Opioid receptor stimulation as a means to promote remyelination? Junk the Junk

Du C, Duan Y, Wei W, Cai Y, Chai H, Lv J, Du X, Zhu J, Xie X. Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination. Nat Commun. 2016 Apr 4;7:11120. doi: 10.1038/ncomms11120

Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of mu, delta and kappa opioid receptors MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches.

This study says activating opioid receptor inhibits EAE and implicates that this is via augmenation of oligodendrocyte function. We are not advocating going on an opiate binge. 

Low Dose Naltrexone is a opioid receptor antagonist. At typical dosages, LDN significantly blocks activity at mu- and delta-opioid receptors as well as (to a lesser extent) kappa-opioid receptors. 

Does it augment MS...doubt it.

In this study they target kappa opioid receptors and activating this is reported to inhibit EAE. The study stays that there is no effect on immune function yet activating kappa opioid receptor (with U50488) wipes on disease (although there is no dose response Figure1h) which must be associated with a reduction of immune activity and there is less infiltration.  Are the mice whacked out and stressed?

This effect was not at the level of the T cell based on T cell transfer experiments, but it is suggested to be due to an effect on remyelination but in the scenario above, you would expect damage to develop before repair can be initiated but the lines immediately split, so I am not sure that the idea is consistent with that piece of data. 

I am also not sure what EAE scores 1-5 means, as it doesn't seem to say in the paper or give a reference (Maybe I missed it. Hopefully it is not a 15 point scale.....Who reviews these papers????. As this is open access you can read).

But there is model of  myelination and in this study lack of opioid receptor blocks remyelination, so again maybe not a good advert for LDN, if this study is translatable. 

What expresses these receptors? They are weakly expressed according to Brain RNAseq by OPC and oligodendrocytes
              Expression of Opioid recepotors Brain RNAseq

So another remyelinating agent perhaps, we have had cannabinoids what next speed and coke?

Already been done, they made EAE worse;-) (click)

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