N&PD Moderators: Skorpio
Antagonists and their tolerance?
polarbearsarecool
Bluelighter
Hello! for about 11 months i have been using a combination of low dose naltrexone and DXM(Delysum) to control opiate tolerance but my question is do antagonists produce a tolerance mechanism of some sort? - A loose connection is the common serotonin antagonists, the atypical ssri- do they cause tolerance also?
Hyperthesis
Bluelighter
The short answer is yes, some kind of tolerance is established by opioid antagonists, too. A recent example:
"Buprenorphine and opioid antagonism, tolerance, and naltrexone-precipitated withdrawal."
J Pharmacol Exp Ther2011, 336(2): 488-95.
The dual antagonist effects of the mixed-action μ-opioid partial agonist/κ-opioid antagonist buprenorphine have not been previously compared in behavioral studies, and it is unknown whether they are comparably modified by chronic exposure. To address this question, the dose-related effects of levorphanol, trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide (U50,488 ), heroin, and naltrexone on food-maintained behavior in rhesus monkeys were studied after acute and chronic treatment with buprenorphine (0.3 mg/kg/day). In acute studies, the effects of levorphanol and U50,488 were determined at differing times after buprenorphine (0.003-10.0 mg/kg i.m.). Results show that buprenorphine produced similar, dose-dependent rightward shifts of the levorphanol and U50,488 dose-response curves that persisted for ≥ 24 h after doses larger than 0.1 mg/kg buprenorphine. During chronic treatment with buprenorphine, the effects of levorphanol, U50,488, heroin, and naltrexone were similarly determined at differing times (10 min to 48 h) after intramuscular injection. Overall, results show that buprenorphine produced comparable 3- to 10-fold rightward shifts in the U50,488 dose-response curve under both acute and chronic conditions, but that chronic buprenorphine produced larger (10- to ≥ 30-fold) rightward shifts in the heroin dose-effect function than observed acutely. Naltrexone decreased operant responding in buprenorphine-treated monkeys, and the position of the naltrexone dose-effect curve shifted increasingly to the left as the time after daily buprenorphine treatment increased from 10 min to 48 h. These results suggest that the μ-antagonist, but not the κ-antagonist, effects of buprenorphine are augmented during chronic treatment. In addition, the leftward shift of the naltrexone dose-effect function suggests that daily administration of 0.3 mg/kg buprenorphine is adequate to produce opioid dependence.
rudiecantfail
Greenlighter
I don't know about opiod antagonists, but tolerence to cholinergique antagonists like diphenhydramine is very noticeable.
DooMMooD
Bluelighter
Correct me if i'm wrong, but i was under the impression that naltrexone is not an antagonist, but rather a reverse agonist.
Mr Bigglesworth
Greenlighter
chaos_destroy
Bluelighter
^Not necessarily. An antagonist returns a receptor to its baseline activity as if bound by neither an agonist or inverse agonist. An inverse agonist however drops the activity below this level. Kind of like a volume knob normally set to 5, which is where an antagonist keeps it. Agonist might turn it up to 10 while an inverse agonist would turn it down below 5 maybe down to 0 depending on strength.
Hyperthesis
Bluelighter
Really functioning and unambiguous (!) definitions of the terms direct/indirect/inverse/reverse/silent agonist resp. antagonists look a bit more complicated than the ones cited so far in this thread, no offense intended though. I think I could write a short summary soon to explain what I mean, because this kind of confusion seems to appear over and over again. In short just one note: All these definitions changed throughout the last decades several times and the current version(s) strongly depend on the most recent results in the protein-related fields. There are no simple black'n'white patterns possible as definition, as the vast majority of effector proteins in nature do not work in a binary fashion (ON/OFF) but by graduaded, tunable, modifiable ways.
Anyway, the point is that tolerance is theoretically possible for all kinds of physiologically active ligands:
1st: It doesn't matter if a ligand binds to its target effector and simply inhibits it to perform its duty, may it be to intracellularly release a second messenger, to open a ion-, water-, whatever-selective channel/pore, to catalyse a chemical reaction, to change its conformation, to break up into two or more fragments resp. the contrary, to aggregate to dimers, trimers, ...I hope I didn't forget any prominent possibility
2nd: It doesn't matter if a ligand increases the activity of said duty.
3rd It doesn't matter if a ligand decreases this activity, either to a lower level or entirely to zero (...the latter case would equal the "1st" point above, ie. nothing at all is happening). As a side-note: Per definition there can't be negative values for a protein's activity. Either a protein does something or it does nothing and is simply floating around silently resp. sticks lazy to a membrane. What is actually possible, is that it does something else. Many proteins are able to perform more than one task, resp. many (GPCR-)receptors can cause more than just one reaction (see next point).
4rd: It doesn't matter if ligand B (eg. a drug) causes a protein to do something entirely different than the usual ligand A (eg. the endogenous neurotransmitter).
...in any of the above cases development of tolerance is possible: I would bet some money that one could find examples simply by searching through PubMed with the right search terms. Because any of the above cases will cause an interference with the normal neurochemistry (to stick with psychoactive drugs for now), there has to be some kind of physiological reactions. Of course do we know exceptions (eg. [almost] no tolerance to miosis and obstipation from opioids), but then again are only extremely few regulatory systems in nature absolute.
