Interaction of Opioids with TLR4—Mechanisms and Ramifications

Abstract

The innate immune receptor toll-like receptor 4 (TLR4) is known as a sensor for the gram-negative bacterial cell wall component lipopolysaccharide (LPS). TLR4 activation leads to a strong pro-inflammatory response in macrophages; however, it is also recognised to play a key role in cancer. Recent studies of the opioid receptor (OR)-independent actions of opioids have identified that TLR4 can respond to opioids. Opioids are reported to weakly activate TLR4, but to significantly inhibit LPS-induced TLR4 activation. The action of opioids at TLR4 is suggested to be non-stereoselective, this is because OR-inactive (+)-isomers of opioids have been shown to activate or to inhibit TLR4 signalling, although there is some controversy in the literature. While some opioids can bind to the lipopolysaccharide (LPS)-binding cleft of the Myeloid Differentiation factor 2 (MD-2) co-receptor, pharmacological characterisation of the inhibition of opioids on LPS activation of TLR4 indicates a noncompetitive mechanism. In addition to a direct interaction at the receptor, opioids affect NF-κB activation downstream of both TLR4 and opioid receptors and modulate TLR4 expression, leading to a range of in vivo outcomes. Here, we review the literature reporting the activity of opioids at TLR4, its proposed mechanism(s), and the complex functional consequences of this interaction.

Lactobacillus plantarum RS-09 Induces M1-Type Macrophage Immunity Against Salmonella Typhimurium Challenge via the TLR2/NF-κB Signalling Pathway

“…Salmonella is an intracellular pathogen that elicits an inflammatory response once taken up by intestinal epithelial cells. This action can activate innate immune cells, one pathway being through the bacterial component recognized by TLRs, and results in the release of cytokines, such as IFN-γ, into circulation ( Benoun et al, 2018 ; Gabr et al, 2021 ). M1 Macrophages can be stimulated by IFN-γ after intracellular pathogen challenge ( Ramarathinam et al, 1993 ).…”

Morphine-3-Glucuronide, Physiology and Behavior

“…One interesting hypothesis suggests the existence of an alternative non-opioid receptor that could mediate M3G effects ( Table 3 ). More precisely, in silico studies have indicated that M3G is able to bind the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 (MD-2) complex through an interaction with the lipopolysaccharide (LPS) binding pocket of MD-2 ( Hutchinson et al, 2010 ; Lewis et al, 2010 ; Grace et al, 2014 ) (for a review of opioid interactions with TLR4, see Gabr et al, 2021 ). TLR4 downstream signaling involves the activation of 3 parallel intracellular pathways: the NF-κB, the MAPK and the PI3K/AKT pathway.…”

Effect of Opioids on Survival in Patients with Cancer

“…Opioid-immune effects can be due to direct actions of opioids on immune cells (via MOR and Toll-like receptor 4; TLR4) or mediated centrally (via the sympathetic nervous system and hypothalamic pituitary adrenal axis) ( Figure 1 ) [ 15 , 22 ]. Toll-like receptor 4 (TLR4) is an innate immune receptor which is activated by lipopolysaccharide (LPS), from the cell wall of Gram-negative bacteria [ 23 , 24 ]. This results in a pro-inflammatory response, which can be modulated by opioids [ 24 ].…”

“…Toll-like receptor 4 (TLR4) is an innate immune receptor which is activated by lipopolysaccharide (LPS), from the cell wall of Gram-negative bacteria [ 23 , 24 ]. This results in a pro-inflammatory response, which can be modulated by opioids [ 24 ]. The effect of opioids via TLR4 varies dependent on the cell type and activating stimulus.…”