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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  • How to stimulate the reception of an opioid channel can be good for EAE / MS ?!

    Paralleling with a "joke" I know of a famous rock star who abused the use of opioids and had a first event classified as CIS…

    And if so same exercise would make MS worse, as it has the means of action reward similar to LDN, and is not what we see in practice, people still manage to do better work and have fewer relapses, etc. …

  • Another selective KOR agonist salvinorin produces state of dissociation with hallucinations of EXTREME intensity accompanied by complete ego loss, extreme time dilation, dysphoria and horror in humans. It's like you've being tied to the rope and dragged all the way through out the hell and back for the infinite number of iterations for the whole eternity.
    I don't know how this kind of compounds could be of use in humans and pretty sure mice are shocked by such kind of experience. )

    • well looks like the same is true for any other known KOR agonist, so I doubt this pathway is of any use in humans even if it would be found to be beneficial for MS. unless there is a way to block psychological effects related to kappa receptor activation via different pathway

    • I suspect you are right, if this hadn't been in a Nature journal I would not have paid much attention, I suspect the mice were out of their heads but havent researched the dose so may not be.

      Today a paper on cannabis compound likewise says it inhibits disease. The dose used would have had the animals essentially out of it for hours, many degrees below their normal temperature maybe having fits. A total waste of time and not ethical use of animals in my opinion. Yes it was ethically approved by the US institution what does this say?

    • By the way, idea for the registry lookup. to my knowledge most potent KOR antagonist known is buprenorphine. And I suspect there should be some MSers on long term opioid replacement therapy, would ones on methadone do better then on buprenorphine in MS sense.

  • my pet python, which is a distinguished scientist in the filed of pythonian psychedelic research, conducted a series of semi accurate experiments involving bioassaying of different compounds on his fellow hominide and report the following:
    – psychological effects of inhaled salvia extract almost completely blocked by premedicating with minuscule (~200ug) dose of buprenorphine
    – but only partially blocked by the standard oral dose of naltrexone, which is in line with naltrexone’s low affinity for KORs
    – surprisingly pretreatment with atypical antipsychotic quetiapine makes experience even more weird and awful, but interesting thing is that visuals are considerably reduced, but mindspace is still completely turned inside out in a very bad way and anxiety/disphoria are barely bearable
    – natural tolerance develops very quickly despite the fact that it is found salvinorin-a tend not to internalise KORs unlike U50488. but again tolerance is incomplete, e.g. there are still noticeable longterm memory readout and body control impairment during the experience though to a much lesser degree, and anxiety/dysphoric effects are least affected by this tolerance build up. which probably would be a serious side effect if unresponsible to other medications.
    To resume his opinion has changed. Now he think that in case this class of compounds would be found really useful, than it is possible to build up ones tolerance to it’s cognitive effects to the point enough for one to function and appear normally, at least in a manner like typical pot-heads could train themselves how to appear and operate normally from within distorted and bent headspace being 24/7 under the THC influence. Possibly oral route of administration with careful dose escalation would work, but only if depressive and dysphoric effects can be managed somehow.
    Unfortunately he could not lay his hands (do pythons have a hands??) on U50488, but he thinks that information on properties of this absolutely legal compound derived from the plant kingdom could be useful somehow. (he is not advocating the self administration of any psychoactives though).

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