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Cell Reports Sep 2022Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear....
Low dopamine D2 receptor (D2R) availability in the striatum can predispose for cocaine abuse; though how low striatal D2Rs facilitate cocaine reward is unclear. Overexpression of D2Rs in striatal neurons or activation of D2Rs by acute cocaine suppresses striatal Penk mRNA. Conversely, low D2Rs in D2-striatal neurons increases striatal Penk mRNA and enkephalin peptide tone, an endogenous mu-opioid agonist. In brain slices, met-enkephalin and inhibition of enkephalin catabolism suppresses intra-striatal GABA transmission. Pairing cocaine with intra-accumbens met-enkephalin during place conditioning facilitates acquisition of preference, while mu-opioid receptor antagonist blocks preference in wild-type mice. We propose that heightened striatal enkephalin potentiates cocaine reward by suppressing intra-striatal GABA to enhance striatal output. Surprisingly, a mu-opioid receptor antagonist does not block cocaine preference in mice with low striatal D2Rs, implicating other opioid receptors. The bidirectional regulation of enkephalin by D2R activity and cocaine offers insights into mechanisms underlying the vulnerability for cocaine abuse.
Topics: Analgesics, Opioid; Animals; Cocaine; Cocaine-Related Disorders; Corpus Striatum; Enkephalin, Methionine; Enkephalins; Mice; Narcotic Antagonists; RNA, Messenger; Receptors, Dopamine D1; Receptors, Dopamine D2; Reward; gamma-Aminobutyric Acid
PubMed: 36170833
DOI: 10.1016/j.celrep.2022.111440 -
Oncology Reports Oct 2017Melanoma is a common cutaneous malignancy, that is also found in specific mucosal sites, and is associated with a poor prognosis. The aim of the present study was to...
Melanoma is a common cutaneous malignancy, that is also found in specific mucosal sites, and is associated with a poor prognosis. The aim of the present study was to investigate the cytotoxicity of methionine enkephalin (MENK) for B16 melanoma cells in vivo and in vitro. The results of the present study allowed our conclusion that MENK regulates the proliferation of B16 cells, causing cell cycle arrest in the G0/G1 phase and a decrease in the percentage of cells in the S and G2/M phases. Reverse transcription-quantitative polymerase chain reaction demonstrated that MENK increased opioid receptor expression in the B16 cells. Furthermore, the tumor volume and weight in the MENK-treated group were lower than those in the control group (NS) and MENK and naltrexone (NTX)-treated groups. MENK exerted both significant antitumor activity on the growth of B16 cells and a longer survival time in mice. The mice treated with MENK exhibited an increased ratio of CD4+ to CD8+ T cells as tested by flow cytometry (FCM), resulting in a ratio of 2.03 in the control group, 3.69 in the MENK-treated group, and 2.65 in the MENK and NTX group. Furthermore, a significant increase in plasma levels of IL-2, IFN-γ and TNF-α was revealed as assessed by ELISA. In conclusion, the results of the present study indicate that MENK has a cytotoxic effect on B16 melanoma cells in vitro and in vivo, and suggest a potential mechanism for these bioactivities. Therefore, we posit that MENK should be investigated, not only as a primary therapy for melanoma, but also as an adjuvant therapy in combination with chemotherapies.
Topics: Animals; Cell Cycle Checkpoints; Cell Proliferation; Dendritic Cells; Enkephalin, Methionine; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Interferon-gamma; Interleukin-2; Melanoma, Experimental; Mice; Naltrexone; Tumor Burden; Tumor Necrosis Factor-alpha
PubMed: 28849104
DOI: 10.3892/or.2017.5918 -
Journal of Pharmacological Sciences 2014Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic... (Review)
Review
Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic-pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR.
Topics: Analgesics; Animals; Enkephalin, Methionine; Humans; Hypothalamo-Hypophyseal System; Naloxone; Narcotic Antagonists; Nicotine; Opioid Peptides; Pituitary-Adrenal System; Spinal Cord; Substance Withdrawal Syndrome; Tobacco Use Disorder; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 24882143
DOI: 10.1254/jphs.14r03cp -
British Journal of Pharmacology Feb 19971. A method is described for the rapid extraction of opioid peptides from the brain and other tissues. The method is based on acid extraction of tissues followed by...
