Liquid Biopsy-Based Biomarkers of Inflammatory Nociception Identified in Male Rats

Abstract

Physicians are challenged in treating pain patients due to the lack of quantifiable, objective methods of measuring pain in the clinic; pain sensation is multifaceted and subjective to each individual. There is a critical need for point-of-care quantification of accessible biomarkers to provide objective analyses beyond the subjective pain scales currently employed in clinical care settings. In the present study, we employed an animal model to test the hypothesis that circulating regulators of the inflammatory response directly associate with an objective behavioral response to inflammatory pain. Upon induction of localized paw inflammation, we measured the systemic protein expression of cytokines, and activity levels of matrix metalloproteinases (MMPs) that are known to participate in the inflammatory response at the site of injury and investigated their relationship to the behavioral response across a 24 h period. Intraplantar injection with 1% λ-carrageenan induced a significant increase in paw thickness across this timespan with maximal effects observed at the 8 h timepoint when locomotor activity was also impaired. Expression of the chemokines C-X-C motif chemokine ligand 1 (CXCL1) and C-C motif chemokine ligand 2 (CCL2) positively correlated with paw inflammation and negatively correlated with locomotor activity at 8 h. The ratio of MMP9 to MMP2 activity negatively correlated with paw inflammation at the 8 h timepoint. We postulate that the CXCL1 and CCL2 as well as the ratio of MMP9 to MMP2 activity may serve as predictive biomarkers for the timecourse of inflammation-associated locomotor impairment. These data define opportunities for the future development of a point-of-care device to objectively quantify biomarkers for inflammatory pain states.