Paradoxical relationship between RAVE (relative activity versus endocytosis) values of several opioid receptor agonists and their liability to cause dependence.
OBJECTIVE
To examine the relationship between the RAVE (relative activity versus endocytosis) values of opiate agonists and their dependence liability by studying several potent analgesics with special profiles in the development of physical and psychological dependence.


METHODS
The effects of (-)-cis-(3R,4S,2'R) ohmefentanyl (F9202), (+)-cis-(3R,4S,2'S) ohmefentanyl (F9204), dihydroetorphine (DHE) and morphine on [(35)S]GTP gamma S binding, forskolin-stimulated cAMP accumulation, and receptor internalization were studied in CHO cells stably expressing HA-tagged mu-opioid receptors (CHO-HA-MOR). cAMP overshoot in response to the withdrawal of these compound treatments was also tested.


RESULTS
All four agonists exhibited the same rank order of activity in stimulation of [(35)S]GTP gamma S binding, inhibition of adenylyl cyclase (AC) and induction of receptor internalization: DHE>F9204>F9202>morphine. Based on these findings and the previous in vivo analgesic data obtained from our and other laboratories, the RAVE values of the four agonists were calculated. The rank order of RAVE values was morphine>F9202>F9204>DHE. For the induction of cAMP overshoot, the rank order was F9202>or=morphine>F9204>or=DHE.


CONCLUSIONS
Taken in combination with previous findings of these compounds' liability to develop dependence, the present study suggests that the agonist with the highest RAVE value seems to have a relatively greater liability to develop psychological dependence relative to the agonist with the lowest RAVE value. However, the RAVE values of these agonists are not correlated with their probability of developing physical dependence or inducing cAMP overshoot, a cellular hallmark of dependence.
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Yu-hua
YH
Wang
Jian-feng
JF
Sun
Yi-min
YM
Tao
Xue-jun
XJ
Xu
Zhi-qiang
ZQ
Chi
Jing-gen
JG
Liu
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D005048:Etorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D009293:Opioid-Related Disorders / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005048:Etorphine; D009020:Morphine; C037016:F 7302; D000242:Cyclic AMP; C034765:18,19-dihydroetorphine; D005283:Fentanyl