Does kappa opioid agonism mediate mu opioid-agonist tolerance ?

[copium7777]

The reason I ask is obvious. Ibogaine is well known for totally "resetting " opioid tolerance, and is a kappa opioid agonist, with some similar subjective effects to salvia, which contains the kappa opioid agonists salvinorin a.
However ibogaine is known to have negative effects in the heart and as far as I know salvia isnt (although I suppose it hasn't been studied enough to say for sure ).

Also it seems kappa opioid agonists have some analgesic effect on their own even though they are dissociative and dysphoric rather than euphoric like mu agonists.

The reason I'm interested is bc I'm a chronic pain patient. A drug that could reset opioid tolerance could really be useful as one of the main problems with opioid therapy for chronic pain is that it causes dependence and loses efficacy fast at moderate doses.

So obviously unlike someone who has addiction problems that are devastating but otherwise is physically healthy the cost benefit with iboga heart side effects is not worth it if my use wouldn't be to "turn my life around " but merely to periodically reset opioid receptors.

 

[copium7777]

@dopamimetic

 

[copium7777]

@sekio

 

[sekio]

if kappa agonism stopped/reduced tolerance we would see a lot more pentazocine etc. used as narcotics, or we would see salvia "clinics", unfortunately the effects of kappa agonism are generally reported to be unpleasant and don't have major effects on opioid tolerance at all

 

[copium7777]

unfortunately the effects of kappa agonism are generally reported to be unpleasant and don't have major effects on opioid tolerance at all

Huh, well there are some reports of a kor agonist from Japan helping w mor agonist tolerance. But also even if not helping with tolerance, it seems kor agonists can both be analgesic on their own and help with "addiction" and suppress cravings...

The role of κ-opioid receptor activation in mediating antinociception and addiction - Acta Pharmacologica Sinica

The κ-opioid receptor (KOR), a member of the opioid receptor family, is widely expressed in the central nervous system and peripheral tissues. Substantial evidence has shown that activation of KOR by agonists and endogenous opioid peptides in vivo may produce a strong analgesic effect that is...

www.nature.com

 

[Allylbenzene]

if kappa agonism stopped/reduced tolerance we would see a lot more pentazocine etc. used as narcotics, or we would see salvia "clinics", unfortunately the effects of kappa agonism are generally reported to be unpleasant and don't have major effects on opioid tolerance at all

The beneficial effects of kappa agonism occur downstream and involve D2 dopamine receptors.
mu + kappa agonism is more sustainable than mu alone.

Kappa stimulation feels like stress and probably painful. Cortisol, the stress hormone, releases dynorphin (can be thought of as the opposite of endorphin) which agonizes the Kappa Opioid receptor. Kappa Opioid receptors do many things, but the biggest is to inhibit glutamate in dopaminergic neurons. This would cause the stress, fear, dysphoria, whatever you want to call it.
So I'm not looking forwards to taking high dose menthol. Kappa Opioid stimulation is probably what makes Salvia scary. If Salvinorin A only agonized D2, it would be less potent but considerably more enjoyable.

Perhaps adding a Mu opioid agonist (possibly magnesium as well) would curb most of the effects of Kappa agonism? In fact, adding the mu opioid agonist would increase the hallucinogenic potential. Opioids are quite hallucinogenic in SWIM's opinion, due to all that dopamine.
...
I bet the dopamine inhibition from Kappa opioid agonism would cancel out with the dopamine release from mu opioid agonism, leaving just the increase in D2 from Kappa opioid agonism. It's a long shot, but hey, someone should try this!
Erowid could have combinations like this already documented.
Perhaps adding in lemon oil would be a good idea too. Kappa opioid stimulation might mess with the amygdala, in which case adding oxytocin should reduce any fear-based feelings.