Elsevier

Life Sciences

Volume 61, Issue 26, 21 November 1997, Pages PL409-PL415
Life Sciences

PHARMACOLOGY LETTERS
THE ENDOGENOUS μ-OPIOID AGONISTS, ENDOMORPHIN 1 AND 2, HAVE VASODILATOR ACTIVITY IN THE HINDQUARTERS VASCULAR BED OF THE RAT

https://doi.org/10.1016/S0024-3205(97)01029-1Get rights and content

Abstract

Endomorphin 1 and endomorphin 2 are newly-discovered endogenous ligands for the μ-opioid receptor. In the present study, responses to intra-arterial injections of endomorphin 1 and 2 were investigated in the hindquarters vascular bed of the rat. Under constant-flow conditions, endomorphin 1 and 2 induced dose-dependent decreases in hindquarters perfusion pressure when injected in doses of 3–100 nmol into the hindquarters perfusion circuit. Vasodilator responses to endomorphin 1 and 2 and met-enkephalin were attenuated by the opioid receptor antagonist naloxone (2 mg/kg i.v.) at a time when vasodilator responses to isoproterenol were not altered. In terms of relative vasodilator activity, endomorphin 1 and 2 were similar to ATP, 100-fold less potent than isoproterneol, and 10,000-fold less potent than acetylcholine. These data demonstrate that endomorphin 1 and 2 have significant naloxone-sensitive vasodilator activity in the hindquarters vascular bed of the rat. © 1997 Elsevier Science Inc.

Introduction

The endogenous opioid peptides have been shown to have cardiovascular actions in a variety of species 1, 2, 3. Many of the endogenous opioids have activity that is relatively nonselective in nature 1, 2, 3. It is known that the endorphins exhibit preferential affinity for the δ-opioid receptor and the dynorphins bind κ-opioid receptors with high affinity 1, 2, 3. However, it was not until recently that an endogenous μ-selective ligand was isolated [4]. Zadina and colleagues have recently isolated two endogenous, potent, and selective μ-opioid agonists named endomorphin 1 and 2 [4]. Endomorphin 1 (Tyr-Pro-Trp-Phe-NH2) has been shown to possess high affinity (Ki = 360 pM) and selectivity (4,000- and 15,000-fold preference over the δ and κ receptors) for the μ receptor [4]. Endomorphin 2 differs from the endomorphin 1 by one amino acid (Tyr-Pro-Phe-Phe-NH2), yet also possesses a high affinity (Ki = 690 pM) and selectivity (>13,000-fold preference over δ receptors) for the μ-opioid receptor [4]. Moreover, an immunohistochemical study has demonstrated endomorphin 1 to be localized in several brain regions, including the thalamus, hypothalamus, striatum, and frontal cortex [4]. The discovery of these novel opioids, which have high affinity and selectivity for the μ receptor, may lead to the development of new analgesic agents, which have less addictive properties than morphine to the development of a new class of vasodilator agents, which may be useful in the treatment of peripheral vaso-occlusive disorders.

While a recent study has shown that endomorphin 1 and 2 decrease systemic arterial pressure in the rat, little if anything is known about responses to the endomorphins in the regional vascular bed of this species [5]. The present study was, therefore, undertaken to determine if the newly discovered μ-opioid receptor selective tetrapeptides, endomorphin 1 and endomorphin 2, have vasodilator activity in the hindquarters vascular bed of the rat and to study the effects of the opioid receptor antagonist naloxone on responses to the newly discovered μ-receptor agonists.

Section snippets

Methods

Sprague-Dawley rats of either sex, weighing 290–360 g, were anesthetized with pentobarbital sodium (50 mg/kg i.v.). Supplemental doses of pentobarbital were given during the course of the experiment to ensure a uniform level of anesthesia. The trachea was cannulated, and the rats breathed spontaneously or were ventilated with a Harvard model 683 rodent ventilator at a tidal volume of 2.5 ml and at a rate of 30 breaths/min with room air enriched with 95% O2/5% CO2. Catheters were inserted into

Results

Responses to endomorphin 1 and 2 were investigated in the hindquarters vascular bed and were compared with responses to the well-known physiologically important vasodilators acetylcholine and ATP and to the beta receptor agonist isoproterenol. Under constant-flow conditions, injections of endomorphin 1 and 2 into the perfusion circuit in doses of 3–100 nmol caused dose-related decreases in hindquarters perfusion pressure (Fig. 1). Injections of acetylcholine (1–10 ng) [0.0055–0.055 nmol], ATP

Discussion

The results of the present study demonstrate that endomorphin 1 and 2 decrease hindquarters perfusion pressure in a dose-related manner in the rat. Inasmuch as blood flow to the hindquarters vascular bed was maintained constant, the decreases in perfusion pressure in response to the opioid peptides reflect decreases in hindquarters vascular resistance. The vasodilator responses were rapid in onset and were similar in duration. In terms of relative vasodilator activity in the hindquarters

Acknowledgements

The studies were supported, in part, by NIH grant HL15580 and a grant from the American Heart Association-Louisiana, Inc. Hunter C. Champion was supported by NIH grant HL9474.

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