1. A method is described for the rapid extraction of opioid peptides from the brain and other tissues. The method is based on acid extraction of tissues followed by adsorption of the extract onto Amberlite XAD-2 resin. Elution with methanol separates the enkephalins and α-endorphin from β-endorphin. 2. Over 90% of the opioid peptide activity isolated from brain and gut of several species by our method was due to methionine- and leucine-enkephalin. In contrast, the major opioid peptide activity recovered from the pituitary was due to peptides of much greater mol. wt. than the enkephalins. 3. An opioid peptide with properties unlike those of the known endorphins or enkephalins was present in brain extracts. This peptide, termed ∈-endorphin, has an apparent mol. wt. of 700 to 1200; it constituted between 5 to 10% of the total opioid activity in our extracts. 4. A differential assay of methionine- and leucine-enkephalin was made either by destroying methionine-enkephalin activity with cyanogen bromide or by separating the peptides by thin layer chromatography. 5. The ratio of methionine-enkephalin to leucine-enkephalin varied greatly in different brain regions. The highest proportions of leucine-enkephalin were found in the cerebral cortex and hippocampus. 6. Formaldehyde perfusion and fixation of the brain had no significant effect on the brain content of enkephalin, indicating that proteolytic breakdown is not a major problem in the extraction of these peptides. 7. It is suggested that the enkephalins may have a neurotransmitter role in both brain and peripheral tissues and that methionine- and leucine-enkephalin may subserve separate neuronal functions.
Topics: Animals; Biological Assay; Brain; Enkephalin, Leucine; Enkephalin, Methionine; Guinea Pigs; History, 20th Century; Ileum; Mice; Pituitary Gland; Rabbits; Rats; Tissue Distribution
PubMed: 9142421
DOI: 10.1111/j.1476-5381.1997.tb06829.x -
Zhongguo Yao Li Xue Bao = Acta... Jan 1998Methionine enkephalin (Met-Enk), the endogenous neuropeptide, is suggested to be involved in the regulatory loop between immune and neuroendocrine systems. Our studies... (Review)
Review
Methionine enkephalin (Met-Enk), the endogenous neuropeptide, is suggested to be involved in the regulatory loop between immune and neuroendocrine systems. Our studies showed that Met-Enk over a wide range of concentrations increased interleukin-1 (IL-1) production from mouse peritoneal macrophages induced by lipopolysaccharides (LPS) and naloxone did not block the enhancing effect. Met-Enk promoted the proliferation of mouse splenocyte and the production of IL-2 and IL-6 in a dose-dependent manner. The up-regulating effects of IL-2 and IL-6 not only augmented their mRNA transcription but also increased their stability. Thus Met-Enk appears to be an important immunomodulatory signaling molecule to exert regulatory actions concerned with the expressing of pre-inflammatory cytokines.
Topics: Animals; Enkephalin, Methionine; Interleukin-1; Interleukin-2; Mice; Neuroimmunomodulation; Tumor Necrosis Factor-alpha
PubMed: 10375747
DOI: No ID Found -
Science (New York, N.Y.) Mar 2022Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal...
Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced µ-opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but it led to a decrease in conditioned place preference caused by fentanyl administration and an enhancement of reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit while mitigating the risk of addiction.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Behavior, Animal; Captopril; Enkephalin, Methionine; Female; Fentanyl; Male; Mice; Miniature Postsynaptic Potentials; Neuronal Plasticity; Nucleus Accumbens; Opioid Peptides; Patch-Clamp Techniques; Peptidyl-Dipeptidase A
PubMed: 35201898
DOI: 10.1126/science.abl5130 -
BMC Immunology Oct 2023Novel prophylactic drugs and vaccination strategies for protection against influenza virus should induce specific effector T-cell immune responses in pulmonary airways...
Novel prophylactic drugs and vaccination strategies for protection against influenza virus should induce specific effector T-cell immune responses in pulmonary airways and peripheral lymphoid organs. Designing approaches that promote T-cell-mediated responses and memory T-cell differentiation would strengthen host resistance to respiratory infectious diseases. The results of this study showed that pulmonary delivery of MENK via intranasal administration reduced viral titres, upregulated opioid receptor MOR and DOR, increased the proportions of T-cell subsets including CD8 T cells, CD8 T cells, NP/PA-effector CD8 T cells in bronchoalveolar lavage fluid and lungs, and CD4/CD8 T cells in lymph nodes to protect mice against influenza viral challenge. Furthermore, we demonstrated that, on the 10th day of infection, the proportions of CD4 T and CD8 T cells were significantly increased, which meant that a stable T and T lineage was established in the early stage of influenza infection. Collectively, our data suggested that MENK administered intranasally, similar to the route of natural infection by influenza A virus, could exert antiviral activity through upregulating T-cell-mediated adaptive immune responses against influenza virus.
