Endomorphins have orexigenic and anxiolytic activities in mice

Asakawa, Akihiro; Inui, Akio; Momose, Kazuhiro; Ueno, Naohiko; Fujino, Masayuki; Kasuga, Masato

doi:10.1097/00001756-199807130-00022

Cited by 81 publications

(44 citation statements)

References 4 publications

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“…These results indicate that the Antidepressant effect of endomorphins J Fichna et al effect of endomorphins is mediated, in great part, through central m-opioid receptors. Endomorphin-1 and endomorphin-2 were shown to possess a high affinity and an extreme selectivity for the m-opioid receptors and most of their effects are mediated through the m-binding sites (Champion et al, 1997;Asakawa et al, 1998;Czapla et al, 2000;Fichna et al, 2005). It has also been demonstrated that there is a significant association between the m-opioid receptors and the etiology of depressive disorders.…”

Section: Discussionmentioning

confidence: 99%

Antidepressant-Like Effect of Endomorphin-1 and Endomorphin-2 in Mice

Fichna

Janecka

Piestrzeniewicz

et al. 2006

Neuropsychopharmacol

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Endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 ) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 ) are two recently isolated m-opioid selective peptides with a potent antinociceptive activity, involved in a number of physiological processes, including food intake, vasomotricity, sexual behavior, as well as neuroendocrine and cardiorespiratory functions. The neuroanatomical distribution of endomorphins prompted us to study their antidepressant activity in two animal behavioral models of depression: forced-swimming and tail-suspension tests. In both tests, the intracerebroventricular (i.c.v.) injection of either endomorphin-1 or endomorphin-2 significantly decreased the duration of immobility, interpreted as an expression of 'behavioral despair', which could be related to the depression syndrome. These effects of endomorphins did not result from the stimulation of the animal motor activity. We have also demonstrated that the antidepressant-like effect of endomorphins was antagonized by the universal opioid antagonist, naloxone and the m-opioid receptor selective antagonist, b-funaltrexamine. In contrast, this effect was not antagonized by d-and k-opioid receptor selective antagonists, naltrindole and nor-binaltorphimine, respectively. The results of the present study demonstrate that endomorphin-1 and endomorphin-2 produce potent antidepressant-like effects after i.c.v. injection in mice. We may suggest that endomorphins and the m-opioid receptors might be involved in the physiopathology of depressive disorders, and that the endomorphinergic system could serve as a novel target for the development of antidepressant drugs. Neuropsychopharmacology (2007) 32, 813-821.

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Section: Discussionmentioning

confidence: 99%

Antidepressant-Like Effect of Endomorphin-1 and Endomorphin-2 in Mice

Fichna

Janecka

Piestrzeniewicz

et al. 2006

Neuropsychopharmacol

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“…11,12) Intraperitoneally (i.p.) administered soymorphins-5, -6, and -7 at doses of 3-10 mg/kg increased the percentage (%) of time spent in the open arms (Fig.…”

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confidence: 99%

Soymorphins, Novel μ Opioid Peptides Derived from Soy β-Conglycinin β-Subunit, Have Anxiolytic Activities

