dependence/tolerance & up-regulation/down-regulation

[i are spectre]

in theory:

would forcing up-regulation of opioid receptors cause a decline in tolerance/physical dependence/withdrawal symptoms associated with opioid abuse?

consider a person consuming plenty of opioids for years. this should cause a down-regulation in opioid receptors due to the abundance of the chemical.

would this contribute to withdrawal symptoms, dependence, and tolerance?

let's say this person abstains from opioids "cold turkey". endorphins are not being produced at their normal levels and the down-regulation of receptors would make it much harder for these few endorphins to bind. cells would then create more receptors/up-regulate for the endorphins until he/she is back to normal, correct?

is this what tolerance and dependence is?

 

[23536]

yes, and see this article for how co-administration of an opioid receptor antagonist helps a chronic user bypass withdrawal.

Is it clinically confirmed that chronic opiate use lowers endogenous endorphin production? Has this been measured?

 

[endotropic]

The total amount of mu receptor doesn’t change much with chronic opiate use, the receptors that are there just become less effective at coupling to downstream signalling pathways. That effect plays a much bigger role in tolerance than actual destruction/reduction of the receptor number.

Also endorphins are produced at such low levels under normal conditions that even if they were downregulated following opiate use, there wouldn’t be enough of a change to account for the severity of the withdrawal syndrome. It seems like the real players in withdrawal are downstream of the actual opiate receptors, most likely starting with changes in cAMP production. Basically opiates inhibit cAMP production, so when you take opiates chronically your body responds by increasing the rate at which cAMP is produced. When you come off, there’s an overshoot and you have way too much cAMP for a time, your neural networks are hyperexcitable, and that leads to the withdrawal state.

So amazingly its looking less and less like endorphins and the opiate receptors themselves are the key players in withdrawal!

If you want more details, all of this information is from http://www.ncbi.nlm.nih.gov/pubmed/18414400

 

[i are spectre]

thank you very much!

 

[tyrael]

Firstly, awesome thread i are spectre!! This is the area of study I want to do my masters in (when I eventually get there! lol).

.....
would forcing up-regulation of opioid receptors cause a decline in tolerance/physical dependence/withdrawal symptoms associated with opioid abuse?
....

However, what would the ramifications be if this was done, after all is said and done? Would this possibly cause another set of problems?