Lipopolysaccharide from Rhodobacter sphaeroides (TLR4 antagonist) attenuates hypersensitivity and modulates nociceptive factors

Abstract

Context: Accumulating evidence has demonstrated that Toll-like receptors (TLRs), especially TLR4 localized on microglia/macrophages, may play a significant role in nociception.Objective: We examine the role of TLR4 in a neuropathic pain model. Using behavioural/biochemical methods, we examined the influence of TLR4 antagonist on levels of hypersensitivity and nociceptive factors whose contribution to neuropathy development has been confirmed.Materials and methods: Behavioural (von Frey’s/cold plate) tests were performed with Wistar male rats after intrathecal administration of a TLR4 antagonist (LPS-RS ULTRAPURE (LPS-RSU), 20 μG: lipopolysaccharide from Rhodobacter sphaeroides, InvivoGen, San Diego, CA) 16 H and 1 h before chronic constriction injury (cci) to the sciatic nerve and then daily for 7 d. three groups were used: an intact group and two cci-exposed groups that received vehicle or LPS-RSU. tissue [spinal cord/dorsal root ganglia (DRG)] for western blot analysis was collected on day 7.Results: The pharmacological blockade of TLR4 diminished mechanical (from ca. 40% to 16% that in the INTACT group) and thermal (from ca. 51% to 32% that in the INTACT group) hypersensitivity despite the enhanced activation of IBA-1-positive cells in DRG. Moreover, LPS-RSU changed the ratio between IL-18/IL-18BP and MMP-9/TIMP-1 in favour of the increase of antinociceptive factors IL-18BP (25%-spinal; 96%-DRG) and TIMP-1 (15%-spinal; 50%-DRG) and additionally led to an increased IL-6 (40%-spinal; 161%-DRG), which is known to have analgesic properties in neuropathy.Conclusions: Our results provide evidence that LPS-RSU influences pain through the expression of TLR4. TLR4 blockade has analgesic properties and restores the balance between nociceptive factors, which indicates its engagement in neuropathy development.

Granulocyte-Macrophage Colony Stimulating Factor As an Indirect Mediator of Nociceptor Activation and Pain

“…Furthermore, Shepherd et al (2018) showed that the angiotensin II receptor (AT2R) antagonist reduces neuropathic pain by blocking the downstream signalling of AT2R in infiltrating peripheral macrophages, as sensory neurons lack expression of this receptor. Blocking of macrophage activation using TLR antagonists (Jurga et al, 2018) and inhibitors of p38 MAPK/MMP9 (Hutchinson et al, 2008;Mika et al, 2007), PI3K and NF-kB (Popiolek-Barczyk et al, 2015) has analgesic effects in various models of neuropathic pain, consistent with our proposed mechanism of action.…”

Bidirectional effects of moxifloxacin on the pro‑inflammatory response in lipopolysaccharide‑stimulated mouse peritoneal macrophages

“…In the present study, LPS was utilized as an agent to induce a pro-inflammatory state. It was demonstrated that the expression of TLR4 and NF-κB, and the secretion of IL-6 and TNF-α was significantly induced by treatment with LPS, which was consistent with the LPS-induced pro-inflammatory states demonstrated in previous studies ( 38 , 39 ).…”

Toll-like receptor 4 agonist and antagonist lipopolysaccharides modify innate immune response in rat brain circumventricular organs

“…RS-LPS produced no significant effects on the NF-κB nuclear translocation in the CVOs. Studies have revealed that RS-LPS acts a TLR4 antagonist with analgesic properties in a rat neuropathic model, modulating the release of cytokines [42]. Nonetheless, our results suggest that the existing basal immune activation, evaluated through NF-κB nuclear translocation, in the CVOs was not diminished by the presence of RS-LPS.…”