Bamboozle
Bluelighter
- Joined
- Oct 24, 2003
- Messages
- 64
I'm just going to use this thread as a means to post any information regarding how exogenous opioid use can be manipulated, for better or worse in the body. These are mostly just some random thoughts, facts and studies found regarding opiates and substances that may hopefully enhance euphoria. I am doing this a) Because it is quite interesting and may be useful and b) Because right now I am so very bored and have no means of transportation.
If you have ANY comments, suggestions, critisizims, personal notes, experiences or anything to add, please do. That's why I am posting this.
________________Notes;
Opiate receptors presynaptically inhibit transmission of excitatory pathways;
Acetylcholine, catecholamines, serotonin, and substance P.
Primary Opiate Receptors: mu, delta, kappa.
The brain's primary reward pathway is the mesolimbic dopamine system.
Neurons called dopaminergic because dopamine is manufactured, transported down the length of the neuron, for release into the synapses.
GABA normally plays a braking role on the dopaminergic cells.
Opiates and endogenous opioid neurotransmitters activate the presynaptic opioid receptors on GABA neurons.
This inhibits the release of GABA in the ventral tegmental area. Inhibiting GABA allows the dopaminergic neurons to fire more vigorously.
The release of extra dopamine in the nucleus accumbens is intensely pleasurable (no shit).
________________Stuff..;
Opiate receptor Mu is most prevalent in overall neuropharmacology
ACl & Serotonin are inhibited by Opiate receptors.
* S inhibitance due to dopamine ^ | or increases opioid effect?
Opiod euphoria is primarily caused by the Dopamine system
* hypothesized (medical) if other system exists it is not proven or observed currently.
GABA is inhibited , therefore DA neurons are more active.
* Further inhibition of GABA may increase Euphoria / duration of opioid?
* Find / investigate GABA inhibitors V.S morphine/opioids VIA medline.
Serotonin and Dopamine - mood /pleasure – Self regulate each other.
* Direct modulation / antagonization of each other, or co-incedental?
*Does inrease serotonin effect mood, pleasure or nasea w/ opioids?
________________studies;
Abstracts condensed (for relevance).
Right now I’m going to make a hypotheses that if a substance has the effect of raising analgesia (the absence of normal sensitivity to pain, typically, being in a semiconscious state) than chances are that its euphoric effect is also improved. For some strange reason the national library of medicine has few studies directly relating to increasing the euphoria of narcotics, they tend to focus more on the ‘legitimate medical uses’ of each drug. Strange I know.
5-HTP + Opioid
* To investigate serotonin.
Full studies available for reference on Medline:
Analgesic properties of a systemically-administered synthetic dipeptide of 5-hydroxytryptophan.
Synthetic peptides of 5-hydroxytryptophan (5-HTP), including N-acetyl-5-HTP-5-HTP amide (5-HTP-ACETYL-DP), specifically inhibit the binding of serotonin to serotonin binding protein. 5-HTP-ACETYL-DP also produces a long-lasting, opiate-sensitive analgesia following central, but not systemic administration.
Kappa opioid analgesia is dependent on serotonergic mechanisms.
The serotonergic dependence of mu and kappa opioid analgesia was compared in the mouse tail-flick and hot-plate assays using morphine and the selective kappa agonist, U-50, 488H, respectively. Depletion of serotonin with p-chlorophenylalanine resulted in a marked antagonism of U-50,488H analgesic potency in both assays
Both of these effects were dose-related and the latter was reversed by treatment with the serotonin precursor, 5-hydroxytryptophan. Several reputed serotonin antagonists (cyproheptadine, ketanserin and pirenperone) also antagonized U-50,488H analgesia. In contrast, the analgesic potency of morphine was only decreased slightly by p-chlorophenylalanine and reserpine, and not at all by the serotonin antagonists. Thus, kappa, but not mu, analgesia is strongly dependent upon serotonergic mechanisms in these assays. However 5-hydroxytryptophan did not enhance U-50,488H analgesia in nonpretreated mice or in mice made tolerant to U-50,488H. On this basis it appears that kappa opioid tolerance is not due to serotonergic hypofunction.
