Behavioral and neuroendocrine actions of endomorphin-2
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.
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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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Intracerebroventricular administration of CYX-6, a potent μ-opioid receptor agonist, a δ- and κ-opioid receptor antagonist and a biased ligand at μ, δ & κ-opioid receptors, evokes antinociception with minimal constipation and respiratory depression in rats in contrast to morphine
2020, European Journal of PharmacologyCitation Excerpt :Supraspinal administration of morphine and opioid peptides produced convulsions in rodents and many other species usually at doses higher than the antinociceptive doses (Snead, 1983, 1986; Takemori and Portoghese, 1993; Tortella et al., 1981; Urca and Frenk, 1982). Additionally, increased locomotion was evoked by i.c.v. administration of EM-1 and EM-2 in mice (Bujdoso et al., 2001). Following i.c.v. injection of dynorphin A (2–17) in rats, the neuroexcitatory behaviors observed included convulsions, ataxia, myoclonic jerks and postural abnormality (Hemstapat et al., 2009).
Neuropeptide FF attenuates the acquisition and the expression of conditioned place aversion to endomorphin-2 in mice
2013, Behavioural Brain ResearchCitation Excerpt :The present study demonstrated that 30 nmol EM-2 (i.c.v.) caused a slight, but not statistically significant hyperlocomotor activity. However, the previous reports indicated that low doses (0.25 and 0.5 μg) of EM-2 produced marked hyperlocomotor activity while higher doses (1, 3, 10 and 30 μg) of EM-2 had no effects on locomotor activity after i.c.v. administration [51,52]. It is notable that EM-2 can produce effects different from other MOP receptor agonists, which are mediated by the release of endogenous opioids and subsequently act on KOP receptor [7].
Endomorphins
2013, Handbook of Biologically Active PeptidesOrexigenic effects of endomorphin-2 (em-2) related to decreased crh gene expression and increased dopamine and norepinephrine activity in the hypothalamus
2013, PeptidesCitation Excerpt :Furthermore, we found a significant dose-related decrease of CRH gene expression in EM-2 treated rats, while CART, orexin-A, POMC, AgRP and NPY gene expression was not modified with respect to vehicle (ANOVA, P < 0.0001; post-hoc *P < 0.001 vs. vehicle) (Fig. 2). On the other hand, in a previous work EM-2 dose–response curves exhibited inverted U-shape that is typical of numerous neuropeptides, as regards to both behavioral and neuroendocrine effects [12]. When we evaluated hypothalamic aminergic neurotransmitter levels, we found a significant dose-indipendent increase of hypothalamic DA and NE steady state concentrations after EM-2 treatment, without any effect on 5-HT (ANOVA, P < 0.05; post-hoc *P < 0.05 vs. vehicle) (Table 1).
The action of a synthetic derivative of Met<sup>5</sup>-enkephalin-Arg <sup>6</sup>-Phe<sup>7</sup> on behavioral and endocrine responses
2011, PeptidesCitation Excerpt :Even a one order of magnitude lower dose of NALDI abolished the neuroendocrine responses elicited by DADN. Consequently, in support of earlier published studies [5,6,20], the regulation of neuroendocrine responses by the opioid system is a predominantly μ-receptor-mediated process. Furthermore, our data corroborate the in vitro finding [30,31] that, in sharp contrast with the receptor profile of MERF, it is the μ-receptors that transmit the actions of DADN in vivo.