Antinociception induced by artemisinin nanocapsule in a model of postoperative pain via spinal TLR4 inhibition

Elisei, Lívia; Moraes, Thamyris Reis; Malta, Iago Henrique Silva; Charlie-Silva, Ives; Sousa, Ilza Maria de Oliveira; Veras, Flávio P.; Foglio, Mary Ann; Fraceto, Leonardo Fernandes; Galdino, Giovane

doi:10.1007/s10787-020-00756-w

Cited by 10 publications

(6 citation statements)

References 49 publications

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“…Elisei et al have reported that TLR4 is involved in SMIR‐induced CPSP in the spinal cord, and inhibition of TLR4 can alleviate mechanical hypersensitivity caused by SMIR. However, they did not report the molecular mechanism by which spinal TLR4 is involved in SMIR‐induced CPSP (Elisei et al, 2020). In the present study, we detected a significant increase in TLR4 expression in both the spinal cord and within DRGs of SMIR rats.…”

Section: Discussionmentioning

confidence: 99%

The different mechanisms of peripheral and central TLR4 on chronic postsurgical pain in rats

Han

Ren

et al. 2021

Journal of Anatomy

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Chronic postsurgical pain (CPSP) is a common complication after surgery; however, the underlying mechanisms of CPSP are poorly understood. As one of the most important inflammatory pathways, the Toll‐like receptor 4/nuclear factor‐kappa B (TLR4/NF‐κB) signaling pathway plays an important role in chronic pain. However, the precise role of the TLR4/NF‐κB signaling pathway in CPSP remains unclear. In the present study, we established a rat model of CPSP induced by skin/muscle incision and retraction (SMIR) and verified the effects and mechanisms of central and peripheral TLR4 and NF‐κB on hyperalgesia in SMIR rats. The results showed that TLR4 expression was increased in both the spinal dorsal horn and dorsal root ganglia (DRGs) of SMIR rats. However, the TLR4 expression pattern in the spinal cord was different from that in DRGs. In the spinal cord, TLR4 was expressed in both neurons and microglia, whereas it was expressed in neurons but not in satellite glial cells in DRGs. Further results demonstrate that the central and peripheral TLR4/NF‐κB signaling pathway is involved in the SMIR‐induced CPSP by different mechanisms. In the peripheral nervous system, we revealed that the TLR4/NF‐κB signaling pathway induced upregulation of voltage‐gated sodium channel 1.7 (Nav1.7) in DRGs, triggering peripheral hyperalgesia in SMIR‐induced CPSP. In the central nervous system, the TLR4/NF‐κB signaling pathway participated in SMIR‐induced CPSP by activating microglia in the spinal cord. Ultimately, our findings demonstrated that activation of the peripheral and central TLR4/NF‐κB signaling pathway involved in the development of SMIR‐induced CPSP.

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Section: Discussionmentioning

confidence: 99%

The different mechanisms of peripheral and central TLR4 on chronic postsurgical pain in rats

Han

Ren

et al. 2021

Journal of Anatomy

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“…The floor of the glass boxes is composed by small metal grids that allow the filaments to access the evaluated paws of each animal. After that, different thicknesses of filaments (0.07, 0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 grams) were applied to the plantar surface of right paw of each animal, and the mean of pressure values corresponding to three withdrawals was recorded as the nociceptive threshold ( 14 ).…”

Section: Methodsmentioning

confidence: 99%

Spinal HMGB1 participates in the early stages of paclitaxel-induced neuropathic pain via microglial TLR4 and RAGE activation

Moraes,

Veras,

Barchuk

et al. 2024

Front. Immunol.

