Mechanisms of Melatonin in Obesity: A Review

Obesity and its complications have become a prominent global public health problem that severely threatens human health. Melatonin, originally known as an effective antioxidant, is an endogenous hormone found throughout the body that serves various physiological functions. In recent decades, increasing attention has been paid to its unique function in regulating energy metabolism, especially in glucose and lipid metabolism. Accumulating evidence has established the relationship between melatonin and obesity; nevertheless, not all preclinical and clinical evidence indicates the anti-obesity effect of melatonin, which makes it remain to conclude the clinical effect of melatonin in the fight against obesity. In this review, we have summarized the current knowledge of melatonin in regulating obesity-related symptoms, with emphasis on its underlying mechanisms. The role of melatonin in regulating the lipid profile, adipose tissue, oxidative stress, and inflammation, as well as the interactions of melatonin with the circadian rhythm, gut microbiota, sleep disorder, as well as the α7nAChR, the opioidergic system, and exosomes, make melatonin a promising agent to open new avenues in the intervention of obesity.

Synthesis and Antinociceptive Effect of Some Thiazole-Piperazine Derivatives: Involvement of Opioidergic System in the Activity

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a–3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a–3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.

Role of Opioidergic System in Regulating Depression Pathophysiology

Background: There is a clear clinical need for a better understanding of the biological underpinnings of major depressive disorder (MDD), allowing for the development of a treatment that is targeted to pathophysiology. Recent data indicate a role for the endogenous opioidergic system in MDD. This article reviews the roles and physiological interactions of the endogenous opioidergic system in the pathophysiology and heterogeneity of MDD. Methods: Articles on the pathophysiology of MDD, as well as on the endogenous opioidergic system and mitochondrial function, form the basis of this review article. Results: The endogenous opioidergic system is intimately linked to wider MDD pathophysiology, including alterations in the gut microbiome, gut permeability, circadian rhythm, amygdala-prefrontal cortex interactions, and mitochondrial function. A decrease in the μ-/κ-opioid receptor ratio is an important mediator of the changes in mood in MDD, with effects not only on neurons, but also on glia and immune cells. Conclusion: The endogenous opioidergic system is intimately interwoven with MDD pathophysiology and provides a relevant target for novel treatment development, as well as providing a focus for the integration of wider MDD pathophysiology.

The Opioidergic System of Immune Cells: A New Pharmacological Target in the Therapy of “Cytokine Storm”

This article proposes a new pharmacological approach to suppressing “cytokine storm” syndromes based on the use of opioid peptides. Immune cells possess a complete opioid signaling system consisting of all three types of opioid receptors: mu (μ), delta (δ) and kappa (κ). These cells also express proopiomelanocortin, proenkephalin and prodinorphin, which serve as precursors for such receptor agonists as β-endorphin, methenkephalin and dynorphins, respectively. A distinct feature of the opioid system of immunocytes consists in an increased expression of all its components in response to the action of cytokines and inflammation, which indicates participation of this system in regulating the immune response. It has been recently shown that dynorphins are likely to play an important role in inhibiting the expression of proinflammatory cytokines by immune cells through impeding the translocation of the active nuclear factor kappa B (NF-κB) dimer. Given the key role of the canonical pathway of NF-κB activation in cytokine expression realized when activating a variety of receptors, suppression of this pathway using opioid peptides provides a new pharmacological approach to solving the “cytokine storm” problem. The relevance of this approach is associated with the COVID-19 coronavirus infection pandemic, the role of the “cytokine storm” in which has been established by numerous studies.

Protagonist Role of Opioidergic System on Post-Traumatic Stress Disorder and Associated Pain

