Distribution and analgesia of [3H][D-Pen2,D-Pen5]enkephalin and two halogenated analogs after intravenous administration

S. J. Weber, D. L. Greene, S. D. Sharma, H. I. Yamamura, T. H. Kramer, T. F. Burks, Victor J Hruby, L. B. Hersh, Thomas P Davis

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Abstract

To improve pharmacological characteristics of the delta-selective, cyclic peptide [D-Pen2,D-Pen5]enkephalin (DPDPE), modification by halogenation at the Phe4 residue was undertaken. The present study was to determine the extent [3H]DPDPE, [3H][p-Cl-Phe4]DPDPE and [p-125IPhe4]DPDPE crosses the blood-brain barrier, elicits analgesia and to characterize selective organ distribution and stability after i.v. administration. A significantly greater percentage of total [3H][p-Cl-Phe4]DPDPE reached the brain after 10, 20 and 40 min as compared to [3H]DPDPE and both peptides were significantly displaced by pretreatment with naloxone or naltrindole. The amount of [3H]DPDPE detected in the brain was greater than that of [p-125IPhe4]DPDPE. Distribution results revealed large amounts of the administered peptides were sequestered rapidly in the gall bladder and secreted into the small intestine. Hot-plate antinociception tests 5 min after i.v. administration (30 and 60 mg/kg) revealed [p-Cl-Phe4]DPDPE to elicit a much greater analgesic effect as compared to DPDPE or [p-125IPhe4]DPDPE. These results provide evidence that [p-Cl-Phe4]DPDPE has a greater apparent distribution to the brain and has a greater effect on the antinociception threshold as tested on the hot-plate than DPDPE or [p-125IPhe4]DPDPE. Stability of unlabeled and tritiated DPDPE and [p-Cl-Phe4]DPDPE was determined both in vitro and in vivo; both unlabeled and tritiated DPDPE and [p-Cl-Phe4]DPDPE remain intact.

Original languageEnglish (US)
Pages (from-to)1109-1117
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume259
Issue number3
StatePublished - 1991

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D-Penicillamine (2,5)-Enkephalin
Intravenous Administration
Analgesia
naltrindole
Brain

ASJC Scopus subject areas

  • Pharmacology

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Distribution and analgesia of [3H][D-Pen2,D-Pen5]enkephalin and two halogenated analogs after intravenous administration. / Weber, S. J.; Greene, D. L.; Sharma, S. D.; Yamamura, H. I.; Kramer, T. H.; Burks, T. F.; Hruby, Victor J; Hersh, L. B.; Davis, Thomas P.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 259, No. 3, 1991, p. 1109-1117.

Research output: Contribution to journalArticle

Weber, S. J. ; Greene, D. L. ; Sharma, S. D. ; Yamamura, H. I. ; Kramer, T. H. ; Burks, T. F. ; Hruby, Victor J ; Hersh, L. B. ; Davis, Thomas P. / Distribution and analgesia of [3H][D-Pen2,D-Pen5]enkephalin and two halogenated analogs after intravenous administration. In: Journal of Pharmacology and Experimental Therapeutics. 1991 ; Vol. 259, No. 3. pp. 1109-1117.
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AU - Greene, D. L.

AU - Sharma, S. D.

AU - Yamamura, H. I.

AU - Kramer, T. H.

AU - Burks, T. F.

AU - Hruby, Victor J

AU - Hersh, L. B.

AU - Davis, Thomas P

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