Elsevier

Peptides

Volume 22, Issue 9, September 2001, Pages 1459-1463
Peptides

Behavioral and neuroendocrine actions of endomorphin-2

https://doi.org/10.1016/S0196-9781(01)00466-1Get rights and content

Abstract

The effects of intracerebroventricularly administered endomorphin-2 (EM2) on open-field activity and the hypothalamo-pituitary-adrenal (HPA) system were investigated. EM2 (0.25–1 μg) significantly increased both the locomotor and the rearing activity, resulting in a bell-shaped dose-response curve. EM2 also enhanced corticosterone release, with an even more profound downturn phase at higher concentrations. The corticotropin-releasing hormone (CRH) antagonist α-helical CRH9–41 completely abolished the EM2-evoked endocrine and behavioral responses. These findings reinforce the hypothesis that the endomorphins may play a significant role in the regulation of locomotion, rearing activity and the HPA system through the release of CRH.

Introduction

Endomorphin-1 (EM1) and endomorphin-2 (EM2) form a novel group of opioid peptides, which selectively bind to the μ-opioid receptor [11], [45].

Previous publications revealed a dense distribution of the endomorphins (EMs) throughout the central nervous system (CNS) [22], [24], [46] and demonstrated versatile physiological actions of this new family of opioids on nociception [23], [31] and cardiovascular processes [5], [8]. These data support the concept that the EMs might function as endogenous ligands of the μ-opioid receptors.

Despite the fact that EM1 (Tyr-Pro-Trp-Phe-NH2) and EM2 (Tyr-Pro-Phe-Phe-NH2) are quite similar in chemical structure [45], they display some noteworthy functional differences. EM1 and EM2 possess distinct analgesic features [34], [39] and they also appear to differ in their actions on autonomic processes [1], [9]. Histologic studies have revealed that their distributional patterns in the CNS differ too [22]: EM1-like immunoreactivity is more widely and densely distributed in the brain, whereas EM2 is more prominent in the spinal cord.

We have recently demonstrated a profound effect of EM1 on the hypothalamo-pituitary-adrenal (HPA) system and on two behavioral paradigms: locomotion and rearing [4]. Since the above-mentioned differences in the biochemical and physiological profiles of the EMs raised the possibility that EM2 might have a divergent role in the regulation of the behavioral and hormonal processes, in the present study the effects of EM2 on the HPA axis and some behavioral phenomena are characterized and compared with those of EM1. Corticotropin-releasing hormone (CRH) plays a very important role in the activation of the HPA axis [42], and has a marked impact on behavioral phenomena, too. It was reported that microinfusion of CRH into the paraventricular nucleus induces locomotion [25], and an increase in rearing has also been described in several publications [35], [43]. In the present experiments, therefore the CRH antagonist α-helical CRH9–41 was applied before the administration of EM2, in order to clarify its possible role in mediation of the EM2-evoked neuroendocrinological responses.

Section snippets

Animals and surgery

Male CFLP mice weighing 25–35 g were used. The animals were kept and handled during the experiments in accordance with the instructions of the University of Szeged Ethical Committee for the Protection of Animals in Research. The mice were allowed a minimum of 1 week to acclimatize before surgery. A polyethylene cannula was implanted into the right lateral brain ventricle under pentobarbital (Nembutal 55 mg/kg) anesthesia 1 week before the experiment. At the end of the experiment, the correct

Study 1. Effects of EM2 on open-field behavior and HPA system

Different doses of EM2 (0.25–1 μg) administered into the right lateral brain ventricle caused significant changes in the behavioral tests (Table 1). A dose of 0.25 μg increased the number of squares explored (F(3, 48), P < 0.05 vs. control), but the most effective dose was 0.5 μg (P < 0.01 vs. the control). A higher dose of the peptide (1 μg) did not give rise to a further increase in locomotion (P = 0.28 vs. the control). The tetrapeptide dose (0.25 μg) that led to a significant response in

Discussion

The present experiments clearly demonstrate that EM2 leads to a marked activation of locomotion and rearing and evokes corticosterone release. The EM2 dose-response curves exhibit inverted U-shape, and the effective concentration range is narrow. Such a dose-response curve is typical of numerous neuropeptides [28], and was described previously for the EMs [44] and their derivatives [18].

Our findings are in harmony with those of earlier studies that showed opioids to have a pronounced impact on

Acknowledgements

The work was supported by the Hungarian National Research Foundation (OTKA T 022230, T 006084 and T 030086), the Hungarian Ministry of Education (FKFP 0091) and the Hungarian Ministry of Social Welfare (T-02–670/96).

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