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) approximately 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 (A(50)) 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.
authors.affiliation: Department of Pharmacology, The University of Arizona College of Medicine, 1501 N. Campbell Avenue, P.O. Box 24-5050, Tucson, AZ 85724, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huber
authors.forename: Chris R
authors.initials: CR
authors.lastname: Campos
authors.forename: Richard D
authors.initials: RD
authors.lastname: Egleton
authors.forename: Ken
authors.initials: K
authors.lastname: Witt
authors.forename: Lihong
authors.initials: L
authors.lastname: Guo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Roberts
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bentley
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D004745:Enkephalins / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D004745:Enkephalins; D011092:Polyethylene Glycols; C053673:biphalin