While we concentrated on the novel ELK1 findings, there is also clear dysregulation of other components of striatal MOR signaling, including MOR and β-arrestin2. Such impairments may relate to altered drug sensitivity or tolerance to heroin, as β-arrestin2 modulates MOR internalization and desensitization in rodent models.(77) These events contribute significantly to drug tolerance as evidenced by the fact that β-arrestin2 knockout mice do not develop tolerance.(43) A lack of MOR desensitization or proper recycling due to deficits in β-arrestin2 may lead to heightened reward response with repeated heroin use.(78) Human opiate abusers also have reduced expression in the frontal cortex of MOR, β-arrestin2, and GRK2,(79) a kinase that also contributes to MOR desensitization and internalization, which together with the current findings would suggest similar MOR-related pathology in brain areas critically involved in addictive behaviors.
