Limpet_Chicken
Bluelighter
Seeing as how NMDA antagonism results in a reduction of tolerance/dependence on opioids (amongst other things), and that activation of AMPA type glutamate receptor input feeds forward, to over a certain threshhold, trigger opening of the NMDAr ion channel with corresponding expulsion of Mg+ and thus enable NMDAr signalling, is it likely that an allosteric positive modulator of AMPARs by enabling a net increase in NMDAr mediated glutamatergic neurotransmission would have the inverse effect.
I.E causing the body to develop a greater tolerance/dependence upon an opioid (chronically used).
Is it a known effect? at least intuitively and logically I believe that it may do so, and what effects is the specific type of positive modulation, likely to have in the way of interaction with a tolerant and physically dependend opioid user, as there are several binding sites on AMPArs, some ligands being selective for the flip, and some for the flop isoforms (with variable Ca++ and Na+ permeability), and at differing binding sites noncompetitively binding to allosteric regulation sites, also probably somewhere amongst all those known ligands there are likely to be some that show selectivity for those edited at the Q/R single amino-acid codon change site on the GLUr2 subunit, altering calcium conductance. Although almost all AMPARs in the adult human are of one Q or R edited type, I forget which one off the top of my head, I did most of my research into the AMPAkines around a year(ish) ago, and my entire reason for that, is my memory is quite badly impaired to begin with![:\](https://bluelight.org/xf/BL_Images/Orig_Emoji/wrygrin.gif "wry grin :\")
And the AMPAkines as a class look to be perhaps the creme de la creme of nootropics, increasing hippocampal and I would guess dentate gyrus LTP in response to activation and thus specifically targeting memory and learning, as well as apparently being wakefullness inducing agents.
Some AMPAkines act to slow desensitisation kinetics at the receptor in question, preventing the normal lightening fast desensitization in response to glutamate binding (or administration of an exogenous agonist, and those are just plain fucking nasty, see domoic acid for an example...ick), AMPARs being the main fast excitatory system in the brain.
Others increase channel open time, allowing more ion flux and should result in greater depolarization amplitude, or at least extended duration of action potential, contrast with a barbiturate at the barb-sensitive GABAa allosteric site, benzos increase open probability, whereas barbs lock the GABAa chloride channel open for longer, basically forcing the door not to close with a big hairy booted foot, rather than the polite, chivalrous holding the door to let lady Cl- pass unhindered resulting in a longer duration of Cl- flux as the bitch does a runner, and as such the barbs have potential for much stronger inhibitory signalling than the benzos.
I imagine this mode of binding and potentiation to have a greater likelyhood of NMDAr-mediated upregulation of opioid tolerance, if the inverse effect to an NMDAr antagonist actually does occur than an AMPAkine acting to slow desensitization of AMPARs (and indeed potential for possible side effects)
There are various kinase-phosphorylation sites at different aminoacid residues in the receptor protein located on different subunits, some increasing channel open probability/threshhold for activation, open time, and at LEAST one known phosphorylation site on a subunit that increases the LTD response., in short, a metric fuck-ton of said kind of regulatory post-transcriptional modifying sites although these as far as I know are not the targets of the AMPAkines, but instead mediated through PKC and PKA.
Theory: AMPAkines may in vivo, cause increase of tolerance via upstream activation of NMDARs, causing the inverse effect upon tolerance that for instance ketamine, DXM would have, I think in practise, AMPAkines acting via decreasing the speed of desensitization would either be less prone, or less likely to effect such a potentiation of opioid tolerance development than those which kick the door in, so speak, and lock the channel in an open state, or slow ion channel closing. And those increasing probability of any single channel firing in response to glutamate binding (there are four agonist binding sites for glutamate on an AMPA receptor, two of which must be filled for the channel open and current to pass, but total conductance is increased as more neurotransmitter binds) probably, I believe, assuming this reversed reversal of opioid tolerance actually occurs in response to the use of an AMPAkine of one flavour or another that the larger and longer the ion flux, coupled with the amount of glutamate binding (which could be affected if the AMPAkine in question alters the receptor conformation to one that binds glutamate more tightly or slows down the removal of glutamate stimulation***
***Question there***
Concerning receptor/ligand on-off kinetics and dissociation, once a receptor binds sufficient ligand to activate it and trigger an action potential, does the receptor remain constantly stimulated whilst the ligand is bound (assuming one is dealing with an agonist or positive modulator) or is it a case of repetitive, rapid stimulation via fast dissociation and re-binding, in a sense re-priming the gun ready to fire again on the next chamber, analogous to a revolver being cocked ready to fire once again after the trigger is pulled (firing off the action potential), to visualise it?
