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BEHAVIORAL PHARMACOLOGY

Behavioral Pharmacology of the µ/ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts (G.P.D.C., S.S.N.); University of Arizona, Tucson, Arizona (R.P.); University of New England, Biddeford, Maine (E.J.B.); Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland (K.C.R.); and Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (S.S.N.)

H₂N-Tyr-D-Thr-Gly-Phe-Leu-Ser-(O-β-D-lactose)-CONH₂ (MMP2200) is a novel glycopeptide opioid agonist with similar affinities for µ and 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 µ/ antinociceptive interactions after systemic administration in primates. To address this issue, the present study compared the effects of MMP2200 and the µ-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 µ-selective antagonist naltrexone (0.01 mg/kg), the -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, µ/-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.

Address correspondence to: Dr. S. Stevens Negus, Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th Street, PO Box 980613, Richmond, VA 23298. E-mail: ssnegus{at}vcu.edu