Opioid Receptor Research Articles

Treatment-Resistant Depression and Medications

The management of treatment-resistant depression (TRD) is challenging. Researchers have identified novel targets, especially the glutamatergic system, in the pathogenesis of depressive disorder. N-methyl-D-aspartate (NMDA) receptor antagonists, like ketamine, have revolutionized the treatment of TRD due to their rapid antidepressant and antisuicidal effect. Various other receptor systems, including GABAergic, opioid receptors, the endogenous cannabinoid system, and cholinergic receptors, are novel targets to produce an antidepressant response. The US Food and Drug Administration (FDA) has approved intra-nasal ketamine as an add-on therapy to conventional antidepressants for TRD. Other compounds are in various stages of development. Identification and development of novel compounds by future research can help in overcoming the challenges of treating TRD. [ Psychiatr Ann . 2024;54(6):e177–e181.]

Central Nervous System Medications: Pharmacokinetic and Pharmacodynamic Considerations for Older Adults.

Most drugs have not been evaluated in the older population. Recognizing physiological alterations associated with changes in drug disposition and with the ultimate effect, especially in central nervous system-acting drugs, is fundamental. While considering pharmacokinetics, it should be noted that the absorption of most drugs from the gastrointestinal tract does not change in advanced age. There are only few data about the effect of age on the transdermal absorption of medications such as fentanyl. Absorption from an intramuscular injection may be similar in older adults as in younger patients. The distribution of lipophilic drugs (such as diazepam) is increased owing to a relative increase in the percentage of body fat, causing drug accumulation and prolonged drug elimination following cessation. Phase I drug biotransformation is variably decreased in aging, impacting elimination, and hepatic drug clearance has been shown to decrease in older individuals by 10-40% for most drugs studied. Lower doses of phenothiazines, butyrophenones, atypical antipsychotics, antidepressants (citalopram, mirtazapine, and tricyclic antidepressants), and benzodiazepines (such as diazepam) achieve the same extent of exposure. For renally cleared drugs with no prior metabolism (such as gabapentin), the glomerular filtration rate appropriately estimates drug clearance. Important pharmacodynamic changes in older adults include an increased sedative effect of benzodiazepines at a given drug exposure, and a higher sensitivity to mu opiate receptor agonists and to opioid adverse effects. Artificial intelligence, physiologically based pharmacokinetic modeling and simulation, and concentration-effect modeling enabling a differentiation between the pharmacokinetic and the pharmacodynamic effects of aging might help to close some of the gaps in knowledge.

Are Opioid Receptor Antagonists Effective at Treating Antipsychotic-Induced Weight Gain? A Systematic Review and Meta-Analysis

Are Opioid Receptor Antagonists Effective at Treating Antipsychotic-Induced Weight Gain? A Systematic Review and Meta-Analysis

Melissa officinalis Interaction with Opioid Receptors Attenuates Stress-Induced Anxiety-Like and OCD-Like Behaviors

Melissa officinalis Interaction with Opioid Receptors Attenuates Stress-Induced Anxiety-Like and OCD-Like Behaviors

Opioids and Cancer: Current Understanding and Clinical Considerations.

Pain is one of the most common symptoms in patients with cancer. Pain not only negatively affects the quality of life of patients with cancer, but it has also been associated with reduced survival. Pain management is therefore a critical component of cancer care. Prescription opioids remain the first-line approach for the management of moderate-to-severe pain associated with cancer. However, there has been increasing interest in understanding whether these analgesics could impact cancer progression. Furthermore, epidemiological data link a possible association between prescription opioid usage and cancer development. Until more robust evidence is available, patients with cancer with moderate-to-severe pain may receive opioids to decrease suffering. However, future studies should be conducted to evaluate the role of opioids and opioid receptors in specific cancers.

A targeted CRISPR-Cas9 mediated F0 screen identifies genes involved in establishment of the enteric nervous system.

The vertebrate enteric nervous system (ENS) is a crucial network of enteric neurons and glia resident within the entire gastrointestinal tract (GI). Overseeing essential GI functions such as gut motility and water balance, the ENS serves as a pivotal bidirectional link in the gut-brain axis. During early development, the ENS is primarily derived from enteric neural crest cells (ENCCs). Disruptions to ENCC development, as seen in conditions like Hirschsprung disease (HSCR), lead to the absence of ENS in the GI, particularly in the colon. In this study, using zebrafish, we devised an in vivo F0 CRISPR-based screen employing a robust, rapid pipeline integrating single-cell RNA sequencing, CRISPR reverse genetics, and high-content imaging. Our findings unveil various genes, including those encoding opioid receptors, as possible regulators of ENS establishment. In addition, we present evidence that suggests opioid receptor involvement in the neurochemical coding of the larval ENS. In summary, our work presents a novel, efficient CRISPR screen targeting ENS development, facilitating the discovery of previously unknown genes, and increasing knowledge of nervous system construction.