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IntroductionChemotherapy-induced neuropathic pain (CINP) is one of the main adverse effects of chemotherapy treatment. At the spinal level, CINP modulation involves glial cells that upregulate Toll-like receptor 4 (TLR4) and signaling pathways, which can be activated by pro-inflammatory mediators as the high mobility group box-1 (HMGB1).ObjectiveTo evaluate the spinal role of HMGB1 in the paclitaxel-induced neuropathic pain via receptor for advanced glycation end products (RAGE) and TLR4 activation expressed in glial cells.MethodsMale C57BL/6 Wild type and TLR4 deficient mice were used in the paclitaxel-induced neuropathic pain model. The nociceptive threshold was measured using the von Frey filament test. In addition, recombinant HMGB1 was intrathecally (i.t.) injected to confirm its nociceptive potential. To evaluate the spinal participation of RAGE, TLR4, NF-kB, microglia, astrocytes, and MAPK p38 in HMGB1-mediated nociceptive effect during neuropathic pain and recombinant HMGB1-induced nociception, the drugs FPS-ZM1, LPS-RS, PDTC, minocycline, fluorocitrate, and SML0543 were respectively administrated by i.t. rout. Microglia, astrocytes, glial cells, RAGE, and TLR4 protein expression were analyzed by Western blot. ELISA immunoassay was also used to assess HMGB1, IL-1β, and TNF-α spinal levels.ResultsThe pharmacological experiments demonstrated that spinal RAGE, TLR4, microglia, astrocytes, as well as MAPK p38 and NF-kB signaling are involved with HMGB1-induced nociception and paclitaxel-induced neuropathic pain. Furthermore, HMGB1 spinal levels were increased during the early stages of neuropathic pain and associated with RAGE, TLR4 and microglial activation. RAGE and TLR4 blockade decreased spinal levels of pro-inflammatory cytokines during neuropathic pain.ConclusionTaken together, our findings indicate that HMGB1 may be released during the early stages of paclitaxel-induced neuropathic pain. This molecule activates RAGE and TLR4 receptors in spinal microglia, upregulating pro-inflammatory cytokines that may contribute to neuropathic pain.

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“…CBD was solubilized in ethanol, cremophor, and sterile saline at 1:1:18 ratio. The doses of minocycline, fluorocitrate, LPS‐RS, AM630 and CBD were chosen according to previous literature studies 19–23 . No signs of toxicity were observed in mice after treatment with drugs and substances (up to the highest doses) used in the current study.…”

Section: Methodsmentioning

confidence: 99%

“…Then, LPS or vehicle was administered intrathecally, and other nociceptive threshold measurements were performed after 1, 3, 5, 7 and 24 h (Figure 1A). Group sizes were based on our previous experience in this measurement, 19,21 and mice were randomly assigned to each group using Random.org software (Trinity College, Dublin, Ireland). No animal was excluded from the study.…”

Section: Experimental Protocolmentioning

confidence: 99%

Cannabidiol reduces lipopolysaccharide‐induced nociception via endocannabinoid system activation

Santos

Veras

Netto

et al. 2023

Basic Clin Pharma Tox

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Bacterial infections are often accompanied by fever and generalized muscle pain. However, the treatment of pain with an infectious aetiology has been overlooked. Thus, we investigated the impact of cannabidiol (CBD) in bacterial lipopolysaccharide (LPS)-induced nociception. Male Swiss mice received intrathecal (i.t.) LPS injection, and the nociceptive threshold was measured by the von Frey filaments test. Spinal involvement of the cannabinoid CB 2 receptor, toll-like receptor 4 (TLR4), microglia and astrocytes were evaluated by i.t. administration of their respectively antagonists or inhibitors. Western blot, immunofluorescence, ELISA and liquid chromatography-mass spectrometry were used to assess Cannabinoid CB 2 receptors and TLR4 spinal expression, proinflammatory cytokines and endocannabinoid levels. CBD was administered intraperitoneally at 10 mg/kg. The pharmacological assay demonstrated TLR4 participation in LPS-induced nociception. In addition, spinal TLR4 expression and proinflammatory cytokine levels were increased in this process. CBD treatment prevented LPS-induced nociception and TLR4 expression. AM630 reversed antinociception and reduced CBD-induced endocannabinoids up-regulation. Increased spinal expression of the cannabinoid CB 2 receptor was also found in animals receiving LPS, which was accompanied by reduced TLR4 expression in CBD-treated mice. Taken together, our findings indicated that CBD is a potential treatment strategy to control LPS-induced pain by attenuating TLR4 activation via the endocannabinoid system.

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Antinociception induced by artemisinin nanocapsule in a model of postoperative pain via spinal TLR4 inhibition

Cited by 10 publications

References 49 publications

The different mechanisms of peripheral and central TLR4 on chronic postsurgical pain in rats

The different mechanisms of peripheral and central TLR4 on chronic postsurgical pain in rats

Spinal HMGB1 participates in the early stages of paclitaxel-induced neuropathic pain via microglial TLR4 and RAGE activation

Cannabidiol reduces lipopolysaccharide‐induced nociception via endocannabinoid system activation

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