Antinociceptive profile of biphalin, a dimeric enkephalin analog

P. J. Horan, A. Mattia, E. J. Bilsky, S. Weber, Thomas P Davis, H. I. Yamamura, E. Malatynska, S. M. Appleyard, J. Slaninova, A. Misicka, A. W. Lipkowski, Victor J Hruby, Frank Porreca

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

The dimeric enkephalin biphalin (Tyr-D-Ala-Gly-Phe-NH)2 was evaluated in mice using antinociceptive, gastrointestinal and physical dependence paradigms and compared with that of morphine (reference μ agonist) and etorphine (ultrapotent opioid agonist). Intracerebroventricular biphalin was 6.7- and 257-fold more potent than etorphine or morphine in eliciting antinociception. When administered i.t., biphalin produced only a 60% maximal antinociceptive effect in the tail-flick test even when given at doses up to 3 orders of magnitude higher than those effective i.c.v.; morphine was equipotent in this assay when given i.c.v. or i.t. Both morphine and biphalin were equipotent after i.p. administration. In spite of its antinociceptive effectiveness after i.p. administration, only a small fraction of [125I]biphalin was shown to penetrate to the brain (0.051 ± 0.011%, at 20 min). After i.c.v. administration, biphalin antinociception was antagonized by receptor selective doses of β-funaltrexamine (μ antagonist), naloxonazine (μ1 antagonist), ICI 174,864 (δ antagonist) and [D- Ala2,Cys4]deltorphin (δ2 antagonist), but not by [D- Ala2,Leu5,Cys6]enkephalin (δ1 antagonist) or nor-binaltorphimine (κ antagonist), whereas etorphine antinociception was significantly antagonized only by β-funaltrexamine and naloxonazine. Intracerebroventricular biphalin inhibited gastrointestinal propulsion at doses 8-fold higher than those producing i.c.v. antinociception; i.c.v. morphine showed a similar antinociceptive and gastrointestinal propulsion A50. Intraperitoneal biphalin, but not i.p. morphine, showed little, if any, physical dependence, but both biphalin and morphine produced significant physical dependence when equiantinociceptive doses were infused i.c.v. These results demonstrate an unusual profile for biphalin which suggests a potentially novel mechanism which may involve, in part, the putative opioid receptor complex of physically or functionally interacting μ and δ2 opioid receptors. Biphalin may thus represent the first in a series of such compounds which may lead to significant therapeutic advantages.

Original languageEnglish (US)
Pages (from-to)1446-1454
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume265
Issue number3
StatePublished - 1993

Fingerprint

Enkephalins
Morphine
Etorphine
Opioid Receptors
biphalin
Opioid Analgesics
Tail

ASJC Scopus subject areas

  • Pharmacology

Cite this

Horan, P. J., Mattia, A., Bilsky, E. J., Weber, S., Davis, T. P., Yamamura, H. I., ... Porreca, F. (1993). Antinociceptive profile of biphalin, a dimeric enkephalin analog. Journal of Pharmacology and Experimental Therapeutics, 265(3), 1446-1454.

Antinociceptive profile of biphalin, a dimeric enkephalin analog. / Horan, P. J.; Mattia, A.; Bilsky, E. J.; Weber, S.; Davis, Thomas P; Yamamura, H. I.; Malatynska, E.; Appleyard, S. M.; Slaninova, J.; Misicka, A.; Lipkowski, A. W.; Hruby, Victor J; Porreca, Frank.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 265, No. 3, 1993, p. 1446-1454.

