Codeine and 6-acetylcodeine analgesia in mice.
1. Acetylation of morphine at the 6-position changes its pharmacology. To see if similar changes are seen with codeine, we examined the analgesic actions of codeine and 6-acetylcodeine. 2. Like codeine, 6-acetylcodeine is an effective analgesic systemically, supraspinally and spinally, with a potency approximately a third that of codeine. 3. The sensitivity of 6-acetylcodeine analgesia to the mu-selective antagonists beta-FNA and naloxonazine confirmed its classification as a mu opioid. However, it differed from the other mu analgesics in other paradigms. 4. Antisense mapping revealed the sensitivity of 6-acetylcodeine to probes targeting exons 1 and 2 of the mu opioid receptor gene (Oprm), a profile distinct from either codeine or morphine. Although heroin analgesia also is sensitive to antisense targeting exons 1 and 2, heroin analgesia also is sensitive to the antagonist 3-O-methylnaltrexone, while 6-acetylcodeine analgesia is not. 5. Thus, 6-acetylcodeine is an effective mu opioid analgesic with a distinct pharmacological profile.
Milo
Steven
S
Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, New York 10021, USA.
Ansonoff
Michael
M
King
Michael
M
Rossi
Grace C
GC
Zuckerman
Amy
A
Pintar
John
J
Pasternak
Gavril W
GW
D000698:Analgesia / Q000379:methods*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D003061:Codeine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; C053740:acetylcodeine; D009020:Morphine; D003061:Codeine