Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Opioids inhibit breathing in mammals, especially in newborns, and are also implicated in the control of hypoxic anapyrexia. We measured breathing patterns and metabolic responses to 12% oxygen in six adult male wildtype C57B/6J mice and six preproenkephalin knockout (PPNK-/-) mice in a flow-through respirometer and barometric plethysmograph with ambient temperature maintained in the thermoneutral zone. Breathing air, there was no significant difference between the two groups of mice in ventilation ((.)V), oxygen consumption ((.)V(O(2)), convection requirement ((.)V/(.)V(O(2)), tidal volume (V(t)), frequency (f), or inspiratory time (T(i)); however, PPNK-/- mice had a significantly shorter expiratory time (T(e)). The breathing pattern response to 5% CO(2) was the same between wildtype and PPNK-/- in terms of absolute values, but the % change in V(t) was greater in the wildtype. Breathing 12% O(2), there was no significant difference in V , V(t), f, T(i), T(e) or body temperature between groups, but there was a significant difference in (.)V(O(2) (PPNK-/- 1.24+/-0.05 ml O(2)min(-1) versus 0.91+/-0.05 for wildtype, P<0.001) and % change in (.)V(O(2), (2.3+/-6.6% for PPNK-/- versus -28+/-3.8% for wildtype); in ((.)V/(.)V(O(2)), (54+/-4 versus 78+/-10, P<0.05) and the % change in (.)V/(.)V(O(2), (37+/-9 versus 131+/-28, P<0.01). These data implicate enkephalin as a signaling molecule in the control of hypoxic depression of metabolism in mice.
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PMID:Absence of an hypoxic depression of metabolism in preproenkephalin knockout mice. 1609 81

In the present study, we first observed up-regulation in preproenkephalin (PPE)-like immunoreactivity (-LIR), a precursor of Met- and Leu-enkephalin, in the rat ipsilateral medial vestibular nucleus (ipsi-MVN) after unilateral labyrinthectomy (UL). By means of double-staining immunohistochemistry with PPE and Fos, a putative regulator of PPE gene expression, we revealed that some of these PPE-LIR neurons were also Fos immunopositive. The time course of decay of these double-stained neurons was quite parallel to that of UL-induced behavioral deficits. This suggests that these double-labeled neurons could have something to do with development of vestibular compensation. We next examined correlation between Fos and PPE expression in the ipsi-MVN by means of a 15-min pre-UL application of antisense oligonucleotide probes against c-fos mRNA into the ipsi-MVN. Gel shift assay and Western blotting revealed that elimination of Fos expression significantly reduced both AP-1 DNA binding activity and PPE expression in the ipsi-MVN after UL. C-fos antisense study also revealed that depression of Fos-PPE signaling in the ipsi-MVN caused significantly more severe behavioral deficits during vestibular compensation. Furthermore, studies with PPE antisense and naloxone, an opioid receptor antagonist, demonstrated that specific depression of enkephalinergic effects in the ipsi-MVN significantly delayed vestibular compensation. All these findings suggest that, immediately after UL, Fos induced in some of the ipsi-MVN neurons could regulate consequent PPE expression via the AP-1 activation and facilitate the restoration of balance between bilateral MVN activities via the opioid receptor activation, resulting in progress of vestibular compensation.
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PMID:Fos-enkephalin signaling in the rat medial vestibular nucleus facilitates vestibular compensation. 1654 69

Clinical, preclinical, and pharmacological studies have suggested that decreased enkephalin tone is associated with depression-like symptoms and increase in enkephalin signaling could have a therapeutic value in the treatment of depression. In this study we demonstrate that, surprisingly, animals lacking enkephalin (preproenkephalin, Penk1(-/-)) showed no depression-related phenotype in the Porsolt forced swimming or tail suspension tests. Moreover, Penk1(-/-) mice had a lower frequency of depression-related behavior in stress-induced hypoactivity and ultrasonic vocalization models of depression, similar to animals treated with antidepressant drugs, although this effect was specific to the genetic background. In addition, there was no significant difference in the efficacy of antidepressant reference compounds in wild-type and knockout animals. Nialamide and amitriptyline were even slightly more effective in animals with genetic deletion of Penk1, whereas the minimal effective dose of imipramine and fluoxetine was the same in the two genotypes. The dual peptidase inhibitor RB-101 was also effective in Penk1(-/-) as well as in Penk1(-/-)/Pdyn(-/-) animals, although its efficacy was somewhat reduced compared with wild-type animals. This result was also surprising because the antidepressant effects of RB-101 were thought to be due to the elevation of enkephalin levels.
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PMID:Preproenkephalin knockout mice show no depression-related phenotype. 1737 41

Enhanced stress reactivity or sensitivity to chronic stress increases the susceptibility to mood pathologies such as major depression. The opioid peptide enkephalin is an important modulator of the stress response. Previous studies using preproenkephalin knockout (PENK KO) mice showed that these animals exhibit abnormal stress reactivity and show increased anxiety behavior in acute stress situations. However, the consequence of enkephalin deficiency in the reactivity to chronic stress conditions is not known. In this study, we therefore submitted wild-type (WT) and PENK KO male mice to chronic stress conditions, using the chronic mild stress (CMS) protocol. Subsequently, we studied the CMS effects on the behavioral and hormonal level and also performed gene expression analyses. In WT animals, CMS increased the expression of the enkephalin gene in the paraventricular nucleus (PVN) of the hypothalamus and elevated the corticosterone levels. In addition, WT mice exhibited enhanced anxiety in the zero-maze test and depression-related behaviors in the sucrose preference and forced swim tests. Surprisingly, in PENK KO mice, we did not detect anxiety and depression-related behavioral changes after the CMS procedure, and even measured a decreased hormonal stress response. These results indicate that PENK KO mice are resistant to the CMS effects, suggesting that enkephalin enhances the reactivity to chronic stress.
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PMID:Enkephalin knockout male mice are resistant to chronic mild stress. 2480 98

Adverse life experiences increase the lifetime risk to several stress-related psychopathologies, such as anxiety or depressive-like symptoms following stress in adulthood. However, the neurochemical modulations triggered by stress have not been fully characterized. Neuropeptides play an important role as signaling molecules that contribute to physiological regulation and have been linked to neurological and psychiatric diseases. However, little is known about the influence of stress on neuropeptide regulation in the brain. Here, we have performed an exploratory study of how neuropeptide expression at adulthood is modulated by experiencing a period of multiple stressful experiences. We have targeted hippocampus and prefrontal cortex (PFC) brain areas, which have previously been shown to be modulated by stressors, employing a targeted liquid chromatography-mass spectrometry (LC-MS) based approach that permits broad peptide coverage with high sensitivity. We found that in the hippocampus, Met-enkephalin, Met-enkephalin-Arg-Phe, and Met-enkephalin-Arg-Gly-Leu were upregulated, while Leu-enkephalin and Little SAAS were downregulated after stress. In the PFC area, Met-enkephalin-Arg-Phe, Met-enkephalin-Arg-Gly-Leu, peptide PHI-27, somatostatin-28 (AA1-12), and Little SAAS were all downregulated. This systematic evaluation of neuropeptide alterations in the hippocampus and PFC suggests that stressors impact neuropeptides and that neuropeptide regulation is brain-area specific. These findings suggest several potential peptide candidates, which warrant further investigations in terms of correlation with depression-associated behaviors.
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PMID:Stress Impacts the Regulation Neuropeptides in the Rat Hippocampus and Prefrontal Cortex. 2940 25


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