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 Citations (Scopus)

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

Fingerprint

Ethylene Glycol
Polyethylene glycols
Molecular Weight
Molecular weight
Analgesia
naltrindole
biphalin
Area Under Curve
Naloxone
Intravenous Administration

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

Conjugation of low molecular weight poly(ethylene glycol) to biphalin enhances antinociceptive profile. / Huber, Jason D.; Campos, Chris R.; Egleton, Richard D.; Witt, Ken; Guo, Lihong; Roberts, Michael J.; Bentley, Michael D.; Davis, Thomas P.

In: Journal of Pharmaceutical Sciences, Vol. 92, No. 7, 01.07.2003, p. 1377-1385.

Research output: Contribution to journalArticle

Huber, JD, Campos, CR, Egleton, RD, Witt, K, Guo, L, Roberts, MJ, Bentley, MD & Davis, TP 2003, 'Conjugation of low molecular weight poly(ethylene glycol) to biphalin enhances antinociceptive profile', Journal of Pharmaceutical Sciences, vol. 92, no. 7, pp. 1377-1385. https://doi.org/10.1002/jps.10406
Huber, Jason D. ; Campos, Chris R. ; Egleton, Richard D. ; Witt, Ken ; Guo, Lihong ; Roberts, Michael J. ; Bentley, Michael D. ; Davis, Thomas P. / Conjugation of low molecular weight poly(ethylene glycol) to biphalin enhances antinociceptive profile. In: Journal of Pharmaceutical Sciences. 2003 ; Vol. 92, No. 7. pp. 1377-1385.
@article{da12b24450de4f82aa92165e09fa2a7a,
title = "Conjugation of low molecular weight poly(ethylene glycol) to biphalin enhances antinociceptive profile",
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.",
keywords = "μ-opioid receptor, Analgesia, Opioid peptide, Tail flick",
author = "Huber, {Jason D.} and Campos, {Chris R.} and Egleton, {Richard D.} and Ken Witt and Lihong Guo and Roberts, {Michael J.} and Bentley, {Michael D.} and Davis, {Thomas P}",
year = "2003",
month = "7",
day = "1",
doi = "10.1002/jps.10406",
language = "English (US)",
volume = "92",
pages = "1377--1385",
journal = "Journal of Pharmaceutical Sciences",
issn = "0022-3549",
publisher = "John Wiley and Sons Inc.",
number = "7",

}

TY - JOUR

T1 - Conjugation of low molecular weight poly(ethylene glycol) to biphalin enhances antinociceptive profile

AU - Huber, Jason D.

AU - Campos, Chris R.

AU - Egleton, Richard D.

AU - Witt, Ken

AU - Guo, Lihong

AU - Roberts, Michael J.

AU - Bentley, Michael D.

AU - Davis, Thomas P

PY - 2003/7/1

Y1 - 2003/7/1

N2 - 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.

AB - 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.

KW - μ-opioid receptor

KW - Analgesia

KW - Opioid peptide

KW - Tail flick

UR - http://www.scopus.com/inward/record.url?scp=0038759641&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038759641&partnerID=8YFLogxK

U2 - 10.1002/jps.10406

DO - 10.1002/jps.10406

M3 - Article

C2 - 12820142

AN - SCOPUS:0038759641

VL - 92

SP - 1377

EP - 1385

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 7

ER -