Kappa opioid receptor agonists promote oligodendrocyte maturation, remyelination and functional recovery in preclinical mouse models

Abstract In multiple sclerosis (MS) the body’s own immune system attacks and destroys the protective myelin sheath surrounding axons leading to impaired saltatory conduction and a range of symptoms such as muscle weakness, fatigue, impaired motor function and paralysis. There is no cure for MS and current treatments target the immune system, however, none initiate myelin repair and enable functional recovery. In MS the failure of oligodendrocyte precursor cells (OPCs) to differentiate into mature myelinating oligodendrocytes is reported to be responsible for lack of repair leading to progressive functional decline. Activation of the kappa opioid receptor (KOR) has recently been shown to promote OPC differentiation onto mature oligodendrocytes (OL). In this study utilising primary cultures of mouse OPCs and high-throughput confocal microscopy techniques, we compareed the ability of KOR agonists to promote OPC differentiation into mature oligodendrocytes in vitro. Utilising two preclinical models of demyelination in C57BL/6J mice, we also showed KOR agonists promoted remyelination and functional recovery. In the experimental autoimmune encephalomyelitis (EAE) model, we found that nalfurafine and salvinorin A analogues, β-tetrahydropyran salvinorin B, ethoxymethyl ether salvinorin B, and Mesyl Sal B, effectively decreased disease severity (paralysis) in a KOR-dependent manner and led to a greater percentage recovery compared to the traditional KOR agonist U50,488. In the cuprizone-induced demyelination model, we showed that the KOR agonists nalfurafine and ethoxymethyl ether salvinorin B led to an increase in the number of mature oligodendrocytes, the number of myelinated axons and the myelin thickness in the corpus callosum. This provides evidence that KOR agonists are a promising target for the development of pharmacotherapies targeting repair and remyelination.