Mu-opioid receptor activation in the habenula modulates synaptic transmission and depression-like behaviors

Opioid system dysregulation in response to stress is known to lead to psychiatric disorders including major depression. Among three different types of opioid receptors, the mu-type receptors (mORs) are highly expressed in the habenula complex, however, the action of mORs in this area and its interaction with stress exposure is largely unknown. Therefore, we investigated the roles of mORs in the habenula using male rats of an acute learned helplessness (aLH) model. First, we found that mOR activation decreased both excitatory and inhibitory synaptic transmission onto the lateral habenula (LHb). Intriguingly, this mOR-induced synaptic depression was reduced in an animal model of depression compared to that of controls. In naïve animals, we found an unexpected interaction between mORs and the endocannabinoid (eCB) signaling occurring in the LHb, which mediates presynaptic alteration occurring with mOR activation. However, we did not observe presynaptic alteration by mOR activation after stress exposure. Moreover, selective mOR activation in the habenula before, but not after, stress exposure effectively reduced helpless behaviors compared to aLH animals. Our observations are consistent with clinical reports suggesting the involvement of mOR signaling in depression, and additionally reveal a critical time window of mOR action in the habenula for ameliorating helplessness symptoms.

Kappa Opioid Receptor Antagonism Restores Phosphorylation, Trafficking and Behavior induced by a Disease Associated Dopamine Transporter Variant.

Aberrant dopamine (DA) signaling is implicated in schizophrenia, bipolar disorder (BPD), autism spectrum disorder (ASD), substance use disorder, and attention-deficit/hyperactivity disorder (ADHD). Treatment of these disorders remains inadequate, as exemplified by the therapeutic use of d-amphetamine and methylphenidate for the treatment of ADHD, agents with high abuse liability. In search for an improved and non-addictive therapeutic approach for the treatment of DA-linked disorders, we utilized a preclinical mouse model expressing the human DA transporter (DAT) coding variant DAT Val559, previously identified in individuals with ADHD, ASD, or BPD. DAT Val559, like several other disease-associated variants of DAT, exhibits anomalous DA efflux (ADE) that can be blocked by d-amphetamine and methylphenidate. Kappa opioid receptors (KORs) are expressed by DA neurons and modulate DA release and clearance, suggesting that targeting KORs might also provide an alternative approach to normalizing DA-signaling disrupted by perturbed DAT function. Here we demonstrate that KOR stimulation leads to enhanced surface trafficking and phosphorylation of Thr53 in wildtype DAT, effects achieved constitutively by the Val559 mutant. Moreover, these effects can be rescued by KOR antagonism of DAT Val559 in ex vivo preparations. Importantly, KOR antagonism also corrected in vivo DA release as well as sex-dependent behavioral abnormalities observed in DAT Val559 mice. Given their low abuse liability, our studies with a construct valid model of human DA associated disorders reinforce considerations of KOR antagonism as a pharmacological strategy to treat DA associated brain disorders.

Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression.

While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (2), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a Tmax of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl.

Understanding Fentanyl A Synthetic Piperidine Opioid Drug: Deciphering the Pain-Relieving Double-Edged Sword

Fentanyl is a synthetic opioid analgesic that has revolutionized pain management in various medical contexts. It has remarkable potency and effectiveness in managing severe pain, owing to its unique mechanisms of action on opioid receptors and modulation of pain perception. Fentanyl can be administered through various routes, such as transdermal patches, intravenous injections, lozenges, and nasal sprays. It is commonly utilized for post-operative pain management, cancer-related pain, and palliative care. However, fentanyl also poses significant risks of addiction, abuse, and overdose. The alarming increase in fentanyl-related fatalities underscores the importance of understanding proper dosage, monitoring patients closely, and implementing harm reduction strategies. Furthermore, the responsible use of fentanyl requires comprehensive patient assessment, individualized treatment plans, and the active involvement of healthcare providers in educating patients and obtaining informed consent. The article also discusses ongoing research efforts to improve fentanyl’s safety profile while maintaining its efficacy. These include emerging technologies, potential formulations, and alternative pain management strategies that could help reduce the dependence on fentanyl and prevent its adverse effects. The article provides a balanced perspective on fentanyl, emphasizing the balance between its pain-relieving benefits and the potential risks it poses. It also reinforces the significance of responsible prescribing, vigilant monitoring, and patient education to ensure optimal pain relief and patient safety.

