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Mechanism of psychostimulant analgesia

negrogesic

negrogesic

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I've noticed that amphetamine, methylphenidate and cocaine exhibit some analgesic properties, though by which mechanism, I am not entirely sure. On a number of occasions, methylphenidate, pemoline and to a lesser extent amphetamine have reversed headaches, and appears to temporarily reduce muscle pain. It seems as though this effect is truly analgesia, and does not have much to do with "improved outlook" (it may be important to add that I don't particularly enjoy stimulants, so i don't think this has much to do with "euphoria").

The issue is that there seems to be a rebound effect, when physical pain becomes intensified as the drug wears off (this was not the case with pemoline, not sure about 4-MAR, i have not had it enough times to accurately say).

In the article below, they mentioned that the phenylethylamine induced analgesia was reversed by naloxone:

http://www.ncbi.nlm.nih.gov/pubmed/6233440

In this article, they focus on norepinephrine as the antinociceptive agent (but acknowledge a possible role of endogenous opioid peptides)

http://www.journalarchive.jst.go.jp...ssue=2&startpage=263&lang=en&from=jnlabstract

Also, what role does serotonin play in analgesia?
 
I always thought it had to do with the fight or flight response triggering endogenous opiod release. Also massive dopamine release surely has anagesic proerties and its no coincidence that speedballs increase opiates analgesia.
 
I don't think so; it isn't antagonized by naloxone (tell me if I'm remembering wrong, though!)
 
I don't think they meant the drugs were directly antagonized by naloxone, but rather the analgesic effects were; yet i thought it was strange as well.

OHPEA (50 mg/kg), amphetamine (0.5-8 mg/kg) or PEA (50 mg/kg) produced an analgesic effect in the absence of MAO inhibitor, and the analgesia was reversed by naloxone (5 mg/kg)
Click to expand...
 
oh it is antagonised. Werd. I'm surprised that PEA on it's own, without the MAOI is an analgesic.

I wonder if it might work for recovering alcoholics, or perhaps make alcohol more euphoric.
 
I think that the opioid potentiating effect of dexamphetamine and methylphenidate is due to increases in perisynaptic noradrenaline (and to a lesser extent dopamine). This is similar to how the non-opioid enantiomer of tramadol, which is a noradrenaline reuptake inhibitor, works to increase the overall analgesia. The selective adrenergic tricyclic desipramine has the same effects. As for the specific effects of pemoline, I have no idea. Alas, it is no longer available, period, so I doubt I'll ever get to try it. I would estimate that it is simply an extra long-acting DA/NA reuptake inhibitor.
 
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Without spending too much time thinking about it or giving it a cursory google once over, I believe I recall reading something about stimulant drugs interfering with the transmission of pain signals in the nerve gates of the spinal cord. Pretty sure I pulled that out of a post by F&B.
 
Riemann Zeta said:
I think that the opioid potentiating effect of dexamphetamine and methylphenidate is due to increases in perisynaptic noradrenaline (and to a lesser extent dopamine). This is similar to how the non-opioid enantiomer of tramadol, which is a noradrenaline reuptake inhibitor, works to increase the overall analgesia. The selective adrenergic tricyclic desipramine has the same effects. As for the specific effects of pemoline, I have no idea. Alas, it is no longer available, period, so I doubt I'll ever get to try it. I would estimate that it is simply an extra long-acting DA/NA reuptake inhibitor.
Click to expand...

Yeah, but if the effect is antagonized by naloxone, that certainly seems to imply a endorphinergic mechanism.
 
At the conclusion of the second article, they mention:

It has been demonstrated that antinociceptive action by PEA derivatives may involve endogenous serotonin and endogenous
opioid peptides (5). Besides these mechanisms, the above findings in the present study suggests the following: PEA derivatives may induce the release of norepinephrine in the CNS, and then the released norepinephrine
may also produce an antinociception.
Click to expand...

I'm still unsure which of these actions is the principle cause of analgesia in stimulants. Perhaps the norepinephrine is potentiating the peptide effect, but i don't know what role serotonin plays.

So they are measuring antagonism by tail-flick, right?
 
however they measured the pain initially.

originally there was an effect, then there wasn't.
 
I don't know why i didn't see this earlier; only a few months after the "amphetamine reversed by naloxone" article, the following was published:

The intrinsic analgesic properties of amphetamine were studied in rats. Subcutaneous injection of amphetamine exerted an additive effect on morphine-induced analgesia in the hot-plate test. Amphetamine itself showed intrinsic analgesic activity in a dose-dependent manner. Administration of naloxone failed to affect the analgesia induced by amphetamine. However, injection of haloperidol totally suppressed the amphetamine-induced change in pain response latency. Both naloxone and haloperidol failed to affect the pain threshold when injected alone, but inhibited morphine-induced analgesia. It is concluded that amphetamine possesses intrinsic analgesic properties which involve catecholamine but not opioid transmission in the brain.

PMID: 6468501

http://www.ncbi.nlm.nih.gov/pubmed/..._DiscoveryPanel.Pubmed_Discovery_RA&linkpos=4
Click to expand...

So then it is just about norepinephrine? This is why I asked about naloxone and the tail-flick, because it seems strange. It appears as though some people got pissed off by the concept of naloxone reversing amphetamine, and made a response disproving it?
 
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If it's being reversed by a D2 antagonist, I don't think so. There are obviously other DA subtypes. I don't know much about this area, but AFAIK Amphetamine causes the release of dopamine in general, and the various receptor subtypes benefit from higher levels in the synapse.

Or is amphetamines euphoria resulting from increased dopamine at D2 receptors?
 
just a thought, you may want to examine MDxx and analgesia. I remember reading a couple papers about that. I'm not sure if they posited a mechanism for it or not or just measured it compared to a control (sobriety probably).

Also, you may want to consider psychological mechanisms not just strictly physiological. Experiencing pain (which is NECESSARILY a subjective experience) is drastically affected by the psychological state and environmental context the organism is realized in.
 
One thing that I find truly bizarre is the fact that LSD can produce opioid-sparing analgesia (for weeks after the trip) in cancer patients. This one can't be explained solely by a decrease in noradrenaline uptake. Stimulants like methylphenidate and the more stimulating tricyclics (specifically desipramine, protripyline and amineptine) seem to only be effective in producing additive analgesia during the acute effects of the drug.
 
Cocaine's analgesic effect is difficult to assess because it has a powerful local anesthetic effect due to blockade of sodium channels, whereas it's rewarding effect is due to blockade of monoamine transporters. Other psychostimulants do not have the local anesthetic effect of cocaine, so any analgesia produced by those substances must be due to monoaminergic actions.
 
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