Fig. 7

Schematic representation of different hypotheses/mechanisms involved in the development of tolerance to the antinociceptive effect of fentanyl and morphine. Down-regulation and desensitization of MOR represent two possible biochemical processes that could underlie JNK-mediated morphine tolerance in vivo. The findings of our study and others suggests that tolerance for the antinociceptive effects of morphine is mediated by JNK signaling, possibly through desensitization of MOR, defined for this study as the functional uncoupling of the receptor from its G protein signaling components. In contrast, inhibition of JNK does not alter tolerance for the antinociceptive effects of fentanyl. Tolerance for the antinociceptive effects of fentanyl appears to be mediated by a classic mechanism involving GRK phosphorylation of MOR followed by βarrestin2 recruitment