRPV1, 24 , 25 the role of TRPA1 in RIH has not yet been thoroughly investigated. In Experiment 1, we confirmed that the TRPA1 expression in DRG neurons was upregulated in RIH model, revealing a link between increased sensory TRPA1 expression and RIH.…”

Section: Discussionmentioning

confidence: 99%

“… 22 , 23 The role of sensory neuron TRPV1 in RIH has been well established. 24 , 25 However, whether TRPA1 participated in RIH remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 4 signaling pathway in sensory neurons mediates remifentanil-induced postoperative hyperalgesia via transient receptor potential ankyrin 1

Liu¹,

Gong²,

Peng³

et al. 2023

Mol Pain

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Background: Remifentanil-induced postoperative hyperalgesia (RIH) refers to a state of hyperalgesia or aggravated pre-existing pain after remifentanil exposure. There has been considerable interest in understanding and preventing RIH. However, the mechanisms responsible for RIH are still not completely understood. Toll-like receptor 4 (TLR4), a classic innate immune receptor, has been detected in sensory neurons and participates in various nociceptive conditions, whereas its role in RIH remains unclear. Transient receptor potential ankyrin 1 (TRPA1) always serves as a nociceptive channel, whereas its role in RIH has not yet been investigated. This study aimed to determine whether the TLR4 signaling pathway in sensory neurons engaged in the development of RIH and the possible involvement of TRPA1 during this process. Methods: A rat model of remifentanil-induced postoperative hyperalgesia (RIH) was established, which presented decreased paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL). The mRNA and protein expression levels of TLR4, phosphorylated NF-κB, and TRPA1 in the dorsal root ganglion (DRG) from RIH model were analyzed by real-time PCR, western blot, and immunofluorescence. The TLR4 antagonist TAK-242 and the TRPA1 antagonist HC-030031 were applied to determine the role of sensory neuron TLR4 signaling and TRPA1 in RIH. Results: Compared with control, PWMT and PWTL were significantly decreased in RIH model. Moreover, the mRNA and protein expression of TLR4 and TRPA1 in DRG were upregulated after remifentanil exposure together with increased NF-κB phosphorylation. TLR4 antagonist TAK-242 mitigated mechanical pain in RIH together with downregulated expression of TLR4, phosphorylated NF-κB, and TRPA1 in DRG neurons. In addition, TRPA1 antagonist HC-030031 also alleviated mechanical pain and decreased TRPA1 expression in RIH without affecting TLR4 signaling in DRG. Conclusions: Our results suggested that activation of TLR4 signaling pathway engaged in the development of RIH by regulating TRPA1 in DRG neurons. Blocking TLR4 and TRPA1 might serve as a promising therapeutic strategy for RIH.

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Chemokine CCL2 prevents opioid-induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn

Cited by 8 publications

References 44 publications

Systemic inflammatory markers in patients with polyneuropathies

Systemic inflammatory markers in patients with polyneuropathies

Neuropeptides, New Ligands of SARS-CoV-2 Nucleoprotein, a Potential Link between Replication, Inflammation and Neurotransmission

Toll-like receptor 4 signaling pathway in sensory neurons mediates remifentanil-induced postoperative hyperalgesia via transient receptor potential ankyrin 1

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