Insights into the Current and Possible Future Use of Opioid Antagonists in Relation to Opioid-Induced Constipation and Dysbiosis.

Opioid receptor agonists, particularly those that activate µ-opioid receptors (MORs), are essential analgesic agents for acute or chronic mild to severe pain treatment. However, their use has raised concerns including, among others, intestinal dysbiosis. In addition, growing data on constipation-evoked intestinal dysbiosis have been reported. Opioid-induced constipation (OIC) creates an obstacle to continuing treatment with opioid analgesics. When non-opioid therapies fail to overcome the OIC, opioid antagonists with peripheral, fast first-pass metabolism, and gastrointestinal localized effects remain the drug of choice for OIC, which are discussed here. At first glance, their use seems to only be restricted to constipation, however, recent data on OIC-related dysbiosis and its contribution to the appearance of several opioid side effects has garnered a great of attention from researchers. Peripheral MORs have also been considered as a future target for opioid analgesics with limited central side effects. The properties of MOR antagonists counteracting OIC, and with limited influence on central and possibly peripheral MOR-mediated antinociception, will be highlighted. A new concept is also proposed for developing gut-selective MOR antagonists to treat or restore OIC while keeping peripheral antinociception unaffected. The impact of opioid antagonists on OIC in relation to changes in the gut microbiome is included.

Pregabalin-Tolperisone Combination to Treat Neuropathic Pain: Improved Analgesia and Reduced Side Effects in Rats.

The current treatment of neuropathic pain (NP) is unsatisfactory; therefore, effective novel agents or combination-based analgesic therapies are needed. Herein, oral tolperisone, pregabalin, and duloxetine were tested for their antinociceptive effect against rat partial sciatic nerve ligation (pSNL)-induced tactile allodynia described by a decrease in the paw withdrawal threshold (PWT) measured by a dynamic plantar aesthesiometer. On day 7 after the operation, PWTs were assessed at 60, 120, and 180 min post-treatment. Chronic treatment was continued for 2 weeks, and again, PWTs were measured on day 14 and 21. None of the test compounds produced an acute antiallodynic effect. In contrast, after chronic treatment, tolperisone and pregabalin alleviated allodynia. In other experiments, on day 14, the acute antiallodynic effect of the tolperisone/pregabalin or duloxetine combination was measured. As a novel finding, a single dose of the tolperisone/pregabalin combination could remarkably alleviate allodynia acutely. It also restored the neuropathy-induced elevated CSF glutamate content. Furthermore, the combination is devoid of adverse effects related to motor and gastrointestinal transit functions. Tolperisone and pregabalin target voltage-gated sodium and calcium channels, respectively. The dual blockade effect of the combination might explain its advantageous acute analgesic effect in the present work.

New Insights into the Opioid Analgesic Profile of cis-(-)-N-Normetazocine-derived Ligands.

In this work, we report on the in vitro and in vivo pharmacological properties of LP1 analogs to complete the series of structural modifications aimed to generate compounds with improved analgesia. To do that, the phenyl ring in the N-substituent of our lead compound LP1 was replaced by an electron-rich or electron-deficient ring and linked through a propanamide or butyramide spacer at the basic nitrogen of the (-)-cis-N-normetazocine skeleton. In radioligand binding assays, compounds 3 and 7 were found to display nanomolar binding affinity for the µ opioid receptor (MOR) (Ki = 5.96 ± 0.08 nM and 1.49 ± 0.24 nM, respectively). In the mouse vas deferens (MVD) assay, compound 3 showed an antagonist effect against DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), a highly selective MOR prototype agonist, whereas compound 7 produced naloxone reversible effect at MOR. Moreover, compound 7, as potent as LP1 and DAMGO at MOR, was able to reduce thermal and inflammatory pain assessed by the mouse tail-flick test and rat paw pressure thresholds (PPTs) measured by a Randall-Selitto test.

Total Synthesis and Structural Plasticity of Kratom Pseudoindoxyl Metabolites.

Mitragynine pseudoindoxyl, a kratom metabolite, has attracted increasing attention due to its favorable side effect profile as compared to conventional opioids. Herein, we describe the first enantioselective and scalable total synthesis of this natural product and its epimeric congener, speciogynine pseudoindoxyl. The characteristic spiro-5-5-6-tricyclic system of these alkaloids was formed through a protecting-group-free cascade relay process in which oxidized tryptamine and secologanin analogues were used. Furthermore, we discovered that mitragynine pseudoindoxyl acts not as a single molecular entity but as a dynamic ensemble of stereoisomers in protic environments; thus, it exhibits structural plasticity in biological systems. Accordingly, these synthetic, structural, and biological studies provide a basis for the planned design of mitragynine pseudoindoxyl analogues, which can guide the development of next-generation analgesics.