Antagonism of the analgesic effect of opioid and non-opioid agents by p-chlorophenylalanine (PCPA).
The ability of p-chlorophenylalanine (PCPA), an inhibitor of serotonin (5HT) biosynthesis to antagonize the antinociceptive effects of three classes of analgesics: opiates agonist (morphine), opiate agonist-antagonist (pentazocine) and non-steroid anti-inflammatory (aspirin and clonixin) were evaluated using the rat yeast paw test. The analgesic effect of equipotent doses of each of these drugs was abolished 48 h after PCPA (300 mg/kg i.p.) PCPA (150 mg/kg i.p.) reduced the relative potencies of morphine and aspirin to the same degree. The effect could not be attributed to a hyperalgesia or to an interaction with inflammatory mechanisms. PCPA did not alter the anti-edema activity of clonixin and it blocked morphine-induced increases in reaction times to pressure applied to the non-inflamed paw to the same extent as in the inflamed paw. The serotonin precursor 5-hydroxytryptophan (5HTP, 80 mg/kg i.p.) restored the antinociceptive activity of all four drugs. These results demonstrate serotonin can modulate sensitivity to analgesics with differing mechanisms of action.
Central action of narcotic analgesics. VII. The role of serotonin
The development of tolerance to morphine-induced motor activity of mice and rats, as well as the influence of drugs which alter the brain serotonergic functions on the development of morphine tolerance was studied.
Tolerance to morphine was induced by subcutaneous implantation of morphine-base pellets. After 72 h pellets were removed and 6 hr later motility was tested. Implantation of morphine pellets caused the development of tolerance to morphine-induced motor activity of mice and rats. Development of morphine tolerance was inhibited in mice and rats by p-chlorophenylalanine (pCPA) or reserpine, drugs which decrease content of brain serotonin.
5-hydroxytryptophan (5-HTP) inhibited the above effect of pCPA in mice, while tryptophan did not. Administration of 5-HTP, which protected serotonin stores against depleting action of reserpine decreased inhibiting action of reserpine on the development of morphine tolerance in rats. Although cyproheptadine and pizotifen did not alter the development of morphine tolerance in rats, nevertheless, it seems from these results that serotonin neurotransmission is of some importance in the development of tolerance to morphine.
Morphine analgesia and its modification by drugs altering serotonin (5-HT) and dopamine levels in the brain.
Morphine analgesia in mice was significantly potentiated by pretreatment with 5-hydroxytryptophan (5-HTP), especially with higher dose of morphine. Morphine analgesia was antagonised by reserpine. With l-dopa it was antogonised when the dose of morphine was minimal but with increased dosage of morphine, there was no significant effect.
Effect of narcotics on the uptake of serotonin precursors by the rat brain.
The extraction of 14C-tryptophan and 14C-hydroxytryptophan (5-HTP) from the blood to the brain was measured using an indicator dilution technique. Acute treatment with morphine caused a dose-related decrease in the extraction of tryptophan by the brain and a increase in that of 5-HTP.
In contrast to acute treatment with morphine, the extractions of tryptophan and 5-HTP were not significantly altered 48 hours after chronic treatment with morphine. The extraction of 5-HTP remained unchanged and that of tryptophan increased significantly 72 hours after chronic morphine treatment. these results suggest that an increase in the rate of central serotonin synthesis after acute treatment with morphine may be due to an increased uptake of 5-HTP from the blood to the brain while that after chronic treatment with morphine may be due to an increased uptake of tryptophan.
If anybody can get a hold of these abstracts please post them!
Eur J Pharmacol. 1973 Jun;22(3):339-43.
Decrease of tolerance development to morphine by 5-hydroxytryptophan and some related drugs. Contreras E, Tamayo L, Quijada L, Silva E.
Nature. 1970 Mar 21;225(238 ):1152-3.
Possible mechanism of action of morphine on brain.Eidelberg E, Schwartz AS.
Fed Proc. 1970 Jan-Feb;29(1):28-31.
Central neurohumoral systems involved with narcotic agonists and antagonists.Harris LS.
