Targeting kappa opioid receptors to treat MS?

Targeting kappa opioid receptors to treat MS?

Multiple sclerosis (MS) is a predominantly T-cell-mediated autoimmune disorder that results in inflammatory damage to the central nervous system (CNS) and causes disability in young adults. The pathogenesis of MS is characterized by a cascade of pathological events, involving the activation of the immune system, infiltration of lymphocytes, activation of microglia, focal inflammatory demyelination and axonal damage. CD4+ T cells, especially the Th17 and Th1 subgroups, have been suggested to cause the early initiation of the disease.

All the currently available treatments for MS target the immune system with mechanisms of action including general immunosuppression/immunomodulation, such as beta-interferons, glatiramer acetate, mitoxantrone, teriflunomide, fingolimod and dimethyl fumerate, and blockade of immune cell infiltration into the CNS, such as natalizumab. Although effective in reducing the relapse rate and the formation of new lesions, these drugs, however, have very limited effects in preventing the progression of disability. Promoting oligodendrocyte progenitor cell (OPC) differentiation, remyelination and subsequent functional recovery of the neurons have been proposed to be the new direction of MS therapy.

The endogenous opioid system has been suggested to play a role in the pathogenesis of MS. In a Theiler’s murine encephalomyelitis virus model of MS, mRNA levels of all the three opioid receptors, that is, the mu, delta and kappa opioid receptors (MOR, DOR and KOR), were significantly decreased in the spinal cord. The loss of opioid receptors might partially explain the central neuropathic pain commonly observed in the MS patients.

Pregnant women have been reported to express higher levels of endogenous opioids. Pregnant MS patients experience remission of the disease and have fewer relapses. However, 3 months after delivery, these women show a marked increase in relapse rate, in contrast to the decrease in endogenous opioid levels.

A pilot clinical study showed that met-enkephalin given intrathecally exerted beneficial effects on 13 patients with chronic severe progressive MS, indicating that activating the opioid receptors might be beneficial. However, several small-scale clinical studies showed that low-dose naltrexone (LDN), a non-selective opioid receptor antagonist, also had protective effects on MS patients. Although the exact mechanism remains unclear, LDN may block opioid receptors intermittently and thus promote the expression of opioid peptides and receptors.

The endogenous opioid responses are mainly mediated by MOR, DOR and KOR, all of which are G-protein-coupled receptors. The previous studies indicate the involvement of opioid system in MS without knowing the exact receptor and mechanism.

Researchers studied the experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS, in MOR, DOR or KOR knockout mice, and find genetic deletion of KOR induces a significantly severer phenotype of EAE. KOR does not affect T-cell differentiation and function.

Instead, it is critically involved in the differentiation of OPC towards myelinating oligodendrocytes (OLs). Activating KOR promotes OPC differentiation and remyelination, whereas KOR knockout prevents agonist-mediated beneficial effects.

The study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches.