Fentanyl, and its structural analogs
lofentanil and
sufentanil, are potent
analgesics used clinically in the management of
pain. However, the high
analgesic potency of these compounds is limited by the development of tolerance after chronic use. To investigate whether their tolerance development may be related to
mu receptor desensitization, the cloned mouse
mu receptor as well as mutant forms of the receptor were stably expressed in HEK 293 cells and tested for their response to continuous
opioid treatment.
Fentanyl and its analogs potently bound to the
mu receptor and effectively inhibited cAMP accumulation. Three-hour pretreatment of
mu receptors with
fentanyl and its analogs desensitized the
mu receptor by uncoupling it from
adenylyl cyclase. The
fentanyl analogs caused a slight internalization of the
mu receptor as accessed by antibody binding to the
epitope-tagged
mu receptor. Truncation of the
mu receptor by removal of its carboxyl terminus at Glu341 did not affect the ability of the
fentanyl analogs to bind to and activate the
mu receptor nor did it prevent the
fentanyl analogs from desensitizing the receptor. In a previous study we showed that
morphine did not desensitize the cloned
mu receptor even though it is a potent and effective agonist at the
mu receptor. Mutagenesis studies revealed that
morphine interacts differently with the
mu receptor to activate it than do the
fentanyl analogs which may explain its lack of desensitization of the
mu receptor. These results indicate that desensitization of the
mu receptor may be a molecular basis for the development of tolerance to
fentanyl and its analogs.