Too much glutamatergic activity doesn't cause inhibiting of excitatory neurotransmission.
The ULD-NTX protocol works by preventing (and if my understanding is correct, also reversing that which has occurred already) a switch between the G-protein coupling that happens on chronic use of opioids, from the naiive state, or nontolerant state with non-regular use of opioids, from Gi/o to Gγ/s (I think, it might be Gbeta/γ I can't remember. But the shift turns the receptors from a (relative to one another) population having low affinity for naltrexone to a far, far higher affinity state, which unlike the MORs with their G-protein coupling to Gi/o are of an excitatory nature, presumably resulting rather than the classical disinhibition of GABA, DA release, inhibition of noradrenergic release and the like, to the inverse thereof, when stimulated by opioid agonists. This produces an unpleasant, nonrewarding and anxiogenic state (and possibly hyperalgesic although this is certainly also mediated through rather than pleasant (for most people) anxiolytic and euphoriant, relaxing effects.) Not sure if emesis via MOR agonism is mediated directly through MOR1 activity or via MOR1D which is an alternatively spliced MOR1 isoform that forms heterodimers with gastrin-releasing peptide receptors, which is responsible for the histamine releasing effects of opioids.
BTW, are there any highly selective agonists, partial agonists, (silent) antagonists, partial inverse or full inverse agonists known for the MOR1d isoform? would be nice to have a moderate strength selective agonist for this splice variant, in order to increase the histamine release in response to IV morphine, because I like it, and by contrast, not DISlike, but in case of strong opioid agonists for MORs that do not possess much histamine releasing effect. To contrast, I actually find a solid, heavy dose of codeine or dihydrocodeine (half a gram, the maximum in case of codeine, or whatever dose of DHC I can get away with with my tolerance, it being possessed of some intrinsic activity, to IV oxycodone, as long as that oxy dose is not ridiculously greater than equipotent to the DHC or codeine dose) Morphine itself, or dipropionylmorphine being my second favourite and favourite (with the exclusion of an injectable poppy pod isolate or dipropionylated mixed alkaloid fraction with a fair bit of codeine removed beforehand to avoid pulmonary oedema. But heroin, seems to provoke less histamine release subjectively speaking than morphine, dipropionylmorphine does make up for the lesser histamine release than morphine by virtue of its incredible rush, incredibly fast (intravenous) onset, high lipophilicity, loooooooong sexy pair of legs and euphoria fit to make god himself drool in his beard. But other than morphine, dipropionylmorphine, pod tea and propionyl-esterified-everything-phenolic mixture that comes from treating pod isolate with the usual acylation protocol for preparation of such phenol esters, then morphine, unesterified, unmodified, save either being a soluble salt or freebase, is one of the fancier and prettiest of all the phenanthrene crown jewels where opioids of such structure are being spoken of. Even stronger opioids such as fentanyl, remifentanil and alfentanil cannot compare, in my estimation. And it seems like too much of a coincidence that of ALL the opioids I've tried, those with the greatest histamine release, and when that includes weaker ones like DHC and codeine, are my favourites. I'd far, far prefer a solid belt of codeine to an equialangesic/equipotent level of fentanyl or remifentanil butyrfentanil or others, either smoked or IV in the case of fent itself or butyrfentanil smoked,. Not QUITE sure about alfentanil as I haven't had it many times. And I've only had remifentanil IV, likewise alfentanyl I've only had it shot, never smoked it. No POINT in smoking remifent because its way too short acting, like a hooker that will blow you a kiss but snatches her arm away before its even halfway to grasping her hand around a proffered payment (I don't USE hookers, never have never will. I have too much respect for autistic girls to do that anyway even IF I thought I had a chance of finding a Kanner's autie hooker, or even aspie, I'd not wish to engage in activity and degrade them at all in such way), but yeah, remifentanil is just...in and out without even time to shake it all about. BARELY time to have a part of a rollup before it is metabolically wiped out. I would't mind trying a blunt soaked in a solvent solution of it, or a decent sized IM depot shot, but its the ultimate pricktease of an opioid. Might as well be an endogenous opioid peptide for all the length that one lasts. Only any good via a constant infusion, and when that be ceased then its gone within minutes.
Anyhow derailment aside, I am unsure about ULD-naltrexone and partial agonists, does naltrexone even displace bupe? I'm busy eating a chilli con carnage (that is to say, my dad cooked the chilli, and *I* make chili con carnE, because he, adds neither chick-peas, nor adds from neither jar of peppery boletus nor my bags and bags of dried fly agaric. And to me, a chili isn't a chili at all if it hasn't at least the dried Amanita, preferably the Chalciporus as well but its just not a proper chili without a spoonful or two of fly agaric mushroom powder)
The mechanisms of memantine or other NMDAR antagonists and of ULD-NTX are different. Theres both the increase in excitatory, glutamatergic signaling in response to chronic MOR agonist application which increases tolerance. And the switch from inhibitory to excitatory MOR types via the alteration in G-protein coupling. These excitatory MORs are however far higher in affinity for naltrexone than the inhibitory (basline) type, naltrexone binds to filamin-a and prevents (and I believe also) reverses this process but does not impact the glutamatergic (ionotropic receptors, MORs also heterodimerize with one of the metabotropic glutamate receptors, I forget which but its in one of the wikipedia articles on opioids/dependence etc. so being higher affinity by orders of magnitude NTLX is capable of selective binding to the excitatory type and preventing agonist binding, as well as the effects on filamin-a which prevents the G-protein switching.
Please explain what precisely you mean by excitatory inhibition? in MORs coupled to Gi/o then agonists induce disinhibition via GABAergic mechanisms as I understand it, leading to in part their inhibitory properties
Also, it seems like not only NMDARs but AMPARs are involved in regulation of addiction at least. This may not hold true for classical opioids that do not cause tachyphylaxis-type tolerance and strongly internalizing effects upon MORS, because fentanyl and its derivatives bind in a distinct, separate modality from morphinan opioids and most other opioids also.
https://www.ncbi.nlm.nih.gov/pubmed/19295508
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545084/ this too is quite interesting.
Edit-afterthought:
Bear in mind that memantine is quite different from most other NMDA antagonists, such as DXM/DXO, because memantine induces a ligand-gated antagonism of the NMDAR, but unlike other antagonists that voltage-gated antagonist property results in antagonism only (at lower doses, it is, at high doses, indeed dissociative, I've tried it that way and liked it, although it is very long lasting) but at clinical doses then weather or not it antagonizes NMDAR mediated calcium flux in response to agonism via glutamate or aspartate depends on the degree of agonism, too high a degree of NMDAR stimulation (excitatory) trips that voltage threshold then the antagonism proper of memantine.
How does ULD-NTX interact wish partial MOR agonists like bupe, etc. / and how do partial agonists, interact with beta-arrestins, filaminn-a and G-protein coupling?
