The AAPS Journal

, Volume 6, Issue 4, pp 68–73

Stabilized dynorphin derivatives for modulating antinociceptive activity in morphine tolerant rats: Effect of different routes of administration

Article

DOI: 10.1208/aapsj060436

Cite this article as:
Brugos, B., Arya, V. & Hochhaus, G. AAPS J (2004) 6: 68. doi:10.1208/aapsj060436

Abstract

Dynorphins, such as dynorphin A(1–13) (Dyn A(1–13)), have been shown to enhance analgesia in morphine-tolerant animals, despite their very short half-life after intravenous administration. The potential use of dynorphins in humans is therefore of interest. This laboratory has recently evaluated the metabolic fate of stabilized dynorphin derivatives. This study was conducted to evaluate whether such stabilized derivatives, ie, [N-Met-Tyr1]-Dynorphin A(1–13) (N-MT Dyn A, stabilized at the N-terminal end) and [N-Met-Tyr1]-Dynorphin A(1–13) amide (N-MT Dyn A amide, stabilized at the C-and N-terminal ends), would enhance the antinociceptive activity of morphine not only after intravenous administration but also after subcutaneous and pulmonary delivery. Intravenous administration of N-MT Dyn A (5 μmol/kg) and N-MT Dyn A amide (5 μmol/kg) to morphine-tolerant rats resulted in significantly higher tail-flick latencies than those observed for the saline group. These effects could be observed for up to 2.0±0.1 hours after intravenous administration of N-MT Dyn A and for up to 3.4±1.4 hours for N-MT Dyn A amide. The time-averaged effects of both peptides were similar. After pulmonary delivery of the same dose, derivatives remained active. The duration of the effects after pulmonary administration of the amide was 4.4±2.5 hours while that of N-MT Dyn A was slightly shorter (2.8±0.9 hours). No effect was observed after subcutaneous administration of N-MT Dyn A. These results suggest that pulmonary delivery of stabilized dynorphin derivatives represents a possible alternative to intravenous administration.

Keywords

dynorphin derivatives morphine pulmonary delivery tail-flick test suppression of tolerance 

Copyright information

© American Association of Pharmaceutical Scientists 2004

Authors and Affiliations

  • Boglarka Brugos
    • 1
  • Vikram Arya
    • 1
  • Guenther Hochhaus
    • 1
  1. 1.Department of Pharmaceutics, College of PharmacyUniversity of FloridaGainesville

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