Morphine-Induced Receptor Endocytosis in a Novel Knockin Mouse Reduces Tolerance and Dependence

Abstract

Opioid drugs, such as morphine, are among the most effective analgesics available. However, their utility for the treatment of chronic pain is limited by side effects including tolerance and dependence. Morphine acts primarily through the mu-opioid receptor (MOP-R) , which is also a target of endogenous opioids. However, unlike endogenous ligands, morphine fails to promote substantial receptor endocytosis both in vitro, and in vivo. Receptor endocytosis serves at least two important functions in signal transduction. First, desensitization and endocytosis act as an "off" switch by uncoupling receptors from G protein. Second, endocytosis functions as an "on" switch, resensitizing receptors by recycling them to the plasma membrane. Thus, both the off and on function of the MOP-R are altered in response to morphine compared to endogenous ligands. To examine whether the low degree of endocytosis induced by morphine contributes to tolerance and dependence, we generated a knockin mouse that expresses a mutant MOP-R that undergoes morphine-induced endocytosis. Morphine remains an excellent antinociceptive agent in these mice. Importantly, these mice display substantially reduced antinociceptive tolerance and physical dependence. These data suggest that opioid drugs with a pharmacological profile similar to morphine but the ability to promote endocytosis could provide analgesia while having a reduced liability for promoting tolerance and dependence.

Functional characterization of human variants of the mu-opioid receptor gene

“…It has been shown previously that MOR mutants engineered to undergo morphineinduced internalization demonstrate reduced propensity to cause these adaptive responses in heterologous cells (9). Also, mice expressing these mutant receptors show reduced morphine tolerance and dependence (33). Here, we have identified a naturally occurring variant that undergoes internalization with morphine without showing changes in morphine potency.…”

Sensory Neuron-Specific Mas-Related Gene-X1 Receptors Resist Agonist-Promoted Endocytosis

“…In the case of opioids, for example, a strong correlation between tolerance or dependence and receptor endocytosis (relative activity versus endocytosis) has been proposed (Alvarez et al, 2001). In detail, Kim et al (2008) reported recently that mice transgenetically expressing a mutant of the -opioid receptor, which is in contrast to the wild-type receptor prone to morphine-induced endocytosis resist the development of morphine tolerance. These data highlight the correlation between tolerance and receptor endocytosis and indicate that knowledge about agonist-promoted receptor endocytosis provides useful information to interpret or predict the actions of a given drug in vivo.…”

Morphine Desensitization, Internalization, and Down-Regulation of the μ Opioid Receptor Is Facilitated by Serotonin 5-Hydroxytryptamine2AReceptor Coactivation

“…It has been suggested, therefore, that strategies that result in enhanced internalization of the MOP receptor in response to morphine might be useful in limiting the development of tolerance (Finn and Whistler, 2001) without compromising analgesia (Koch et al, 2005). This concept has recently received substantial support following production of a knockin line of mice in which the MOP receptor was replaced by a variant in which a substantial region of the C-terminal tail of the MOP receptor was exchanged for the equivalent sequence from the ␦ opioid peptide receptor (Kim et al, 2008). Such C-terminally modified forms of the MOP receptor had been shown previously to internalize in response to morphine when expressed heterologously and to limit the appearance of biochemical markers associated with the development of tolerance to morphine (Finn and Whistler, 2001).…”