Explanation at the opioid receptor level for differing toxicity of morphine and morphine 6-glucuronide.
The radiolabelled opioid receptor binding affinities of morphine and its active metabolite morphine 6-glucuronide at the total mu, mu 1, mu 2 and delta receptors were determined. Morphine 6-glucuronide was found to have a 4-fold lower affinity for the mu 2 receptor (IC50 17 nM and 82 nM for morphine and morphine 6-glucuronide respectively, P = 0.01), the receptor postulated to be responsible for mediating the respiratory depression and gastrointestinal effects after morphine. This provides a possible explanation for the reduced respiratory depression and vomiting seen following morphine 6-glucuronide in man. A similar reduction in affinity of morphine 6-glucuronide was seen at the total mu receptor whilst there was no significant difference seen at the mu 1 or delta receptor. Hence the increased analgesic potency of morphine 6-glucuronide over morphine remains unexplained.
Hucks
D
D
Department of Chemical Endocrinology, St Bartholomew's Hospital, London, UK.
Thompson
P I
PI
McLoughlin
L
L
Joel
S P
SP
Patel
N
N
Grossman
A
A
Rees
L H
LH
Slevin
M L
ML
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D007700:Kinetics; D009020:Morphine / Q000633:toxicity*; D009022:Morphine Derivatives / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D013347:Subcellular Fractions / Q000378:metabolism
D004745:Enkephalins; D009022:Morphine Derivatives; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine; C035349:morphine-6-glucuronide; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-