Behavioral pharmacology of the mu/delta opioid glycopeptide MMP2200 in rhesus monkeys.

Abstract

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.

• Authors: Gail Pereira Do Carmo, Robin Polt, Edward J Bilsky, Kenner C Rice, S Stevens Negus
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 326 Issue 3 Pg. 939-48 (Sep 2008) ISSN: 1521-0103 [Electronic] United States
• PMID: 18511649 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Analgesics, Opioid
• Glycopeptides
• Opioid Peptides
• Receptors, Opioid, delta
• Receptors, Opioid, mu
• tyrosyl-glycyl-phenylalanyl-leucyl-(O-lactosyl)serinamide

Topics

• Analgesics, Opioid (chemistry, pharmacology)
• Animals
• Behavior, Animal (drug effects, physiology)
• Dose-Response Relationship, Drug
• Female
• Glycopeptides (chemistry, pharmacology)
• Macaca mulatta
• Male
• Opioid Peptides (chemistry, pharmacology)
• Pain Measurement (drug effects, methods)
• Receptors, Opioid, delta (agonists, physiology)
• Receptors, Opioid, mu (agonists, physiology)