Research output: Contribution to journalArticle

Horan, PJ, Mattia, A, Bilsky, EJ, Weber, S, Davis, TP, Yamamura, HI, Malatynska, E, Appleyard, SM, Slaninova, J, Misicka, A, Lipkowski, AW, Hruby, VJ & Porreca, F 1993, 'Antinociceptive profile of biphalin, a dimeric enkephalin analog', Journal of Pharmacology and Experimental Therapeutics, vol. 265, no. 3, pp. 1446-1454.
Horan PJ, Mattia A, Bilsky EJ, Weber S, Davis TP, Yamamura HI et al. Antinociceptive profile of biphalin, a dimeric enkephalin analog. Journal of Pharmacology and Experimental Therapeutics. 1993;265(3):1446-1454.
Horan, P. J. ; Mattia, A. ; Bilsky, E. J. ; Weber, S. ; Davis, Thomas P ; Yamamura, H. I. ; Malatynska, E. ; Appleyard, S. M. ; Slaninova, J. ; Misicka, A. ; Lipkowski, A. W. ; Hruby, Victor J ; Porreca, Frank. / Antinociceptive profile of biphalin, a dimeric enkephalin analog. In: Journal of Pharmacology and Experimental Therapeutics. 1993 ; Vol. 265, No. 3. pp. 1446-1454.
@article{91c8b2a674064cbb9e1645c5f276b735,
title = "Antinociceptive profile of biphalin, a dimeric enkephalin analog",
abstract = "The dimeric enkephalin biphalin (Tyr-D-Ala-Gly-Phe-NH)2 was evaluated in mice using antinociceptive, gastrointestinal and physical dependence paradigms and compared with that of morphine (reference μ agonist) and etorphine (ultrapotent opioid agonist). Intracerebroventricular biphalin was 6.7- and 257-fold more potent than etorphine or morphine in eliciting antinociception. When administered i.t., biphalin produced only a 60{\%} maximal antinociceptive effect in the tail-flick test even when given at doses up to 3 orders of magnitude higher than those effective i.c.v.; morphine was equipotent in this assay when given i.c.v. or i.t. Both morphine and biphalin were equipotent after i.p. administration. In spite of its antinociceptive effectiveness after i.p. administration, only a small fraction of [125I]biphalin was shown to penetrate to the brain (0.051 ± 0.011{\%}, at 20 min). After i.c.v. administration, biphalin antinociception was antagonized by receptor selective doses of β-funaltrexamine (μ antagonist), naloxonazine (μ1 antagonist), ICI 174,864 (δ antagonist) and [D- Ala2,Cys4]deltorphin (δ2 antagonist), but not by [D- Ala2,Leu5,Cys6]enkephalin (δ1 antagonist) or nor-binaltorphimine (κ antagonist), whereas etorphine antinociception was significantly antagonized only by β-funaltrexamine and naloxonazine. Intracerebroventricular biphalin inhibited gastrointestinal propulsion at doses 8-fold higher than those producing i.c.v. antinociception; i.c.v. morphine showed a similar antinociceptive and gastrointestinal propulsion A50. Intraperitoneal biphalin, but not i.p. morphine, showed little, if any, physical dependence, but both biphalin and morphine produced significant physical dependence when equiantinociceptive doses were infused i.c.v. These results demonstrate an unusual profile for biphalin which suggests a potentially novel mechanism which may involve, in part, the putative opioid receptor complex of physically or functionally interacting μ and δ2 opioid receptors. Biphalin may thus represent the first in a series of such compounds which may lead to significant therapeutic advantages.",
author = "Horan, {P. J.} and A. Mattia and Bilsky, {E. J.} and S. Weber and Davis, {Thomas P} and Yamamura, {H. I.} and E. Malatynska and Appleyard, {S. M.} and J. Slaninova and A. Misicka and Lipkowski, {A. W.} and Hruby, {Victor J} and Frank Porreca",
year = "1993",
language = "English (US)",
volume = "265",
pages = "1446--1454",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Antinociceptive profile of biphalin, a dimeric enkephalin analog

AU - Horan, P. J.

AU - Mattia, A.

AU - Bilsky, E. J.

AU - Weber, S.

AU - Davis, Thomas P

AU - Yamamura, H. I.

AU - Malatynska, E.

AU - Appleyard, S. M.

AU - Slaninova, J.

AU - Misicka, A.

AU - Lipkowski, A. W.

