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Simple Summary  Recent evidence indicates that opioids can be active at a receptor that is abundantly expressed on innate immune cells as well as cancer cells: the receptor is termed toll-like receptor 4 (TLR4). TLR4 is increasingly recognised as playing key roles in tumour biology and anticancer defences. However, the issue of whether TLR4 mediates some of the effects of opioids on tumour growth and metastasis is entirely unknown. We review existing evidence, mechanisms, and functional consequences of the action of opioids at TLR4. This opens new avenues of research on the role of opioids in cancer.    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.

Interaction of Opioids with TLR4—Mechanisms and Ramifications