Telmisartan Is a Promising Agent for Managing Neuropathic Pain and Delaying Opioid Analgesic Tolerance in Rats.

Despite the large arsenal of analgesic medications, neuropathic pain (NP) management is not solved yet. Angiotensin II receptor type 1 (AT1) has been identified as a potential target in NP therapy. Here, we investigate the antiallodynic effect of AT1 blockers telmisartan and losartan, and particularly their combination with morphine on rat mononeuropathic pain following acute or chronic oral administration. The impact of telmisartan on morphine analgesic tolerance was also assessed using the rat tail-flick assay. Morphine potency and efficacy in spinal cord samples of treated neuropathic animals were assessed by [35S]GTPγS-binding assay. Finally, the glutamate content of the cerebrospinal fluid (CSF) was measured by capillary electrophoresis. Oral telmisartan or losartan in higher doses showed an acute antiallodynic effect. In the chronic treatment study, the combination of subanalgesic doses of telmisartan and morphine ameliorated allodynia and resulted in a leftward shift in the dose-response curve of morphine in the [35S]GTPγS binding assay and increased CSF glutamate content. Telmisartan delayed morphine analgesic-tolerance development. Our study has identified a promising combination therapy composed of telmisartan and morphine for NP and opioid tolerance. Since telmisartan is an inhibitor of AT1 and activator of PPAR-γ, future studies are needed to analyze the effect of each component.

The Acute Antiallodynic Effect of Tolperisone in Rat Neuropathic Pain and Evaluation of Its Mechanism of Action.

Current treatment approaches to manage neuropathic pain have a slow onset and their use is largely hampered by side-effects, thus there is a significant need for finding new medications. Tolperisone, a centrally acting muscle relaxant with a favorable side effect profile, has been reported to affect ion channels, which are targets for current first-line medications in neuropathic pain. Our aim was to explore its antinociceptive potency in rats developing neuropathic pain evoked by partial sciatic nerve ligation and the mechanisms involved. Acute oral tolperisone restores both the decreased paw pressure threshold and the elevated glutamate level in cerebrospinal fluid in neuropathic rats. These effects were comparable to those of pregabalin, a first-line medication in neuropathy. Tolperisone also inhibits release of glutamate from rat brain synaptosomes primarily by blockade of voltage-dependent sodium channels, although inhibition of calcium channels may also be involved at higher concentrations. However, pregabalin fails to affect glutamate release under our present conditions, indicating a different mechanism of action. These results lay the foundation of the avenue for repurposing tolperisone as an analgesic drug to relieve neuropathic pain.

Recent Molecular Insights into Agonist-specific Binding to the Mu-Opioid Receptor.

Opioid agonists produce their analgesic effects primarily by acting at the µ-opioid receptor (µOR). µOR agonists with different efficacies exert diverse molecular changes in the µOR which dictate the faith of the receptor's signaling pathway and possibly it's the degree of desensitization. Since the development of the active conformations of the µOR, growing data have been published in relation to ligand-specific changes in µOR activation. In this regard, this review summarizes recent data regarding the most studied opioid agonists in in silico µOR activation, including how these ligands are recognized by the µOR, how their binding signal is transmitted toward the intracellular parts of the µOR, and finally, what type of large-scale movements do these changes trigger in the µOR's domains.

Transcriptome analysis of Plantago major as a phytoremediator to identify some genes related to cypermethrin detoxification.

