Behavioral pharmacology of the mu/delta opioid glycopeptide MMP2200 in rhesus monkeys.
H(2)N-Tyr-D-Thr-Gly-Phe-Leu-Ser-(O-beta-D-lactose)-CONH(2) (MMP2200) is a novel glycopeptide opioid agonist with similar affinities for mu and delta receptors. Glycosylation promoted brain penetration and production of centrally mediated behavioral effects in mice; however, it is unknown whether the magnitude of enhanced brain penetration is sufficient to permit central mediation of drug effects and production of synergistic mu/delta antinociceptive interactions after systemic administration in primates. To address this issue, the present study compared the effects of MMP2200 and the mu-agonist morphine in four behavioral procedures in rhesus monkeys. In an assay of thermal nociception, morphine (1.0-5.6 mg/kg) produced dose-dependent antinociception, whereas MMP2200 (10-56 mg/kg) was ineffective. In an assay of capsaicin-induced thermal allodynia, both morphine (0.01-1.0 mg/kg) and MMP2200 (0.032-3.2 mg/kg) produced dose-dependent antiallodynic effects. MMP2200-induced antiallodynia was blocked by the moderately mu-selective antagonist naltrexone (0.01 mg/kg), the delta-selective antagonist naltrindole (1.0 mg/kg), and the peripherally selective opioid antagonist quaternary naltrexone (0.32 mg/kg). In an assay of schedule-controlled behavior, both morphine (0.01-1.0 mg/kg) and MMP2200 (10-56 mg/kg) decreased response rates. Morphine effects were antagonized by naltrexone (0.001-0.01 mg/kg); however, the effects of MMP2200 were not antagonized by either naltrexone (0.01 mg/kg) or naltrindole (1.0 mg/kg). In an assay of drug self-administration, morphine (0.0032-0.32 mg/kg/injection) produced reinforcing effects, whereas MMP2200 (0.032-0.32 mg/kg/injection) did not. These results suggest that systemically administered MMP2200 acted as a peripheral, mu/delta-opioid agonist with limited distribution to the central nervous system in rhesus monkeys. These results also suggest the existence of species differences in the pharmacokinetics and brain penetration of glycopeptides.
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA.
Gail Pereira
GP
Do Carmo
Robin
R
Polt
Edward J
EJ
Bilsky
Kenner C
KC
Rice
S Stevens
SS
Negus
D000701:Analgesics, Opioid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006020:Glycopeptides / Q000737:chemistry / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D018847:Opioid Peptides / Q000737:chemistry / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology*
D000701:Analgesics, Opioid; D006020:Glycopeptides; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C531935:tyrosyl-glycyl-phenylalanyl-leucyl-(O-lactosyl)serinamide