_____
Need nourishment- will be continued ..
Want to look at dopamine precursors, gaba inhibitors and enzyme-inducers.
(OTC / Supplemental) Also the nootropic angle; DMAE / vinpocetine.
If you have ANY comments, suggestions, critisizims, personal notes, experiences or anything to add, please do. That's why I am posting this.
________________Notes;
Opiate receptors presynaptically inhibit transmission of excitatory pathways;
Acetylcholine, catecholamines, serotonin, and substance P.
Primary Opiate Receptors: mu, delta, kappa.
The brain's primary reward pathway is the mesolimbic dopamine system.
Neurons called dopaminergic because dopamine is manufactured, transported down the length of the neuron, for release into the synapses.
GABA normally plays a braking role on the dopaminergic cells.
Opiates and endogenous opioid neurotransmitters activate the presynaptic opioid receptors on GABA neurons.
This inhibits the release of GABA in the ventral tegmental area. Inhibiting GABA allows the dopaminergic neurons to fire more vigorously.
The release of extra dopamine in the nucleus accumbens is intensely pleasurable (no shit).
________________Stuff..;
Opiate receptor Mu is most prevalent in overall neuropharmacology
ACl & Serotonin are inhibited by Opiate receptors.
* S inhibitance due to dopamine ^ | or increases opioid effect?
Opiod euphoria is primarily caused by the Dopamine system
* hypothesized (medical) if other system exists it is not proven or observed currently.
GABA is inhibited , therefore DA neurons are more active.
* Further inhibition of GABA may increase Euphoria / duration of opioid?
* Find / investigate GABA inhibitors V.S morphine/opioids VIA medline.
Serotonin and Dopamine - mood /pleasure – Self regulate each other.
* Direct modulation / antagonization of each other, or co-incedental?
*Does inrease serotonin effect mood, pleasure or nasea w/ opioids?
________________studies;
Abstracts condensed (for relevance).
Right now I’m going to make a hypotheses that if a substance has the effect of raising analgesia (the absence of normal sensitivity to pain, typically, being in a semiconscious state) than chances are that its euphoric effect is also improved. For some strange reason the national library of medicine has few studies directly relating to increasing the euphoria of narcotics, they tend to focus more on the ‘legitimate medical uses’ of each drug. Strange I know.
5-HTP + Opioid
* To investigate serotonin.
Full studies available for reference on Medline:
Analgesic properties of a systemically-administered synthetic dipeptide of 5-hydroxytryptophan.
Synthetic peptides of 5-hydroxytryptophan (5-HTP), including N-acetyl-5-HTP-5-HTP amide (5-HTP-ACETYL-DP), specifically inhibit the binding of serotonin to serotonin binding protein. 5-HTP-ACETYL-DP also produces a long-lasting, opiate-sensitive analgesia following central, but not systemic administration.
Kappa opioid analgesia is dependent on serotonergic mechanisms.
The serotonergic dependence of mu and kappa opioid analgesia was compared in the mouse tail-flick and hot-plate assays using morphine and the selective kappa agonist, U-50, 488H, respectively. Depletion of serotonin with p-chlorophenylalanine resulted in a marked antagonism of U-50,488H analgesic potency in both assays
Both of these effects were dose-related and the latter was reversed by treatment with the serotonin precursor, 5-hydroxytryptophan. Several reputed serotonin antagonists (cyproheptadine, ketanserin and pirenperone) also antagonized U-50,488H analgesia. In contrast, the analgesic potency of morphine was only decreased slightly by p-chlorophenylalanine and reserpine, and not at all by the serotonin antagonists. Thus, kappa, but not mu, analgesia is strongly dependent upon serotonergic mechanisms in these assays. However 5-hydroxytryptophan did not enhance U-50,488H analgesia in nonpretreated mice or in mice made tolerant to U-50,488H. On this basis it appears that kappa opioid tolerance is not due to serotonergic hypofunction.
Antagonism of the analgesic effect of opioid and non-opioid agents by p-chlorophenylalanine (PCPA).
