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neurochemical systems contributing to Kratom's analgesic effect

leungkachong

leungkachong

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Luckily, I will have a chance to try something like this experimentally (PM for preliminary protocol if your interested), but I thought I'd ask for some input.

Now, it has been shown that certain alkaloids from Mitragyna speciosa provide antinociceptive/analgesic effects independant from opioid-receptor agonism (administration of naloxone did not ablate pain relief for specific alkaloids and such). I also believe it has also been shown that there is some post-synaptic noradrenergic stimulation (a2-adrenoceptor), and postulated that it can provide 5-HT2A blockade (since there was a supression of the 5-HT2A mediated head-twitch in rats from 5-MeO-DMT). What would you postulate the cause this secondary analgesic effect is?
 
Amitriptyline and the like are antidepressants often passed off by doctors as analgesics. Na+ and Ca2+ channels are thought to play an important role in pain trafficking. If these channels can be blocked then this leads to anagesia via a differing mechanism to opies that work differently. This is in the same domain as nicotinic agonists and perhaps other receptor groups subtypes etc, that can also block pain signals. They are also regarded as neuroprotective agents that may be useful in treating parkinsonism and alzheimer disease. Aspirin and Cortisone both inhibit formation of prostaglandins albeit by very dissimilar mechanisms. However I am not aware of how this is of value in pain management although it does lower inflamation.

In summary it has something to do with slowing/blocking the electrochemical channels that are involved in pain processing signals. Metaphorically this could be compared to the application of ice to an area of inflamation. At a different level, by making a patient less depressed they become less concerned with their physiology and thus become less aware of nervous signaling for pain. Consider the nervous system as a sort of highway where the vehicles are signalling differing messages. If there are vehicles coding for positive thoughts this may dilute or block the vehicles that code for negative things such as chronic pain. Although pain signaling is essential for lessening physical damage. Chronic pain sufferers may be getting pain messages triggered for 'no reason'.
 
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leungkachong said:
Luckily, I will have a chance to try something like this experimentally (PM for preliminary protocol if your interested), but I thought I'd ask for some input.

Now, it has been shown that certain alkaloids from Mitragyna speciosa provide antinociceptive/analgesic effects independant from opioid-receptor agonism (administration of naloxone did not ablate pain relief for specific alkaloids and such). I also believe it has also been shown that there is some post-synaptic noradrenergic stimulation (a2-adrenoceptor), and postulated that it can provide 5-HT2A blockade (since there was a supression of the 5-HT2A mediated head-twitch in rats from 5-MeO-DMT). What would you postulate the cause this secondary analgesic effect is?
Click to expand...


So I assume the naloxone insensitivity is unpublished? Because it is rather at ends with research, or are we talking about not mitragynine?

This is were I get confused, mitragynine has allready been shown once or twice to be completely depended on opioid receptor activation, (mu/delta). If you're talking about non-mitragynine, then research on mitragynine is of no consequence.

Meanwhile, supression of 5-MeO-DMT head-twitch is a classical Mu mediated response.

Can you fill us in with the details man? either the unplublished study, or the reference to it, or something?

(p.s great to see you back!)
 
autoreceptors

I also believe it has also been shown that there is some post-synaptic noradrenergic stimulation (a2-adrenoceptor),

Is it saying that mitragynine is an alpha-2 antagonist? That would make sense in explaining the initial stimulation that's felt with kratom, as it effectivly prevents NA from producing any negative feedback (on NA release) by stimulating the alpha-2 autoreceptor.

Considering that it's structure and configuration isn't that far from that of yohimbine, and yohimbine's stimulant effects are brought about by being an alpha-2 antagonist, it shouldn't be too surprising to find that they have something in common. The stimulant effects from kratom are much smoother (less anxiety) than yohimbine, but I suppose that's due to the mu/delta agonist activity (I've found that classic mu agonist opiates are very good anxiolytics!)
 
If it is an alpha-2 antagonist then it could throw someone into deeper opiate withdrawal theoretically. Clonidine, the blood pressure drug used to calm down a lot of withdrawal symptoms, is an alpha-2 agonist. Basically it calms down the part of the brain that is stimulated during withdrawal.
 
Not if it's also acting as an agonist at the mu receptors. If the mu receptors are being stimulated by an agonist, the alpha-2 antagonism isn't going to cause withdrawl, as it's not a mu antagonist. The excess of NA floating around during is due to the lack of mu agonist, not the cause of it
 
Still... I don't think alpha-2 antagonism is going to either explain antinociceptive or euphoriant properties...
 
Yes, but mitragynine is also a (weak) mu agonist, and that effect comes to predominate after 45-60 mins. I don't know whether weak means 90% of morphine's activity, or if it means only a small fraction of morphine's activity (from subjective effects, it can produce a fairly good copy of the effects of eating opium, so I'd tend towards the former figure); so the antinociceptive and euphoriant properties, are mostly a product of mu agonist activity.
 
Um... Yeah, but OP:
Now, it has been shown that certain alkaloids from Mitragyna speciosa provide antinociceptive/analgesic effects independant from opioid-receptor agonism (administration of naloxone did not ablate pain relief for specific alkaloids and such). I also believe it has also been shown that there is some post-synaptic noradrenergic stimulation (a2-adrenoceptor), and postulated that it can provide 5-HT2A blockade (since there was a supression of the 5-HT2A mediated head-twitch in rats from 5-MeO-DMT). What would you postulate the cause this secondary analgesic effect is?
Click to expand...
 
Well, the only other receptor that mitragynine has any effect on is the delta opiate receptor, but I'm not too hot on the effects it has in terms of psychopharmacology, unless it is one of the minor components of kratom that's responsible for it. Other than that, I'm at a bit of a loss to explain how it works
 
The only receptor? Whats your reference for that? And according to this, it's more mu than it is delta.
 
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