Neuropeptide Kyotorphin Impacts on Lipopolysaccharide-Induced Glucocorticoid-Mediated Inflammatory Response. A Molecular Link to Nociception, Neuroprotection, and Anti-Inflammatory Action.

Abstract

Neuropeptide kyotorphin (KTP) is a potent analgesic if administered directly into the brain. In contrast, KTP-amide (KTP-NH) is analgesic, neuroprotective, and anti-inflammatory following systemic administration, albeit its mechanism of action is unknown. The aim of this study was to shed light on the mechanism of action of KTP-NHat the molecular level. KTP-NHdoes not inhibit the enkephalinases angiotensin-converting-enzyme and dipeptidyl-peptidase 3. Intravital microscopy showed that KTP-NHdecreased the number of rolling leukocytes in a mouse model of inflammation induced by lipopolysaccharide (LPS). Pretreatment with metyrapone abrogated the action of KTP-NH. Interestingly, stimulating rolling leukocytes using CXCL-1 is also counteracted by the KTP-NH, but this effect is not abrogated by metyrapone. We conclude that KTP-NHhas dual action: a glucocorticoid-mediated action, which is dominant in the full-fledged LPS-induced inflammation model, and a glucocorticoid-independent mechanism, which is predominant in models in which leukocyte rolling is stimulated but inflammation is not totally developed.