PKA inhibition kills L-asparaginase-resistant leukemic cells from relapsed acute lymphoblastic leukemia patients.

Despite the success in treating newly diagnosed pediatric acute lymphoblastic leukemia (aLL), the long-term cure rate for the 20% of children who relapse is poor, making relapsed aLL the primary cause of cancer death in children. By unbiased genome-wide retroviral RNAi screening and knockdown studies, we previously discovered opioid receptor mu 1 (OPRM1) as a new aLL cell resistance biomarker for the aLL chemotherapeutic drug, L-asparaginase, i.e., OPRM1 loss triggers L-asparaginase resistance. Indeed, aLL cell OPRM1 level is inversely proportional to L-asparaginase IC50: the lower the OPRM1 level, the higher the L-asparaginase IC50, indicating that aLL cells expressing reduced OPRM1 levels show resistance to L-asparaginase. In the current study, we utilized OPRM1-expressing and -knockdown aLL cells as well as relapsed patient aLL cells to identify candidate targeted therapy for L-asparaginase-resistant aLL. In OPRM1-expressing cells, L-asparaginase induces apoptosis via a cascade of events that include OPRM1-mediated decline in [cAMP]i, downregulation of PKA-mediated BAD S118 phosphorylation that can be reversed by 8-CPT-cAMP, cyt C release from the mitochondria, and subsequent caspase activation and PARP1 cleavage. The critical role of PKA inhibition due to a decrease in [cAMP]i in this apoptotic process is evident in the killing of OPRM1-knockdown and low OPRM1-expressing relapsed patient aLL cells by the PKA inhibitors, H89 and 14-22 amide. These findings demonstrate for the first time that PKA can be targeted to kill aLL cells resistant to L-asparaginase due to OPRM1 loss, and that H89 and 14-22 amide may be utilized to destroy L-asparaginase-resistant patient aLL cells.

#2131 Difelikefalin in the management of pruritus associated with chronic kidney disease (Pa-CKD) in hemodialysis: Results from Andalusia

Abstract Background and Aims Pruritus associated with chronic kidney disease (CKD-aP) is a debilitating and common symptom in patients with chronic kidney disease on hemodialysis, with a prevalence of moderate to severe pruritus around 40–45%. The pathogenesis is not yet fully understood. It has been formally attributed mainly to abnormal levels of uremic toxins. The most recent data indicate a significant role for the dysregulation of the kappa opioid receptor (KOR) along with an imbalance in the mu-opioid receptor (MOR). Difelikefalin (DFK) is a KOR agonist approved for the treatment of moderate to severe CKD-aP in patients on hemodialysis in the USA, European Union (EU), Switzerland, Canada, Singapore, and Australia. It has shown rapid and sustained improvement in pruritus and is generally very well tolerated. Method We present the real-world experience of DFK in an early access program for patients in a hemodialysis (HD) program three times a week, diagnosed with CKD-aP, receiving the administration of DFK at 0.5 mcg/kg per HD session. A total of 14 HD patients with severe to very severe CKD-aP (WI-NRS >7) and (moderate-severe SADS) were treated with DFK. The severity of itching was assessed using the numerical rating scale (WI-NRS). Quality of life was assessed using the Self-Assessed Disease Severity Score (SADS). Results The results are shown in Table 1. 78.5% of the patients showed a reduction in WI-NRS of at least 3 points within the first 2 weeks and 92% showed a reduction of ≥ 5 points at 4 weeks, with positive effects on the patients' quality of life, describing a change from SADS C (severe deterioration of quality of life) to SADS A (mild deterioration). Conclusion Currently, 11 out of the 14 patients continue with Difelikefalin and maintain a sustained response in both itch intensity and quality of life. The availability of this new treatment, along with a new understanding of the impact of pruritus on our patients, has the potential to significantly improve the lives of patients living with CKD-aP. Sharing the clinical experience of DFK in series like this is important to raise awareness, not only of DFK but also of CKD-aP, particularly in the absence of specific treatments.

Distinct µ-opioid ensembles trigger positive and negative fentanyl reinforcement

Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement1. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement2,3 (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs4. Among the opioid receptors, µ-opioid receptors have a key role5, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.