Cypermethrin (CYP) is a toxic manmade chemical compound belonging to pyrethroid insecticides contaminating the environment. Plantago major (PM) has numerous excellent advantages like high biomass yield and great stress tolerance, which make it able to increase the efficacy of phytoremediation. So far, no study has directly or indirectly made a transcriptome analysis (RNA-seq) of PM under CYP stress. The aim of this study is to identify the genes in PM related to CYP detoxification (10 µg mL-1) and compared with control. In this study, BGISEQ-500 high-throughput sequencing technology independently developed by BGI was used to sequence the transcriptome of P. major. Six libraries were constructed including (CK_1, CK_2, and CK_3) and (CYP_1, CYP_2, and CYP_3) were sequenced for transcripts involved in CYP detoxification. Our data showed that de novo assembly generated 138,806 unigenes with an average length of 1129 bp. Analyzing the annotation results of the KEGG database between the samples revealed 37,177 differentially expressed genes (DEGs), 18,062 down- and 19,115 upregulated under CYP treatment compared with control. A set of 107 genes of cytochrome P450 (Cyt P450), 43 genes of glutathione S-transferases (GST), 25 genes of glycosyltransferases (GTs), 113 genes from ABC transporters, 21 genes from multidrug and toxin efflux (MATE), 11 genes from oligopeptide transporter (OPT), and 3 genes of metallothioneins (MT) were upregulated notably. By using quantitative real-time PCR (qRT-PCR), the results of gene expression for 12 randomly selected DEGs were confirmed, showing the different patterns of response to CYP in PM tissues. Furthermore, the enzyme activity of Cyt P450 and GST in PM under CYP stress was significantly increased in roots and leaves than in control. This study introduces a clue to understand the metabolic pathways of plants used in phytoremediation by identifying the highly expressed genes related to phytoremediation which would be utilized to enhance pesticide detoxification and reduce pollution problem.

Antidepressant activity of anti-hyperglycemic agents in experimental models: A review.

BACKGROUND AND AIMS: Diabetes Mellitus (DM) and depression occur comorbidly and share some pathophysiological mechanisms. The course of depression in patients with the two conditions is severe. Treatment of depression in diabetic patients requires special attention because most of psychopharmacological agents can worsen glycemic control. This article aims to review studies evaluating the antidepressant effect of anti-hyperglycemic agents from preclinical perspective. METHODS: A literature search was performed with PubMed and Google Scholar using relevant keywords (antidiabetic; diabetes; depression; antidepressant; animals) to extract relevant studies evaluating the antidepressant activity of anti-hyperglycemic agents in experimental models. RESULTS: Several studies have reported that some traditional anti-hyperglycemic agents reduce depression-like behavior in the absence or presence of diabetes. These drugs include insulin, glyburide, metformin, pioglitazone, vildagliptin, liraglutide, and exenatide. The antidepressant activity of anti-hyperglycemic agents may be mediated by reducing the blood glucose level, ameliorating the central oxidative stress and inflammation, and regulating the hypothalamic-pituitary-adrenal axis (HPAA). CONCLUSIONS: Drugs which have both antidiabetic and antidepressant activities can provide better treatment strategy for patients with diabetes-associated depression. However, further research studies are still required in human subjects.

Impact of some oral hypoglycemic agents on type 2 diabetes-associated depression and reserpine-induced depression in rats: the role of brain oxidative stress and inflammation.

Diabetes mellitus and depression are comorbid diseases affecting many patients all over the world. The current study was designed to compare the antidepressant effect of some antidiabetic drugs such as vildagliptin, pioglitazone, glyburide, and metformin on depression-related or unrelated to type 2 diabetes mellitus (T2DM). T2DM was induced by high-fat diet and streptozotocin, while diabetes-unrelated depression was induced by reserpine. Antidiabetic agents reduced diabetes-associated depression as indicated by the reduction in the immobility time in the forced swim test, elevation of cortical and hippocampal serotonin and brain-derived neurotrophic factor (BDNF), and the increase in serum ß-Amyloid 1-42 (Aß1-42) levels. Antidiabetic agents also reduced serum corticosterone levels suggesting their inhibitory effect on hypothalamus-pituitary-adrenal axis activity. The antidepressant activity of the tested compounds was associated with reduction of oxidative stress and inflammation in brain. Vildagliptin showed the highest, while glyburide showed the least antidiabetic and antidepressant activity. Antidepressant activities of pioglitazone and metformin were comparable. The difference in antioxidant and anti-inflammatory activities between groups showed the same pattern of the antidepressant effect suggesting that these two pathways may play role in ameliorating depression in diabetic rats. On the other hand, the administration of reserpine in small doses (0.2 mg/kg) induced depression associated with hyperglycemia in non-diabetic rats. Although all treatments improved glycemic parameters to similar levels, vildagliptin showed the greatest effect on Aß1-42, serotonin, norepinephrine, and BDNF levels. In conclusion, vildagliptin seems to be the leading drug among the tested antidiabetics and may be the most appropriate antidiabetic for managing diabetes-associated depression.