Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and mu-opioid receptor deficient mice.
BACKGROUND
Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic properties. The influence of M6G on respiratory and antinociceptive responses was investigated in mice lacking the micro -opioid receptor (MOR) and compared with morphine.


METHODS
Experiments were performed in mice lacking exon 2 of the MOR (n=18) and their wild type (WT) littermates (n=20). The influence of M6G and morphine on respiration was measured using whole body plethysmography during three elevations of inspired carbon dioxide. Antinociception was assessed using tail flick and hotplate tests.


RESULTS
In WT but not null mutant mice, a dose-dependent depression of the slope of the ventilatory carbon dioxide response was observed after M6G and morphine. Similarly, both opioids were devoid of antinociceptive effects in null mutant mice, but showed potent dose-dependent analgesia in WT animals. Potency differences between M6G and morphine in WT mice were of the same order of magnitude for analgesia and respiration.


CONCLUSIONS
The data indicate that the desired (antinociceptive) and undesired (respiratory depression) effects of M6G and morphine are linked to the same gene product; that is the MOR. Other opioid- and non-opioid-receptor systems may play a minor role in the actions of M6Gs and morphine. The clinical implications of our findings are that any agent acting at the MOR will invariably cause (potent) analgesia in combination with (variable) respiratory depression.
Romberg
R
R
Department of Anesthesiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Sarton
E
E
Teppema
L
L
Matthes
H W D
HW
Kieffer
B L
BL
Dahan
A
A
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002245:Carbon Dioxide; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000494:pharmacology*; D017288:Pain Threshold / Q000187:drug effects*; D010993:Plethysmography, Whole Body; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology; D012677:Sensation / Q000187:drug effects
D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D017450:Receptors, Opioid, mu; D002245:Carbon Dioxide; C035349:morphine-6-glucuronide; D009020:Morphine