Topics: Mice; Animals; Humans; Influenza, Human; CD8-Positive T-Lymphocytes; Enkephalin, Methionine; Memory T Cells; Influenza A virus; Immunologic Memory; Mice, Inbred C57BL
PubMed: 37828468
DOI: 10.1186/s12865-023-00573-0 -
World Journal of Gastroenterology Mar 2014Opioid growth factor (OGF), chemically termed [Met⁵]-enkephalin, and its receptor, OGF receptor (OGFr), form a biological axis that tonically regulates cell... (Review)
Review
Opioid growth factor (OGF), chemically termed [Met⁵]-enkephalin, and its receptor, OGF receptor (OGFr), form a biological axis that tonically regulates cell proliferation by delaying the G₁/S interface of the cell cycle under homeostatic conditions or in neoplasia. Modulation of the OGF-OGFr pathway mediates the course of pancreatic cancer, with exogenous OGF or upregulation of OGFr repressing growth of human pancreatic cancer cells in culture and in nude mice. OGF therapy alone or in combination with standard chemotherapies such as gemcitabine and 5-fluorouracil results in enhanced inhibition of DNA synthesis and tumor growth. Molecular manipulation of OGFr confirms that the receptor is specific for OGF's inhibitory action. Preclinical studies have warranted Phase I and Phase II clinical trials using OGF infusions as a treatment for patients with advanced, unresectable pancreatic cancers. OGF, an endogenous neuropeptide, is a safe, non-toxic, and effective biotherapy that utilizes the OGF-OGFr axis to mediate pancreatic tumor progression.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Disease Models, Animal; Enkephalin, Methionine; Humans; Mice; Pancreatic Neoplasms; Receptors, Opioid; Signal Transduction; Treatment Outcome; Tumor Burden
PubMed: 24605021
DOI: 10.3748/wjg.v20.i9.2218 -
The Journal of Clinical Investigation Mar 1982To elucidate the physiological and pathophysiological significance of methionine- and leucine-enkephalin (Met-and Leu-enkephalin, respectively) in human sympathoadrenal...
To elucidate the physiological and pathophysiological significance of methionine- and leucine-enkephalin (Met-and Leu-enkephalin, respectively) in human sympathoadrenal system, the contents of these peptides in normal human sympathetic nervous system, adrenal medulla, and pheochromocytomas were determined by specific radioimmunoassays combined with reverse-phase high-performance liquid chromatography. Met-enkephalin-LI and Leu-enkephalin-LI, respectively) were detected by radioimmunoassay in adrenal glands, adrenal medulla, stellate ganglia, sympathetic trunks, and celiac ganglia, and their contents in adrenal medulla were highest. Existence of authentic Met- and Leu-enkephalin was confirmed by reverse-phase high-performance liquid chromatography. Met-enkephalin was approximately 74% of Met-enkephalin-LI, whereas Leu-enkephalin was approximately 30% of Leu-enkephalin-LI in human adrenal medulla. The ratio of Met- to Leu-enkephalin was 2.6 in human adrenal medulla, whereas it was higher in sympathetic ganglia or trunks. In four cases of pheochromocytoma marked difference in Met- and Leu-enkephalin contents was found between medullary and extramedullary tumors. The contents were about three orders higher and the Met- to Leu-enkephalin ratio was lower in medullary than in extramedullary pheochromocytomas, reflecting the tissues where the tumors arose. These results suggest the physiological roles of Met- and Leu-enkephalin in sympathetic nervous system and adrenal glands and their pathophysiological significances in pheochromocytomas.
Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Chromatography, High Pressure Liquid; Endorphins; Enkephalin, Leucine; Enkephalin, Methionine; Enkephalins; Humans; Pheochromocytoma; Radioimmunoassay; Sympathetic Nervous System
PubMed: 7061706
DOI: 10.1172/jci110491 -
Brain Research Dec 2004Enkephalin plays a role in the social behaviors of many species, but no corresponding role for this peptide has been investigated in the male Syrian hamster, a species...
Enkephalin plays a role in the social behaviors of many species, but no corresponding role for this peptide has been investigated in the male Syrian hamster, a species in which brain nuclei controlling social behaviors have been identified. Previous studies have shown the distribution of dynorphin and beta-endorphin throughout social behavior circuits within the male hamster brain. To date, the only studies of enkephalin in the hamster brain address the distribution of this peptide in the olfactory bulb and hippocampus. The present study provides a complete map of enkephalinergic neurons within the forebrain and midbrain of the male Syrian hamster and addresses the question of whether enkephalin immunoreactive (Enk-ir) cells are found within brain regions relevant to male hamster social behaviors. Following immunocytochemistry for either methionine enkephalin (met-enkephalin) or leucine enkephalin (leu-enkephalin), we observed enkephalin localization consistent with data that have previously been reported in the rat, with notable exceptions including lateral septum, ventromedial nucleus of the hypothalamus and cingulate gyrus. Additionally, met- and leu-enkephalin localization patterns largely overlap. Consistent with the post-translational processing of preproenkephalin, met-enkephalin was more abundant than leu-enkephalin both within individual cells (darker staining), and within given brain nuclei (more met-enkephalin immunoreactive cells). Two exceptions were the posterointermediate bed nucleus of the stria terminalis, containing more neurons heavily labeled for leu-enkephalin, and the main olfactory bulb, where only met-enkephalin was observed. Of most interest for this study was the observation of Enk-ir cells and terminals in areas implicated in both sexual and agonistic behaviors in this species.
Topics: Aggression; Animals; Brain; Brain Chemistry; Colchicine; Cricetinae; Enkephalin, Leucine; Enkephalin, Methionine; Immunohistochemistry; Male; Mesocricetus; Sexual Behavior, Animal; Social Behavior
PubMed: 15567335
DOI: 10.1016/j.brainres.2004.09.034