Dopaminergic Effect of Very Euphorigenic Opioids
The Monkey Mantra said:
What I'd be looking for if I were you is delta opioid receptor activity (DOR). I believe the DOR is more tied into the inhibition of the GABAergic activity which suppressed dopamine release. Morphine, one of the LEAST stimulating opioids IMO, is basically pure MOR. Stuff like levorphanol was always rather stimulating to me, and I've had friends who ate large doses of my prescription and had sleepless nights because of it.
My experience with delta agonist like SNC 80 has been one where tolerance seems anecdotally inhibited somewhat when combined with various mu agonists. I have not taken Kratom, but want to note that with plants, it is not always apparent which compounds are involved. For example with nicotine, we see much less of a pleasure response in the mesolimbic system from iv nicotine than from smoking a cigarette in smokers. This has been suggested to be from some of the harma alkaloids in tobacco that are MAO-B inhibitors (MAO-B is responsible for the catabolism of dopamine and phenethylamine, but not serotonin or norepinephrine.) So other components of kratom may explain the excitation that you are saying is associated with it.
By stimulant effect, are you talking about not being able to sleep when taking a dose of opiates? If so, drugs like morphine and codeine have this effect as well as drugs like heroin or oxycodone. It appears that initially, a dose large enough to get someone nice and high in an opiate naive person will do this across the board. This effect attenuates over time and completely disappears once dependency upon that drug is achieved. It is possible to use a drug that may hit different receptor splice variants and get this effect ephemerally.
Splice variant research has really made us rethink opioid receptors, and perhaps receptor theory in general. By splice variants, I am referring to homodimeric, heterodimeric as well as polymeric combinations of the different human opioid receptors, MOR, DOR, KOR and ORL (and possibly others like sigma-1). Recent data has putatively shown us that these play a normal physiologic role in the opiodergic system, and much of the receptor binding variations that occur from drugs such as heroin (which is not just converted to morphine before being active,) may account for some of the differences in drugs like 6-MAM and heroin when compared to morphine. But it does not appear to be all of the difference involved.
It is very obvious to most people who have sampled some of the more euphorigenic opioids like fentanyl, sufentanil, AMF, BHAMF, phenazocine, oxymorphone, N-phenethyl normorphine, N-phenethyl noroxymorphone, etc. that there are extreme differences in these opioids from say morphine, codeine, methadone or propoxyphene. Even on the scales used to arbitrarily categorize these differences (the ARCI-MBG Drug Liking Scale; ARCI-PCAG Sedation Scale; ARCI-ASSS Stimulation Scale; as well as the DQM and VAS Scale equivalents), that the differences do not appear to be a result of opiodergic differences alone.
All drugs of abuse putatively have an effect on the mesolimbic reward pathway (Ventral Tegmental Area [VTA] and the Nucleus Accumbens [NA]), and the dorsal Caudate Nucleus [DCP] ; some also affect the dopaminergic systems in the prefrontal cortex, but the common underlying event is an increase in extracellular dopamine in the NA. Opioids all seem to stimulate the VTA directly, which then connects to the NA; but the more euphorigenic opioids putatively affect the NA directly as well as indirectly through the VTA.
Using the example of fentanyl, phenazocine, N-phenethyl normorphine or some of the interesting propioanilides when compared to morphine, if you examine the three dimensional structure, it putatively has some characteristics like a stimulant of the amphetamine or 4-methylaminorex type molecule. Whether these molecules affect the DAT (Dopamine Transporter), the VMAT-2 (Vesicular Monoamine Transporter) or directly bind to D2 receptors in the NA has not been determined yet, but using a D2 selective antagonist like raclopride or eticlopride directly injected into the NA, fol owed by intraventricular the tritiated opioid (e.g., [H3]fentanyl) will help move research in that direction.
Some other future experiments are to use opiates that use parts of some stimulants of the cocaine type like tropane based cocaine analogues such as WIN 36,065-2 or WIN 35,428, CFT, RTI-55, RTI-121 (which also could possibly affect serotonin); or some novel arecoline derived analogues like (-)-methyl 1-methyl-4beta-(2-naphthyl)piperidine-3beta-carboxylate, which is mostly involved with the DAT only.
MobiusDick
