-
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 -
Experimental Biology and Medicine... Dec 2018This mini-review presents information on the intermittent blockade of the opioid growth factor (OGF)-OGF receptor (OGFr) axis by low-dose naltrexone (LDN), and the role... (Review)
Review
This mini-review presents information on the intermittent blockade of the opioid growth factor (OGF)-OGF receptor (OGFr) axis by low-dose naltrexone (LDN), and the role of enkephalin (i.e. OGF) in autoimmune disorders, specifically multiple sclerosis, Crohn's, and fibromyalgia. Clinical reports on subjects taking LDN have documented reduced fatigue, few side-effects, and improved overall health. Preclinical studies on mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, revealed that immunization for EAE reduces serum OGF. Intermittent OGFr blockade with LDN restores serum enkephalin levels that correlate with reduced behavioral and pathological signs of EAE; LDN also increases enkephalin levels in naïve mice. The interplay between LDN, and the onset and treatment of autoimmune diseases, chronic pain, and other addictive behaviors requires further investigation, but highlights a central role for enkephalins and intermittent blockade of the OGF-OGFr pathway in pathogenesis and treatment of these disorders.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Humans; Mice; Multiple Sclerosis; Naltrexone; Narcotic Antagonists; Receptors, Opioid
PubMed: 30541348
DOI: 10.1177/1535370218817746 -
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 -
International Journal of Molecular... Sep 2022Pain is a worldwide public health problem and its treatment is still a challenge since clinically available drugs do not completely reverse chronic painful states or...
Pain is a worldwide public health problem and its treatment is still a challenge since clinically available drugs do not completely reverse chronic painful states or induce undesirable effects. Crotalphine is a 14 amino acids synthetic peptide that induces a potent and long-lasting analgesic effect on acute and chronic pain models, peripherally mediated by the endogenous release of dynorphin A and the desensitization of the transient receptor potential ankyrin 1 (TRPA1) receptor. However, the effects of crotalphine on the central nervous system (CNS) and the signaling pathway have not been investigated. Thus, the central effect of crotalphine was evaluated on the partial sciatic nerve ligation (PSNL)-induced chronic neuropathic pain model. Crotalphine (100 µg/kg, p.o.)-induced analgesia on the 14th day after surgery lasting up to 24 h after administration. This effect was prevented by intrathecal administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists. Besides that, crotalphine-induced analgesia was reversed by CTOP, nor-BNI, and naltrindole, antagonists of , , and -opioid receptors, respectively, and also by the specific antibodies for β-endorphin, dynorphin-A, and met-enkephalin. Likewise, the analgesic effect of crotalphine was blocked by the intrathecal administration of minocycline, an inhibitor of microglial activation and proliferation. Additionally, crotalphine decreased the PSNL-induced IL-6 release in the spinal cord. Importantly, in vitro, crotalphine inhibited LPS-induced CD86 expression and upregulated CD206 expression in BV-2 cells, demonstrating a polarization of microglial cells towards the M2 phenotype. These results demonstrated that crotalphine, besides activating opioid and cannabinoid analgesic systems, impairs central neuroinflammation, confirming the neuromodulatory mechanism involved in the crotalphine analgesic effect.
Topics: Amino Acids; Analgesia; Analgesics; Analgesics, Opioid; Ankyrins; Cannabinoid Receptor Antagonists; Cannabinoids; Dynorphins; Enkephalin, Methionine; Humans; Interleukin-6; Lipopolysaccharides; Microglia; Minocycline; Neuralgia; Peptides; Phenotype; Receptors, Opioid; Spinal Cord; beta-Endorphin
PubMed: 36232883
DOI: 10.3390/ijms231911571 -
Biochemical Pharmacology Oct 2021Diabetes is a multi-faceted disorder with increasing prevalence and rising healthcare costs. The burden of diabetes is increased because of associated complications... (Review)
Review
Diabetes is a multi-faceted disorder with increasing prevalence and rising healthcare costs. The burden of diabetes is increased because of associated complications affecting nearly all organs including the eye. The underlying pathophysiology for the onset of these ocular surface disorders is not well known. Enkephalins are endogenous opioids that originate in the brain and have numerous actions in the human body. Opioid growth factor (OGF), chemically termed [Met]-enkephalin, binds to a novel, nuclear-associated receptor and mediates cellular homeostasis. Serum OGF levels are elevated in diabetic individuals and rodent models of diabetes. Sustained blockade of the OGF receptor (OGFr) with opioid receptor antagonists, such as naltrexone (NTX), reverses many complications of diabetes in the animal model, including delayed cutaneous wound healing, dry eye, altered corneal surface sensitivity, and keratopathy. The increased enkephalin levels observed in diabetes suggest a relationship between endogenous opioid peptides and the pathophysiology of diabetes. It is common for diabetic patients to undergo insulin therapy to restore normal blood glucose levels. However, this restoration does not alter OGF serum levels nor ameliorate ocular surface complications in the animal model of diabetes. Moreover, sex differences in the prevalence of diabetes, response to insulin therapy, and abnormalities in the OGF-OGFr axis have been reported. This review highlights current knowledge on the dysregulation of the OGF-OGFr pathway and possible relationships of insulin and enkephalins to the development of ocular surface defects in diabetes. It proposes that this dysregulation is a fundamental mechanism for the pathobiology of diabetic complications.
Topics: Animals; Corneal Diseases; Diabetes Complications; Diabetes Mellitus; Dry Eye Syndromes; Enkephalins; Humans; Insulin; Naltrexone; Narcotic Antagonists; Receptors, Opioid
PubMed: 34324868
DOI: 10.1016/j.bcp.2021.114712 -
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 -
Folia Histochemica Et Cytobiologica 2021A recent study has shown a close neuroanatomical relationship between the enkephalinergic (methionine-enkephalin) and tachykininergic (substance P) systems in the alpaca...
INTRODUCTION
A recent study has shown a close neuroanatomical relationship between the enkephalinergic (methionine-enkephalin) and tachykininergic (substance P) systems in the alpaca diencephalon. In this study, our aim is to show this relationship in the alpaca brainstem.
MATERIAL AND METHODS
Using an immunohistochemical technique, the distribution of immunoreactive (Ir) fibers and cell bodies containing substance P (SP) or methionine-enkephalin (MET) has been studied in the alpaca brainstem. Five adult males were used; brain tissue was fixed and processed by standard methods.
RESULTS
SP- and MET-Ir fibers showed a widespread and similar distribution in the mesencephalon, pons and medulla oblongata. The co-localization of fibers containing SP or MET was found in most of the nuclei/tracts of the alpaca brainstem. This close neuroanatomical relationship suggests multiple physiological interactions between both neuropeptides. The distribution of the cell bodies containing SP was very restricted (cell bodies were only observed in a few nuclei located in the mesencephalon and medulla oblongata), whereas MET-Ir perikarya showed a moderately widespread distribution in the mesencephalon, pons and medulla oblongata.
CONCLUSIONS
This study increases the knowledge on the neuroanatomical distribution/relationship of the tachykininergic (SP) and enkephalinergic (MET) systems in the alpaca central nervous system.
Topics: Animals; Brain Stem; Camelids, New World; Diencephalon; Enkephalin, Methionine; Male; Substance P
PubMed: 34309826
DOI: 10.5603/FHC.a2021.0016 -
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