AU - Hruby, Victor J

AU - Porreca, Frank

PY - 1993

Y1 - 1993

N2 - The dimeric enkephalin biphalin (Tyr-D-Ala-Gly-Phe-NH)2 was evaluated in mice using antinociceptive, gastrointestinal and physical dependence paradigms and compared with that of morphine (reference μ agonist) and etorphine (ultrapotent opioid agonist). Intracerebroventricular biphalin was 6.7- and 257-fold more potent than etorphine or morphine in eliciting antinociception. When administered i.t., biphalin produced only a 60% maximal antinociceptive effect in the tail-flick test even when given at doses up to 3 orders of magnitude higher than those effective i.c.v.; morphine was equipotent in this assay when given i.c.v. or i.t. Both morphine and biphalin were equipotent after i.p. administration. In spite of its antinociceptive effectiveness after i.p. administration, only a small fraction of [125I]biphalin was shown to penetrate to the brain (0.051 ± 0.011%, at 20 min). After i.c.v. administration, biphalin antinociception was antagonized by receptor selective doses of β-funaltrexamine (μ antagonist), naloxonazine (μ1 antagonist), ICI 174,864 (δ antagonist) and [D- Ala2,Cys4]deltorphin (δ2 antagonist), but not by [D- Ala2,Leu5,Cys6]enkephalin (δ1 antagonist) or nor-binaltorphimine (κ antagonist), whereas etorphine antinociception was significantly antagonized only by β-funaltrexamine and naloxonazine. Intracerebroventricular biphalin inhibited gastrointestinal propulsion at doses 8-fold higher than those producing i.c.v. antinociception; i.c.v. morphine showed a similar antinociceptive and gastrointestinal propulsion A50. Intraperitoneal biphalin, but not i.p. morphine, showed little, if any, physical dependence, but both biphalin and morphine produced significant physical dependence when equiantinociceptive doses were infused i.c.v. These results demonstrate an unusual profile for biphalin which suggests a potentially novel mechanism which may involve, in part, the putative opioid receptor complex of physically or functionally interacting μ and δ2 opioid receptors. Biphalin may thus represent the first in a series of such compounds which may lead to significant therapeutic advantages.

AB - The dimeric enkephalin biphalin (Tyr-D-Ala-Gly-Phe-NH)2 was evaluated in mice using antinociceptive, gastrointestinal and physical dependence paradigms and compared with that of morphine (reference μ agonist) and etorphine (ultrapotent opioid agonist). Intracerebroventricular biphalin was 6.7- and 257-fold more potent than etorphine or morphine in eliciting antinociception. When administered i.t., biphalin produced only a 60% maximal antinociceptive effect in the tail-flick test even when given at doses up to 3 orders of magnitude higher than those effective i.c.v.; morphine was equipotent in this assay when given i.c.v. or i.t. Both morphine and biphalin were equipotent after i.p. administration. In spite of its antinociceptive effectiveness after i.p. administration, only a small fraction of [125I]biphalin was shown to penetrate to the brain (0.051 ± 0.011%, at 20 min). After i.c.v. administration, biphalin antinociception was antagonized by receptor selective doses of β-funaltrexamine (μ antagonist), naloxonazine (μ1 antagonist), ICI 174,864 (δ antagonist) and [D- Ala2,Cys4]deltorphin (δ2 antagonist), but not by [D- Ala2,Leu5,Cys6]enkephalin (δ1 antagonist) or nor-binaltorphimine (κ antagonist), whereas etorphine antinociception was significantly antagonized only by β-funaltrexamine and naloxonazine. Intracerebroventricular biphalin inhibited gastrointestinal propulsion at doses 8-fold higher than those producing i.c.v. antinociception; i.c.v. morphine showed a similar antinociceptive and gastrointestinal propulsion A50. Intraperitoneal biphalin, but not i.p. morphine, showed little, if any, physical dependence, but both biphalin and morphine produced significant physical dependence when equiantinociceptive doses were infused i.c.v. These results demonstrate an unusual profile for biphalin which suggests a potentially novel mechanism which may involve, in part, the putative opioid receptor complex of physically or functionally interacting μ and δ2 opioid receptors. Biphalin may thus represent the first in a series of such compounds which may lead to significant therapeutic advantages.

UR - http://www.scopus.com/inward/record.url?scp=0027379024&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027379024&partnerID=8YFLogxK

M3 - Article

C2 - 8389867

AN - SCOPUS:0027379024

VL - 265

SP - 1446

EP - 1454

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -