Mice lacking rhes show altered morphine analgesia, tolerance, and dependence

Rhes, the Ras Homolog Enriched in Striatum, is an intermediate-size GTP binding protein. Although its full functions are not yet known, it has been shown to affect signaling and behaviors mediated by G protein-coupled receptors. Here we have tested whether Rhes affects behaviors mediated by opioid receptors. Wild type and rhes-deficient mice were administered morphine and tested for analgesia in formalin and tail flick tests. Rhes−/− mice showed significantly enhanced analgesia in both tests relative to rhes+/+ mice. Furthermore, rhes−/− mice did not display tolerance to repeated morphine administration and displayed significantly less withdrawal than rhes+/+ mice. These findings indicate that Rhes is involved in behaviors mediated by mu opioid receptors and in the adaptive response to repeated morphine administration.

Research highlights▶ Mice lacking the rhes gene show enhanced analgesia in formalin and tail flick tests. ▶ Rhes mutant mice do not develop tolerance to repeated morphine. ▶ Rhes mutant mice show significantly lower withdrawal compared with wild type mice.