Inhibition of the development of morphine tolerance by a potent dual mu-delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph

Pharmacol Biochem Behav. 2008 Oct;90(4):651-7. doi: 10.1016/j.pbb.2008.05.008.

Abstract

Three analogues of the dual mu-/delta-antagonist, H-Dmt-Tic-R-NH-CH2-Ph (R = 1, Lys-Z; 2, Lys-Ac; 3, Lys) were examined in vivo: 1 and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (delta-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOP, a mu antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Area Under Curve
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Injections, Intraventricular
  • Injections, Subcutaneous
  • Ligands
  • Male
  • Mice
  • Morphine / pharmacology*
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Oligopeptides / pharmacology*
  • Reaction Time / drug effects
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, mu / antagonists & inhibitors*
  • Somatostatin / analogs & derivatives
  • Somatostatin / pharmacology

Substances

  • Analgesics, Opioid
  • H-Dmt-Tic-Lys(Z)-NH-CH2-Ph
  • Ligands
  • Narcotic Antagonists
  • Oligopeptides
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide
  • deltorphin I, Ala(2)-
  • Somatostatin
  • Naltrexone
  • Morphine
  • naltrindole