Blocking potential metabolic sites on NAT to improve its safety profile while retaining the pharmacological profile

The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT, a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood–brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5′-position of the thiophene ring were designed and their structure–activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management.

Comparative Analysis of High-Frequency and Low-Frequency Transcutaneous Electrical Stimulation of the Right Median Nerve in the Regression of Clinical and Neurophysiological Manifestations of Generalized Anxiety Disorder.

Background/Objectives: The anxiolytic effect of transcutaneous electrical nerve stimulation (TENS) is associated with the activation of endogenous inhibitory mechanisms in the central nervous system. Both low-frequency, high-amplitude TENS (LF-TENS) and high-frequency, low-amplitude TENS (HF-TENS) are capable of activating opioid, GABA, serotonin, muscarinic, and cannabinoid receptors. However, there has been no comparative analysis of the effectiveness of HF-TENS and LF-TENS in the treatment of GAD. The purpose of our research was to study the effectiveness of direct HF-TENS and LF-TENS of the right median nerve in the treatment of patients with GAD compared with sham TENS. Methods: The effectiveness of direct HF-TENS and LF-TENS of the right median nerve in the treatment of GAD was studied using Generalized Anxiety Disorder 7-item scale (GAD-7) and the Hamilton Anxiety Rating Scale (HAM-A). 40 patients underwent sham TENS, 40 patients passed HF-TENS (50 Hz-50 μs-sensory response) and 41 patients completed LF -TENS (1 Hz-200 μs-motor response) for 30 days daily. After completion of treatment, half of the patients received weekly maintenance therapy for 6 months. Electroencephalography was performed before and after treatment. Results: Our study showed that a significant reduction in the clinical symptoms of GAD as assessed by GAD-7 and HAM-A was observed after HF-TENS and LF-TENS by an average of 42.4%, and after sham stimulation only by 13.5% for at least 2 months after the end of treatment. However, LF-TENS turned out to be superior in effectiveness to HF-TENS by 51% and only on electroencephalography leads to an increase in PSD for the alpha rhythm in the occipital regions by 24% and a decrease in PSD for the beta I rhythm in the temporal and frontal regions by 28%. The prolonged effect of HF-TENS and LF-TENS was maintained without negative dynamics when TENS treatment was continued weekly throughout the entire six-month observation period. Conclusions: A prolonged anxiolytic effect of direct TENS of the right median nerve has been proven with greater regression of clinical and neurophysiological manifestations of GAD after LF-TENS compared to HF-TENS. Minimal side effects, low cost, safety, and simplicity of TENS procedures are appropriate as a home treatment modality.

Methods of machine learning and big data analysis to establish the molecular mechanisms of the effects of racetams on the metabolism of adipose tissue

Racetams exhibit not only nootropic effects, but also affect the metabolism of fats and carbohydrates. Experimental studies have indicated the possibility of using phenylpiracetam in the treatment of obesity. At the same time, the molecular mechanisms of this pharmacological effect of phenylpiracetam are practically unknown. The paper presents the results of a new artificial intelligence (AI) method for comparative chemoreactome analysis of fonturacetam, piracetam, aniracetam, pramiracetam and levetiracetam. Another AI method, chemoneurocytological analysis, made it possible to compare the neuroprotective effects of molecules on neurons in culture. Despite the similarity of the proteomic interaction profiles of the studied molecules, differential analysis made it possible to establish the molecular mechanisms of the effect of phenylpiracetam on weight loss. Phenylpiracetam can activate β3-adrenoceptors, adenosine, glucagon-like peptide, sphingosine phosphate, and peroxisome proliferator receptors (PPARG); specifically inhibit cannabinoid, opioid, histamine, glutamate, nociceptin, neuropeptide Y and orexin receptors, which is important for normalizing appetite and improving the metabolism of adipose tissue. The synthetic AI method - pharmacoinformatic analysis indicated the advisability of taking phenylpiracetam together with vitamins C, D and group B.