Ohinata

Agui

Yoshikawa

2007

Bioscience, Biotechnology, and Biochemistry

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Based on the amino acid sequence YPFV found in the soy -conglycinin -subunit, which is common to an opioid peptide human -casomorphin-4, peptides YPF-VV, YPFVVN, and YPFVVNA were synthesized according to their primary structure. On guinea pig ileum (GPI) assay, they showed opioid activity (IC 50 = 6.0, 9.2 and 13 M respectively) more potent than humancasomorphins, and were named soymorphins-5, -6, and -7, respectively. Their opioid activities on mouse vas deferens (MVD) assay were less potent than on GPI assay, suggesting that they are selective for the opioid receptor. Human -casomorphin-4 and soymorphin-5 were released from the soy 7S fraction (-conglycinin) by the action of gastrointestinal proteases. Soymorphins-5, -6, and -7 had anxiolytic activities after oral administration at doses of 10-30 mg/kg in the elevated plus-maze test in mice.Key words: opioid peptide; opioid receptor; anxiolytic effect; soy protein; -conglycinin -subunitOpioid is a chemical substance that has morphine-like action. An opioid peptide, bovine -casomorphin-7 (YPFPGPI), isolated from casein peptone, was the first example of bioactive peptides released from food proteins.1) We have reported that human -casomorphin-4 (YPFV) and related peptides derived from human -casein also have opioid activities, though they are less potent than their bovine counterparts.2) Of three soyconglycinin subunits (, 0 , and ), 3) the -subunit has the human -casomorphin-4 sequence (YPFV). Longer peptides, YPFVV, YPFVVN, and YPFVVNA, were synthesized according to the primary structure of theconglycinin -subunit by the Fmoc strategy, and their opioid activities were tested by guinea pig ileum (GPI) and mouse vas deferens (MVD) assay, as previously described.4) All experiments were approved by the Kyoto University Ethics Committee for Animal Research Use.The peptides were found to have opioid activities on GPI assay. Figure 1 indicates the typical suppressive effect of YPFVV on electrically stimulated contractions on GPI assay. YPFVVN and YPFVVNA also dosedependently inhibited ileum contractions (data not shown). These results suggest that YPFVV, YPFVVN, and YPFVVNA have opioid activities; they were named soymorphins-5, -6, and -7 respectively. The opioid activities of synthetic peptides derived from the soyconglycinin -subunit are summarized in Table 1. The IC 50 values of soymorphins-5, -6, and -7 on GPI assay were 6.0, 9.2, and 13 mM respectively, and their opioid activities were more potent than those of humancasomorphin-4, -5, and -6 (IC 50 = 20, 14, and 25 mM, respectively). There are three types of opioid receptors: , , and . 5,6) The opioid activities of soymorphins were larger on GPI assay than those on MVD assay, suggesting that these peptides are selective for theopioid receptor. The affinities for the -opioid receptor were 17, 39, and 47 mM respectively, and the rank order of their affinities for the receptor was consistent with that of the opioid activities on GPI assay. Taking all this 1 µM 3 µM 10 µM 1 min Guinea Pig Ileum (GPI) Assay. Ileum-...

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“…3-30 nmol i.c.v. produced a dose-related increase in food intake (Asakawa et al 1998), and a similar range, 1-30 nmol/kg (i.v. ), of both endomorphins produced a dose-related decrease in systemic arterial pressure (Czapla et al 1998).…”

Section: Figurementioning

confidence: 69%

Endomorphins and activation of the hypothalamo-pituitary-adrenal axis

Coventry

Jessop²,

Finn³

et al. 2001

Journal of Endocrinology

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Endomorphin (EM)-1 and EM-2 are opioid tetrapeptides recently located in the central nervous system and immune tissues with high selectivity and affinity for the µ-opioid receptor. Intracerebroventricular (i.c.v.) administration of morphine stimulates the hypothalamo-pituitary-adrenal (HPA) axis. The present study investigated the effect of centrally administered EM-1 and EM-2 on HPA axis activation. Rats received a single i.c.v. injection of either EM-1 (0·1, 1·0, 10 µg), EM-2 (10 µg), morphine (10 µg), or vehicle (0·9% saline). Blood samples for plasma corticosterone determinations were taken immediately prior to i.c.v. administration and at various time points up to 4 h post-injection. Trunk blood, brains and pituitaries were collected at 4 h. Intracerebroventricular morphine increased plasma corticosterone levels within 30 min, whereas EM-1 and EM-2 were without effect. In addition, pre-treatment of i.c.v. EM-1 did not block the rise in corticosterone after morphine. Corticotrophinreleasing factor (CRF) mRNA and arginine vasopressin (AVP) mRNA in the paraventricular nucleus (PVN) and POMC mRNA in the anterior pituitary were found to be unaffected by either morphine or endomorphins. Since release of other opioids are elevated in response to acute stress, we exposed rats to a range of stressors to determine whether plasma EM-1 and EM-2 can be stimulated by HPA axis activation. Plasma corticosterone, ACTH and -endorphin were elevated following acute restraint stress, but concentrations of plasma EM-1-immunoreactivity (ir) and EM-2-ir did not change significantly. Corticosterone, ACTH and -endorphin were further elevated in adjuvant-induced arthritis (AA) rats by a single injection of lipopolysaccharide (LPS), but not by restraint stress. In conclusion, neither EM-1 or EM-2 appear to influence the regulation of the HPA axis. These data suggest that endomorphins may be acting on a different subset of the µ-opioid receptor than morphine. The failure to induce changes in plasma EM-ir in response to the chronic inflammatory stress of AA, the acute immunological stress of LPS, or the psychological stress of restraint, argues against an important role for endomorphins in mediating HPA axis activity.

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Endomorphins have orexigenic and anxiolytic activities in mice

Cited by 81 publications

References 4 publications

Antidepressant-Like Effect of Endomorphin-1 and Endomorphin-2 in Mice

Antidepressant-Like Effect of Endomorphin-1 and Endomorphin-2 in Mice

Soymorphins, Novel μ Opioid Peptides Derived from Soy β-Conglycinin β-Subunit, Have Anxiolytic Activities

Endomorphins and activation of the hypothalamo-pituitary-adrenal axis

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