Rates for the reduction of tolerances (amphetamines, opioids, etc)

I think what the main comment is getting at is that there are many factors that go into recovery from tolerance. Many of these factors are caused by dosing schedules, the specific drug (not just drug class), dose taken, age, and genetics, and the how the user engages in their environment. Interestingly, we are now finding out that there is often a bias between drugs of a similar class in that even though they may produce the same signaling output in one pathway from one target, there are other structure-based interactions and other pathways that contribute to how the cell responds. For example, some drugs with higher affinity and intrinsic efficacy at a certain target and signaling output may develop tolerance more slowly (unless excessive doses are used) simply because they do not have to bind and promote activation of as many receptors. It is a very interesting and complicated phenomenon in biochemistry/pharmacology.

It may be the case that lower affinity compounds with lower efficacy must occupy more receptors to produce the same response as a high affinity and high efficacy ligand. If more receptors are occupied then they may produce more receptor downregulation by one pathway and accelerate tolerance. Since we now know a single receptor may signal through many different pathways at different ratios, this results in different effects. These different effects can include alterations in gene expression, protein synthesis, and protein modification/trafficking. It is an very active area of ongoing research that may help explain these differences we see.

A classic example of this can be seen with various G-protein coupled receptors (GPCRs) such as the beta-adrenergic receptors, muscarinic receptors, opioid receptors, and cannabinoid receptors. I'm sure there are others. But with these receptors, there can be some compounds that promote G-protein activation and those downstream effects to a different degree than they would signal through beta-arrestin 2. Beta-arrestin 2 signaling is a 1:1 ratio between the "desensitized receptor" and beta-arrestin 2 recruitment and signaling, which may cause more long-term regulator changes in the cell. G-protein activation, however, is more amplified in that 1 receptor can activate many G-proteins. It is also thought that more of the acute effects on neuronal excitability are through this G-protein pathway while long-term changes may be through beta-arrestin 2 and p-ERK1/2 signaling.

I am rambling at this point and may not have said anything productive or comprehensible to anyone else. I guess I'm trying to say that different drugs belonging to the same class of drugs can exhibit different acute and long-term effects on cells. The biased signaling output that these drugs produce in very based on structure-activity relationships and is being heavily explored to find drugs that are more on-target with less side effects, including drugs that do not develop tolerance as rapidly.

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