In particular, the AMPAkine I am thinking of specifically is DM-235, or sunifiram, one of the most potent by weight, chemically 1-benzoyl-4-propionylpiperazine , active via IM or SC route at 0.001mg/kg although I realise that does not nescessarily give any information as to the actual efficacy of an agonistic drug.
I will be trying it not too far in the future, something I wished to do quite some time ago but both financial and circumstances prevented that (supporting a housemate I thought in need of protecting against abuse, but who actually turned out to be a psychotic thieving, disrespectful little whore, who was a gigantic drain on my resources and time), in fact I will have the chance to play with a large amount, tens of grams should I wish it, or on the order of as little as 500mg, and the opportunity to bioassay other piperazine substitution patterns, such as other 1-benzoyl-4-alkyl or carboxylamides which are known to be active nootropics, although that will of course, if many, or indeed any others of its class are to be evaluated qualitatively take longer than DM-235 due to the increased time and resources needed to obtain a clean product.
But, whilst my memory is impaired severely enough to make some basic day to day tasks often difficult to accomplish, and what is truly nasty for me personally, as I hate not being able to keep my mind stimulated and active worse than almost anything else, is I seem to have now, a very poor ability to encode new longterm memories from short term memory, a severely impaired ability to keep information in my...how to describe it, but mental workbench, for short term processing perhaps, and I think my ability to recall things I have learned or done that day, or that week is a lot worse than it used to be still in school. I am physically dependent on opiate pain meds, thanks to a longterm disability affecting my knee.
I have been actively taking steps to taper down on my dose of pain meds, hurt the knee as it may be, and I am doing it very slowly to avoid even slight withdrawals, one reason: they suck arse, and reason two: withdrawals cause the typical akathisia restless legs that people experience, only it causes full on akathisia and myoclonic spasms/jerks, the latter were already present and have been for quite some time, although they have been judged benign after an in-patient hospital stay for evaluation by an neurologist, not harmful, aside from pulling muscles, bruising, stretching things that shouldn't be stretched, and on occasion, launching the odd cup of hot coffee or food across the room, and aside from that, annoying nystagmus from time to time, and greater.
difficulty focusing my eyes well enough to read, and really damn difficult to do so without my reading glasses, thanks to getting a face full of hot NaOH solution when I was around 19, I did get what hit me full on out of my right eye bloody quickly, and effectively enough that I was able to salvage part of what erupted out of my project at the time and splattered across the windows/floor/counter top
but it did leave me with poor vision where reading even very large print from more than a couple of feet away, try reading something with and eye like that while they are wiggling back and forth like an E-tard on a solid dose of MDA
And the lack of sleep that causes affects my cognitive abilities very rapidly, I cannot afford sleep deprivation, years ago before my problems sure, if I had to pull an all nighter, fine as long as I caught up with my rest a day or two later if I really had to burn the candle at both ends, now its incapacitating and brings on the myoclonic jerking. When I am even slightly sleep deprived, my body kicks off a shitstorm.
I don't need my efforts at reducing pain med tolerance until it is manageable by using a partial agonist opioid first, then tapering that until I am on a minimal dose, when I absolutely have to, to drop my tolerance down to next to nothing, it has not been a pleasant task, obviously, and I sure as hell don't want to waste the effort, time and misery, only to have it fouled up by something artificially upregulating tolerance for me, despite my efforts.
Anybody think it would be worth taking some time out of any commitments for a week perhaps, and cognitive issues be buggered, but simply make sure I had to do nothing more demanding than eat, sleep, and spend quality time to my dear lady, and using that free time to do a short period of time using moderate doses of an NMDA antagonist, to drop tolerance rapidly as can be, I am on a fairly moderate dose of dihydrocodeine, 120mg/day spread over as much as 4 doses, although if my knee pain gets severe enough I need to walk with a cane, I do occasionally take up to 600-700mg, but that is done infrequently, and as enjoyable as getting that fucked up is, it is not something I do unless pushed.
And I am now down to being able to take, on a good day, 30mg
B/D and that will hold me, but lessening it any, even by a quarter of a tablet pushes me over the edge and triggers off the afforementioned preexisting neurological shit-storm, despite the insignificant dose being taken down (or rather, attempting to lessen)
I do not have access to ketamine, to amantadine/rimantadine yes, but those two are out, bugger me sideways with a sharp and pointy stick if I am willing to use antivirals for that purpose when H1N1 is the most prevalent strain of flu going around the UK at the moment and is getting far more common in general. Memantine is far too expensive for me, and I really do dislike DXM, it just makes me feel nauseous. Methoxetamine would likely be the agent of choice in this case.