Objective Post-traumatic stress disorder (PTSD) and chronic pain often co-occur. Studies have shown an interaction between pain and PTSD. In this narrative review, we aim to support conducting comprehensive studies by describing PTSD, pain and determining whether opioidergic system, its agonist and antagonist manipulation could positively or negatively affect PTSD symptoms and concurrent pain.Methods Term searches was done in Google Scholar, Scopus, ScienceDirect, Web of Science and PubMed databases as well as hand searching in key resource journals from 1979–2019.Results There are a lot of contradictions and disputes when endogenous opioidergic system and opioidergic antagonist system are studied in PTSD patients. Exogenous morphine administration in PTSD patients can decrease the symptoms of PTSD but it doesn’t have a pain reduction effect to an acceptable level. Beta-endorphin as an endogenous opioid is effective in pain reduction in the moment of events but after minutes to hours, the endorphins withdrawal syndrome leads to exaggerated intrusive thoughts and flashbacks of PTSD, which exacerbate the pain. It has also been shown that naloxone, as an opioidergic antagonist, can reduce or increase the PTSD symptoms and its associated pain.Conclusion Data suggest different roles of opioidergic system and their antagonist in pain control and mood in PTSD. However, further investigations need to be done in order to reveal the role of endogenous opioidergic system and opioidergic antagonist system as a mediator in PTSD patients suffering from acute or chronic pain.

Antioxidant Action and In Vivo Anti-Inflammatory and Antinociceptive Activities of Myrciaria floribunda Fruit Peels: Possible Involvement of Opioidergic System

This work evaluated the antioxidant properties and in vivo antinociceptive and anti-inflammatory effects of extracts obtained from fruit peels of Myrciaria floribunda (H. West ex Willd.) O. Berg (Myrtaceae). This plant is popularly known in Brazil as Cambuí or camboim. Different extracts were submitted to comparative analysis to determine the content of selected phytochemical classes (levels of total phenols, flavonoids, and monomeric anthocyanins) and the in vitro antioxidant potentials. The extract with higher potential was selected for in vivo evaluation of its antinociceptive and anti-inflammatory action. Finally, the chemical characterization of this extract was performed by high-performance liquid chromatography (HPLC). MfAE (extract obtained using acetone as solvent) showed the higher levels of phenols (296 mg GAE/g) and anthocyanins contents (35.65 mg Cy-3-glcE/g) that were associated with higher antioxidant activity. MfAE also exhibited in vivo anti-inflammatory and analgesic propertiers. This fraction inhibited the inflammatory and neurogenic phases of pain, and this effect was reversed by naloxone (suggesting the involvement of opioidergic system). MfAE reduced the abdominal contortions induced by acetic acid. The HPLC analysis revealed the presence of gallic acid (and its derivatives) and ellagic acid. Taken together, these data support the use of M. floribunda fruit peels for development of functional foods and nutraceutics.

Antinociceptive Activity of Asiaticoside in Mouse Models of Induced Nociception

The antinociceptive property of Centella asiatica extracts is known but the analgesic activity of its bioactive constituent asiaticoside has not been reported. We evaluated the antinociceptive activity of orally (p. o.) administered asiaticoside (1, 3, 5, and 10 mg/kg) in mice using the 0.6% acetic acid-induced writhing test, the 2.5% formalin-induced paw licking test, and the hot plate test. The capsaicin- and glutamate-induced paw licking tests were employed to evaluate the involvement of the vanilloid and glutamatergic systems, respectively. Asiaticoside (3, 5, and 10 mg/kg, p. o.) reduced the rate of writhing (p < 0.0001) by 25.3, 47.8, and 53.9%, respectively, and increased the latency period (p < 0.05) on the hot plate at 60 min post-treatment until the end of the experiment. Moreover, asiaticoside (3, 5, and 10 mg/kg, p. o.) shortened the time spent in licking/biting the injected paw (p < 0.0001) in the early phase of the formalin test by 45.7, 51.4, and 52.7%, respectively, and in the late phase (p < 0.01) by 23.6, 40.5, and 50.6%, respectively. Antinociception induced by asiaticoside (10 mg/kg) was not antagonized by naloxone in both the 2.5% formalin-induced nociception and the hot plate test, indicating a nonparticipation of the opioidergic system. Asiaticoside (1, 3, 5, and 10 mg/kg, p. o.) reduced the duration of biting/licking the capsaicin-injected paw (p < 0.0001) by 40.5, 48.2, 59.5, and 63.5%, respectively. Moreover, asiaticoside (5 and 10 mg/kg) shortened the time spent in biting/licking the glutamate-injected paw (p < 0.01) by 29.9 and 48.6%, respectively. Therefore, asiaticoside (5 and 10 mg/kg, p. o.) induces antinociception possibly through the vanilloid and glutamatergic systems.