Antinociceptive effect of D-Lys(2), Dab(4)N-(ureidoethyl)amide, a new cyclic 1-4 dermorphin/deltorphin analog

Bożena Antkowiak; Małgorzata Paluch; Magdalena Ciechanowska; Małgorzata Nawrocka; Krzysztof Bańkowski; Olga Michalak; Janusz Kocik; Marek Kowalczyk; Jan Izdebski

doi:10.1016/j.pharep.2014.01.007

Antinociceptive effect of D-Lys(2), Dab(4)N-(ureidoethyl)amide, a new cyclic 1-4 dermorphin/deltorphin analog

Pharmacol Rep. 2014 Aug;66(4):600-5. doi: 10.1016/j.pharep.2014.01.007. Epub 2014 Apr 26.

Authors

Bożena Antkowiak¹, Małgorzata Paluch², Magdalena Ciechanowska², Małgorzata Nawrocka², Krzysztof Bańkowski³, Olga Michalak³, Janusz Kocik², Marek Kowalczyk⁴, Jan Izdebski⁵

Affiliations

¹ Military Institute of Hygiene and Epidemiology, Department of Pharmacology and Toxicology, Warsaw, Poland. Electronic address: bantkowiak@wihe.waw.pl.
² Military Institute of Hygiene and Epidemiology, Department of Pharmacology and Toxicology, Warsaw, Poland.
³ Pharmaceutical Research Institute, Warsaw, Poland.
⁴ Military Institute of Hygiene and Epidemiology, Department of Pharmacology and Toxicology, Warsaw, Poland; Józef Piłsudski University of Physical Education, Warsaw, Poland.
⁵ Warsaw University, Department of Chemistry, Warsaw, Poland.

PMID: 24948060
DOI: 10.1016/j.pharep.2014.01.007

Abstract

Background: A preliminary evaluation of antinociceptive activity of a new cyclic dermorphin/deltorphin tetrapeptide analog restricted via a urea bridge and containing C-terminal ureidoethylamid {[H-Tyr-d-Lys(&(1))-Phe-Dab(&(2))-CH2CH2NHCONH2][&(1)CO&(2)]} (cUP-1) revealed a significant and long-lasting increase of pain threshold to thermal stimulation after systemic application. The current studies were aimed at further evaluation of cUP-1 activity in animal models of somatic and visceral pain. The influence of cUP-1 on motor functions was also investigated.

Methods: The influence of cUP-1 (0.5-2mgkg(-1), iv) on nociceptive threshold to mechanical pressure and analgesic efficacy in formalin and acetic acid-induced writhing tests were estimated. The antinociceptive effect of cUP-1 was compared to that of morphine (MF). The influence of cUP-1 (1, 4 and 8mgkg(-1), iv) on locomotor activity, motor coordination and muscle strength was estimated using open field and rota-rod tests and a grip strength measurement.

Results: Administration of cUP-1 in doses of 1 and 2mgkg(-1) elicited a significant increase of nociceptive threshold to mechanical pressure. MF applied in the same doses induced an antinociceptive effect only at the higher dose (2mgkg(-1)). There were no marked differences between the effect of cUP-1 and MF at each dose, at relative time points. In the writhing test and both phases of the formalin test, cUP-1 showed a significant, dose-dependent antinociceptive effect which did not markedly differ from that of MF. cUP-1 did not significantly affect motor functions of mice.

Conclusions: Systemic application of cUP-1 elicited a dose-dependent antinociceptive effect. The analgesic efficacy of cUP-1 on mechanical nociception, visceral and formalin-induced pain was comparable to that of MF. cUP-1 did not impair motor functions of mice.

Keywords: Antinociception; Deltorphins; Dermorphin; Opioid peptide; Ureidopeptide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics, Opioid / chemistry
Analgesics, Opioid / pharmacology*
Analgesics, Opioid / therapeutic use
Animals
Male
Mice, Inbred BALB C
Motor Activity / drug effects
Nociceptive Pain / drug therapy*
Oligopeptides / chemistry
Oligopeptides / pharmacology*
Oligopeptides / therapeutic use
Pain Measurement
Pain Threshold / drug effects
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Peptides, Cyclic / therapeutic use
Rotarod Performance Test
Visceral Pain / drug therapy

Substances

Analgesics, Opioid
Oligopeptides
Peptides, Cyclic
cUP-1 peptide
deltorphin
tyrosyl-alanyl-phenylalanyl-glycine