Purpose: To investigate the potential interplay between opioid analgesia and tumour metastasis through modulation of μ opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. Experimental design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement pre-operatively and at 3, 6 and 24 h after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. AlphascreenTM cyclic AMP (cAMP) assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue™ hTLR4 were utilised to measure TLR4 activation. Circulating matrix metalloprotease (MMP) and Tissue Inhibitor of Matrix Protease (TIMP) activities were assessed by gelatin zymography and reverse zymography, respectively. Results: Post-operative plasma samples displayed the ability to activate MOR and to inhibit LPS-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was neither correlated to opioid administration nor to MOR activation potential. Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point.
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