Conjugation of low molecular weight poly(ethylene glycol) to biphalin enhances antinociceptive profile

Jason D. Huber, Chris R. Campos, Richard D. Egleton, Ken Witt, Lihong Guo, Michael J. Roberts, Michael D. Bentley, Thomas P. Davis

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The objectives of this study were to examine the effect of poly(ethylene glycol) (PEG) conjugation on the tyrosine residues of biphalin to determine the proper size PEG for optimal efficacy and investigate the antinociceptive profile of PEG - biphalin against biphalin via three routes of administration. All antinociception evaluations were made using a radiant-heat tail flick analgesia meter. (2 kDa)2 PEG - biphalin was identified as the optimal size of PEG to enhance the antinociceptive profile following intravenous administration of 685 nmol kg-1 of biphalin or PEG - biphalin [(1 kDa)2, (2 kDa)2, (5 kDa)2, (12 kDa)2, (20 kDa)2]. (2 kDa)2 PEG - biphalin displayed an area under the curve (AUC) ∼2.5 times that of biphalin with enhanced analgesia up to 300 min postinjection. (2 kDa)2 PEG - biphalin was equipotent to biphalin following intracerebroventricular administration (0.4 nmol kg-1). Both biphalin and (2 kDa)2 PEG biphalin were effectively antagonized with naloxone (10 mg kg-1) and a partial antagonistic effect was seen following pretreatment with naltrindole (20 mg kg-1). (2 kDa)2 PEG - biphalin showed significantly increased potency (A50) when administered intravenously and subcutaneously. Additionally, (2 kDa)2 PEG - biphalin demonstrated a significantly enhanced antinociceptive profile (AUC) via all routes of administration tested. These findings indicate that PEG conjugation to biphalin retains opioid-mediated effects observed with biphalin and is a valuable tool for eliciting potent, sustained analgesia via parenteral routes of administration.

Original languageEnglish (US)
Pages (from-to)1377-1385
Number of pages9
JournalJournal of pharmaceutical sciences
Volume92
Issue number7
DOIs
StatePublished - Jul 1 2003

Keywords

  • Analgesia
  • Opioid peptide
  • Tail flick
  • μ-opioid receptor

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Huber, J. D., Campos, C. R., Egleton, R. D., Witt, K., Guo, L., Roberts, M. J., Bentley, M. D., & Davis, T. P. (2003). Conjugation of low molecular weight poly(ethylene glycol) to biphalin enhances antinociceptive profile. Journal of pharmaceutical sciences, 92(7), 1377-1385. https://doi.org/10.1002/jps.10406