Beta-arrestin is a molecule which is directly involved in tolerance in family of GPCRs. The opioid receptors belong to that family. As expected, there are several studies showing arrestin is intimately related to opioid tolerance, for example:
"... We have previously reported that mice lacking the G protein-coupled receptor regulatory protein, beta-arrestin 2, display profoundly altered morphine responses. beta-Arrestin 2 knockout mice have enhanced and prolonged morphine analgesia with very little morphine tolerance. In this report, we examine whether the side effects of morphine treatment are also augmented in this animal model. Surprisingly, the genetic disruption of opioid receptor regulation, while enhancing and prolonging analgesia, dramatically attenuates the respiratory suppression and acute constipation caused by morphine." J Pharmacol Exp Ther 2005 Sep;314(3):1195-201
Those who have been following studies about salvinorin know that several derivatives have been synthetized which have selective affinity for the Mu-opioid receptor. I recently stumbled upon the following paper (haven't read the full article yet, only the asbtract):
An Opioid Agonist that Does Not Induce Mu Opioid Receptor - Arrestin Interactions or Receptor Internalization.
G protein-coupled receptor desensitization and trafficking are important regulators of opioid receptor signaling that can dictate overall drug responsiveness in vivo. Furthermore, different mu opioid receptor(microOR) ligands can lead to varying degrees of receptor regulation presumably due to distinct structural conformations conferred by agonist binding. For example, morphine binding produces a microOR with low affinity for beta-arrestin proteins and limited receptor internalization whereas enkephalin analogs promote robust trafficking of both beta-arrestins and the receptors. Here, we evaluate microOR trafficking in response to activation by a novel mu-selective agonist derived from the naturally occurring plant product, salvinorin A. Interestingly, this compound, termed herkinorin, does not promote the recruitment of beta-arrestin-2 to the microOR and does not lead to receptor internalization. Moreover, while GRK overexpression can promote morphine-induced beta-arrestin interactions and microOR internalization, such manipulations do not promote herkinorin-induced trafficking. Studies in mice have shown that beta-arrestin-2 plays an important role in the development of morphine-induced tolerance, constipation and respiratory depression. Therefore, drugs that can activate the receptor without recruiting the arrestins may be a promising step in the development of opiate analgesics that distinguish between agonist activity and receptor regulation and may ultimately lead to therapeutics designed to provide pain relief without the adverse side effects normally associated with the opiate narcotics.
An in-vitro study shows that there are cellular markers of tolerance after chronic exposure to herkinorin Synapse 2007 Mar;61(3):166-75
But I still find this pretty exciting and await in vivo study results.