So, worth trying a period of use of it for a moderately short length of time, and then try out the DM-235? or just go straight to it without using the NMDAr antagonist, although it has to be said it is on my to taste list at least a couple of times
I.E causing the body to develop a greater tolerance/dependence upon an opioid (chronically used).
Is it a known effect? at least intuitively and logically I believe that it may do so, and what effects is the specific type of positive modulation, likely to have in the way of interaction with a tolerant and physically dependend opioid user, as there are several binding sites on AMPArs, some ligands being selective for the flip, and some for the flop isoforms (with variable Ca++ and Na+ permeability), and at differing binding sites noncompetitively binding to allosteric regulation sites, also probably somewhere amongst all those known ligands there are likely to be some that show selectivity for those edited at the Q/R single amino-acid codon change site on the GLUr2 subunit, altering calcium conductance. Although almost all AMPARs in the adult human are of one Q or R edited type, I forget which one off the top of my head, I did most of my research into the AMPAkines around a year(ish) ago, and my entire reason for that, is my memory is quite badly impaired to begin with
And the AMPAkines as a class look to be perhaps the creme de la creme of nootropics, increasing hippocampal and I would guess dentate gyrus LTP in response to activation and thus specifically targeting memory and learning, as well as apparently being wakefullness inducing agents.
Some AMPAkines act to slow desensitisation kinetics at the receptor in question, preventing the normal lightening fast desensitization in response to glutamate binding (or administration of an exogenous agonist, and those are just plain fucking nasty, see domoic acid for an example...ick), AMPARs being the main fast excitatory system in the brain.
Others increase channel open time, allowing more ion flux and should result in greater depolarization amplitude, or at least extended duration of action potential, contrast with a barbiturate at the barb-sensitive GABAa allosteric site, benzos increase open probability, whereas barbs lock the GABAa chloride channel open for longer, basically forcing the door not to close with a big hairy booted foot, rather than the polite, chivalrous holding the door to let lady Cl- pass unhindered resulting in a longer duration of Cl- flux as the bitch does a runner, and as such the barbs have potential for much stronger inhibitory signalling than the benzos.
I imagine this mode of binding and potentiation to have a greater likelyhood of NMDAr-mediated upregulation of opioid tolerance, if the inverse effect to an NMDAr antagonist actually does occur than an AMPAkine acting to slow desensitization of AMPARs (and indeed potential for possible side effects)
There are various kinase-phosphorylation sites at different aminoacid residues in the receptor protein located on different subunits, some increasing channel open probability/threshhold for activation, open time, and at LEAST one known phosphorylation site on a subunit that increases the LTD response., in short, a metric fuck-ton of said kind of regulatory post-transcriptional modifying sites although these as far as I know are not the targets of the AMPAkines, but instead mediated through PKC and PKA.
Theory: AMPAkines may in vivo, cause increase of tolerance via upstream activation of NMDARs, causing the inverse effect upon tolerance that for instance ketamine, DXM would have, I think in practise, AMPAkines acting via decreasing the speed of desensitization would either be less prone, or less likely to effect such a potentiation of opioid tolerance development than those which kick the door in, so speak, and lock the channel in an open state, or slow ion channel closing. And those increasing probability of any single channel firing in response to glutamate binding (there are four agonist binding sites for glutamate on an AMPA receptor, two of which must be filled for the channel open and current to pass, but total conductance is increased as more neurotransmitter binds) probably, I believe, assuming this reversed reversal of opioid tolerance actually occurs in response to the use of an AMPAkine of one flavour or another that the larger and longer the ion flux, coupled with the amount of glutamate binding (which could be affected if the AMPAkine in question alters the receptor conformation to one that binds glutamate more tightly or slows down the removal of glutamate stimulation***
***Question there***
Concerning receptor/ligand on-off kinetics and dissociation, once a receptor binds sufficient ligand to activate it and trigger an action potential, does the receptor remain constantly stimulated whilst the ligand is bound (assuming one is dealing with an agonist or positive modulator) or is it a case of repetitive, rapid stimulation via fast dissociation and re-binding, in a sense re-priming the gun ready to fire again on the next chamber, analogous to a revolver being cocked ready to fire once again after the trigger is pulled (firing off the action potential), to visualise it?
In particular, the AMPAkine I am thinking of specifically is DM-235, or sunifiram, one of the most potent by weight, chemically 1-benzoyl-4-propionylpiperazine , active via IM or SC route at 0.001mg/kg although I realise that does not nescessarily give any information as to the actual efficacy of an agonistic drug.
