Question

Alison is a Research Associate who works with a team that is trying to find new treatment drug that will block the development of desensitisation to morphine, the classic drug to manage moderate-to-severe pain. The aim is to have a drug that will ensure that morphine can provide lasting pain relief without the need for escalating doses due to tolerance. In order to prepare for the upcoming meeting in which the team will consider potential targets for these drugs, Alison was asked to review the basic steps believed to be involved in desensitisation. Provide a basic overview of these steps.

Answer 1

μ opioid receptors are targets of native opioid peptides and addictive analgesic drugs. A major clinical liability of opiate drugs is their ability to cause physiological tolerance. Individual opiates, such as morphine and etorphine, differ both in their ability to promote physiological tolerance and in their effects on receptor regulation by endocytosis. Here, we demonstrate that arrestins play a fundamental role in mediating this agonist-selective regulation and that morphine-activated μ receptors fail to undergo arrestin-dependent uncoupling from cognate G proteins. Thus, highly addictive opiate drugs elude a fundamental mode of physiological regulation that is mediated by agonist-specific interaction of opioid receptors with arrestins.

Opioid receptors are G protein-coupled receptors (GPCRs) that are activated both by endogenous opioid peptides and by clinically important alkaloid analgesic drugs such as morphine. Both classes of agonist promote receptor signaling via heterotrimeric G proteins, including inhibition of adenylyl cyclase and regulation of cation channel.

After activation by agonists, μ opioid receptors are regulated by multiple mechanisms (5–11). Of these, rapid endocytosis of opioid receptors is of particular interest because it is differentially regulated by individual peptide agonists and alkaloid drugs, both in cultured cells and native neurons . In particular, opioid peptides stimulate the internalization of μ opioid receptors within minutes while receptors fail to endocytose after prolonged activation with saturating concentrations of morphine, even though morphine strongly activates receptor-mediated signaling via heterotrimeric G proteins Significant differences in the subcellular localization of opioid receptors also are observed in cultured cells after chronic treatment with morphine compared with opioid peptide, suggesting that agonist-specific differences in receptor endocytosis may have long-term physiological consequences Moreover, mice treated chronically with etorphine, which stimulates receptor endocytosis to an extent similar to opioid peptide develop less physiological tolerance than do mice treated chronically with equieffective doses of morphine further demonstrating that agonist-selective internalization could play a key role mediating the different physiological responses to opiate analgesics.