The ability of p-chlorophenylalanine (PCPA), an inhibitor of serotonin (5HT) biosynthesis to antagonize the antinociceptive effects of three classes of analgesics: opiates agonist (morphine), opiate agonist-antagonist (pentazocine) and non-steroid anti-inflammatory (aspirin and clonixin) were evaluated using the rat yeast paw test. The analgesic effect of equipotent doses of each of these drugs was abolished 48 h after PCPA (300 mg/kg i.p.) PCPA (150 mg/kg i.p.) reduced the relative potencies of morphine and aspirin to the same degree. The effect could not be attributed to a hyperalgesia or to an interaction with inflammatory mechanisms. PCPA did not alter the anti-edema activity of clonixin and it blocked morphine-induced increases in reaction times to pressure applied to the non-inflamed paw to the same extent as in the inflamed paw. The serotonin precursor 5-hydroxytryptophan (5HTP, 80 mg/kg i.p.) restored the antinociceptive activity of all four drugs. These results demonstrate serotonin can modulate sensitivity to analgesics with differing mechanisms of action.
Central action of narcotic analgesics. VII. The role of serotonin
The development of tolerance to morphine-induced motor activity of mice and rats, as well as the influence of drugs which alter the brain serotonergic functions on the development of morphine tolerance was studied.
Tolerance to morphine was induced by subcutaneous implantation of morphine-base pellets. After 72 h pellets were removed and 6 hr later motility was tested. Implantation of morphine pellets caused the development of tolerance to morphine-induced motor activity of mice and rats. Development of morphine tolerance was inhibited in mice and rats by p-chlorophenylalanine (pCPA) or reserpine, drugs which decrease content of brain serotonin.
5-hydroxytryptophan (5-HTP) inhibited the above effect of pCPA in mice, while tryptophan did not. Administration of 5-HTP, which protected serotonin stores against depleting action of reserpine decreased inhibiting action of reserpine on the development of morphine tolerance in rats. Although cyproheptadine and pizotifen did not alter the development of morphine tolerance in rats, nevertheless, it seems from these results that serotonin neurotransmission is of some importance in the development of tolerance to morphine.
Morphine analgesia and its modification by drugs altering serotonin (5-HT) and dopamine levels in the brain.
Morphine analgesia in mice was significantly potentiated by pretreatment with 5-hydroxytryptophan (5-HTP), especially with higher dose of morphine. Morphine analgesia was antagonised by reserpine. With l-dopa it was antogonised when the dose of morphine was minimal but with increased dosage of morphine, there was no significant effect.
Effect of narcotics on the uptake of serotonin precursors by the rat brain.
The extraction of 14C-tryptophan and 14C-hydroxytryptophan (5-HTP) from the blood to the brain was measured using an indicator dilution technique. Acute treatment with morphine caused a dose-related decrease in the extraction of tryptophan by the brain and a increase in that of 5-HTP.
In contrast to acute treatment with morphine, the extractions of tryptophan and 5-HTP were not significantly altered 48 hours after chronic treatment with morphine. The extraction of 5-HTP remained unchanged and that of tryptophan increased significantly 72 hours after chronic morphine treatment. these results suggest that an increase in the rate of central serotonin synthesis after acute treatment with morphine may be due to an increased uptake of 5-HTP from the blood to the brain while that after chronic treatment with morphine may be due to an increased uptake of tryptophan.
If anybody can get a hold of these abstracts please post them!
Eur J Pharmacol. 1973 Jun;22(3):339-43.
Decrease of tolerance development to morphine by 5-hydroxytryptophan and some related drugs. Contreras E, Tamayo L, Quijada L, Silva E.
Nature. 1970 Mar 21;225(238 ):1152-3.
Possible mechanism of action of morphine on brain.Eidelberg E, Schwartz AS.
Fed Proc. 1970 Jan-Feb;29(1):28-31.
Central neurohumoral systems involved with narcotic agonists and antagonists.Harris LS.
_____
Need nourishment- will be continued ..
Want to look at dopamine precursors, gaba inhibitors and enzyme-inducers.
(OTC / Supplemental) Also the nootropic angle; DMAE / vinpocetine.