I will be trying it not too far in the future, something I wished to do quite some time ago but both financial and circumstances prevented that (supporting a housemate I thought in need of protecting against abuse, but who actually turned out to be a psychotic thieving, disrespectful little whore, who was a gigantic drain on my resources and time), in fact I will have the chance to play with a large amount, tens of grams should I wish it, or on the order of as little as 500mg, and the opportunity to bioassay other piperazine substitution patterns, such as other 1-benzoyl-4-alkyl or carboxylamides which are known to be active nootropics, although that will of course, if many, or indeed any others of its class are to be evaluated qualitatively take longer than DM-235 due to the increased time and resources needed to obtain a clean product.
But, whilst my memory is impaired severely enough to make some basic day to day tasks often difficult to accomplish, and what is truly nasty for me personally, as I hate not being able to keep my mind stimulated and active worse than almost anything else, is I seem to have now, a very poor ability to encode new longterm memories from short term memory, a severely impaired ability to keep information in my...how to describe it, but mental workbench, for short term processing perhaps, and I think my ability to recall things I have learned or done that day, or that week is a lot worse than it used to be still in school. I am physically dependent on opiate pain meds, thanks to a longterm disability affecting my knee.
I have been actively taking steps to taper down on my dose of pain meds, hurt the knee as it may be, and I am doing it very slowly to avoid even slight withdrawals, one reason: they suck arse, and reason two: withdrawals cause the typical akathisia restless legs that people experience, only it causes full on akathisia and myoclonic spasms/jerks, the latter were already present and have been for quite some time, although they have been judged benign after an in-patient hospital stay for evaluation by an neurologist, not harmful, aside from pulling muscles, bruising, stretching things that shouldn't be stretched, and on occasion, launching the odd cup of hot coffee or food across the room, and aside from that, annoying nystagmus from time to time, and greater.
difficulty focusing my eyes well enough to read, and really damn difficult to do so without my reading glasses, thanks to getting a face full of hot NaOH solution when I was around 19, I did get what hit me full on out of my right eye bloody quickly, and effectively enough that I was able to salvage part of what erupted out of my project at the time and splattered across the windows/floor/counter top
but it did leave me with poor vision where reading even very large print from more than a couple of feet away, try reading something with and eye like that while they are wiggling back and forth like an E-tard on a solid dose of MDAAnd the lack of sleep that causes affects my cognitive abilities very rapidly, I cannot afford sleep deprivation, years ago before my problems sure, if I had to pull an all nighter, fine as long as I caught up with my rest a day or two later if I really had to burn the candle at both ends, now its incapacitating and brings on the myoclonic jerking. When I am even slightly sleep deprived, my body kicks off a shitstorm.
I don't need my efforts at reducing pain med tolerance until it is manageable by using a partial agonist opioid first, then tapering that until I am on a minimal dose, when I absolutely have to, to drop my tolerance down to next to nothing, it has not been a pleasant task, obviously, and I sure as hell don't want to waste the effort, time and misery, only to have it fouled up by something artificially upregulating tolerance for me, despite my efforts.
Anybody think it would be worth taking some time out of any commitments for a week perhaps, and cognitive issues be buggered, but simply make sure I had to do nothing more demanding than eat, sleep, and spend quality time to my dear lady, and using that free time to do a short period of time using moderate doses of an NMDA antagonist, to drop tolerance rapidly as can be, I am on a fairly moderate dose of dihydrocodeine, 120mg/day spread over as much as 4 doses, although if my knee pain gets severe enough I need to walk with a cane, I do occasionally take up to 600-700mg, but that is done infrequently, and as enjoyable as getting that fucked up is, it is not something I do unless pushed.
And I am now down to being able to take, on a good day, 30mg
B/D and that will hold me, but lessening it any, even by a quarter of a tablet pushes me over the edge and triggers off the afforementioned preexisting neurological shit-storm, despite the insignificant dose being taken down (or rather, attempting to lessen)
I do not have access to ketamine, to amantadine/rimantadine yes, but those two are out, bugger me sideways with a sharp and pointy stick if I am willing to use antivirals for that purpose when H1N1 is the most prevalent strain of flu going around the UK at the moment and is getting far more common in general. Memantine is far too expensive for me, and I really do dislike DXM, it just makes me feel nauseous. Methoxetamine would likely be the agent of choice in this case.
So, worth trying a period of use of it for a moderately short length of time, and then try out the DM-235? or just go straight to it without using the NMDAr antagonist, although it has to be said it is on my to taste list at least a couple of times
