Behavioral pharmacology of the μ/δ opioid glycopeptide MMP2200 in rhesus monkeys

Gail Pereira Do Carmo, Robin L Polt, Edward J. Bilsky, Kenner C. Rice, S. Stevens Negus

Research output: Contribution to journalArticle

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Abstract

H2N-Tyr-D-Thr-Gly-Phe-Leu-Ser-(O-β-D-lactose)-CONH 2 (MMP2200) is a novel glycopeptide opioid agonist with similar affinities for μ and δ 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/δ 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 δ-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/δ-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.

Original languageEnglish (US)
Pages (from-to)939-948
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume326
Issue number3
DOIs
StatePublished - Sep 2008

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Glycopeptides
Macaca mulatta
Opioid Analgesics
Pharmacology
Morphine
Naltrexone
naltrindole
Brain
tyrosyl-glycyl-phenylalanyl-leucyl-(O-lactosyl)serinamide
Injections
Self Administration
Nociception
Narcotic Antagonists
Capsaicin
Hyperalgesia
Lactose
Glycosylation
Pharmaceutical Preparations
Primates
Appointments and Schedules

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Behavioral pharmacology of the μ/δ opioid glycopeptide MMP2200 in rhesus monkeys. / Do Carmo, Gail Pereira; Polt, Robin L; Bilsky, Edward J.; Rice, Kenner C.; Negus, S. Stevens.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 326, No. 3, 09.2008, p. 939-948.

Research output: Contribution to journalArticle

Do Carmo, Gail Pereira ; Polt, Robin L ; Bilsky, Edward J. ; Rice, Kenner C. ; Negus, S. Stevens. / Behavioral pharmacology of the μ/δ opioid glycopeptide MMP2200 in rhesus monkeys. In: Journal of Pharmacology and Experimental Therapeutics. 2008 ; Vol. 326, No. 3. pp. 939-948.
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