Effects of morphine and its metabolites on opiate receptor binding, cAMP formation and [3H]noradrenaline release from SH-SY5Y cells.
Opiate receptor occupation leads to a variety of intracellular events including inhibition of adenylyl cyclase and cAMP formation. We have examined the opiate binding characteristics, effects on cAMP formation and [3H]noradrenaline release of morphine, morphine-6 (M6G) and -3 (M3G)-glucuronides, and fentanyl in SH-SY5Y human neuroblastoma cells. M6G and M3G are the major metabolites of morphine formed in vivo whose cellular action remains to be fully elucidated. In binding experiments morphine (affinity, K50 = 96 nM) and fentanyl (K50 = 99 nM) were more potent than M6G (K50 = 393 nM), while M3G was inactive. However, for cAMP inhibition morphine (half maximum inhibition, IC50 = 193 nM) and M6G (IC50 = 113 nM) were roughly equipotent, with fentanyl (IC50 = 27 nM) being more potent and producing a greater maximum inhibition (56%). M3G was inactive. These in vitro data are in general agreement with the in vivo effects of these glucuronides. Moreover, all of the opiates tested failed to inhibit K(+)-evoked release of [3H]noradrenaline. Whilst these data do not support a role for cAMP in neurotransmitter release, alterations in cAMP formation may still have a role to play in the mechanism of analgesia.
Lambert
D G
DG
University Department of Anaesthesia, Leicester Royal Infirmary, U.K.
Atcheson
R
R
Hirst
R A
RA
Rowbotham
D J
DJ
D002460:Cell Line / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis*; D004174:Diprenorphine / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D009020:Morphine / Q000494:pharmacology*; D009447:Neuroblastoma; D009638:Norepinephrine / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism*; D014316:Tritium
D005965:Glucuronates; D011957:Receptors, Opioid; D014316:Tritium; D004174:Diprenorphine; D009020:Morphine; D000242:Cyclic AMP; D005283:Fentanyl; D009638:Norepinephrine