Control of motivation for sucrose in the paraventricular hypothalamic nucleus by dynorphin peptides and the kappa opioid receptor

The dynorphin peptides are the endogenous ligands for the kappa opioid receptor (KOR) and regulate food intake. Administration of dynorphin-A1-13 (DYN) in the paraventricular hypothalamic nucleus (PVN) increases palatable food intake, and this effect is blocked by co-administration of the orexin-A neuropeptide, which is co-released with DYN in PVN from neurons located in the lateral hypothalamus. While PVN administration of DYN increases palatable food intake, whether it increases food-seeking behaviors has yet to be examined. We tested the effects of DYN and norBNI (a KOR antagonist) on the seeking and consumption of sucrose using a progressive ratio (PR) and demand curve (DC) tasks. In PVN, DYN did not alter the sucrose breaking point (BP) in the PR task nor the elasticity or intensity of demand for sucrose in the DC task. Still, DYN reduced the delay in obtaining sucrose and increased licks during sucrose intake in the PR task, irrespective of the co-administration of orexin-A. In PVN, norBNI increased the delay in obtaining sucrose and reduced licks during sucrose intake in the PR task while increasing elasticity without altering intensity of demand in the DC task. However, subcutaneous norBNI reduced the BP for sucrose and increased the delay in obtaining sucrose in the PR task while reducing the elasticity of demand. Together, these data show different effects of systemic and PVN blockade of KOR on food-seeking, consummatory behaviors, and incentive motivation for sucrose and suggest that KOR activity in PVN is necessary but not sufficient to drive seeking behaviors for palatable food.

Expression profile and immunomodulatory roles of methionine-enkephalin and delta opioid receptor in Octopus ocellatus

In this study, the expressions and distributions of methionine-enkephalin (Met-enk) and δ opioid receptor in the nervous system of Octopus ocellatus, and the immune regulatory mechanisms of Met-enk on O. ocellatus were explored. The distributions and expressions of Met-enk and δ opioid receptor were assessed by immunohistochemistry and enzyme-linked immunosorbent assay. UV-spectrophotometer, microplate reader, and flow cytometer were used to examine the effects of different concentrations of Met-enk on phagocytosis, antioxidant effects, and body surface mucus immunity of O. ocellatus hemocytes. The data were used to study the mechanisms of Met-enk immunity regulation in O. ocellatus. According to the results, the expression levels of Met-enk and δ opioid receptor in O. ocellatus lymphocytes were higher than those in hemocytes. The expression levels of Met-enk in the ganglia of O. ocellatus decreased in the following order: pedal ganglia > cerebral ganglia > visceral ganglia > optic ganglia > stellate ganglia. Moreover, the phagocytic activity of O. ocellatus hemocytes was enhanced with increasing Met-enk concentration. With increasing Met-enk concentration, the expressions of nitric oxide, total nitric oxide synthase, inducible nitric oxide synthase, catalase, hydrogen peroxide, myeloperoxidase, reduced glutathione, α-naphthy acetate esterase, and methionine aminopeptidases decreased in serums of O. ocellatus in the experimental group compared to the blank group. Similarly, the content of reduced glutathione in the hemocytes of O. ocellatus was also lower in the experimental group than in the blank group; however, the expressions of other substances were higher compared to the blank group. Furthermore, α-naphthy acetate esterase, myeloperoxidase, and hydrogen peroxide expressions in mucus immunity trials of the body surface were lower in the experimental group compared to the blank group. These results indicate that the distributions and expressions of Met-enk and δ opioid receptor in the nervous system of O. ocellatus were related to axoplasmic transport and immune regulation mechanisms. Met-enk participates in cellular immunity, humoral immunity, and mucus immunity in the form of neurotransmitters, thereby regulating the immune response of O. ocellatus.

Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach.

Opioid receptors belonging to the class A G-protein coupled receptors (GPCRs) are the targets of choice in the treatment of acute and chronic pain. However, their on-target side effects such as respiratory depression, tolerance and addiction have led to the advent of the 'opioid crisis'. In the search for safer analgesics, bivalent and more recently, bitopic ligands have emerged as valuable tool compounds to probe these receptors. The activity of bivalent and bitopic ligands rely greatly on the allosteric nature of the GPCRs. Bivalent ligands consist of two pharmacophores, each binding to the individual orthosteric binding site (OBS) of the monomers within a dimer. Bitopic or dualsteric ligands bridge the gap between the OBS and the spatially distinct, less conserved allosteric binding site (ABS) through the simultaneous occupation of these two sites. Bivalent and bitopic ligands stabilize distinct conformations of the receptors which ultimately translates into unique signalling and pharmacological profiles. Some of the interesting properties shown by these ligands include improved affinity and/or efficacy, subtype and/or functional selectivity and reduced side effects. This review aims at providing an overview of some of the bivalent and bitopic ligands of the opioid receptors and, their pharmacology in the hope of inspiring the design and discovery of the next generation of opioid analgesics.

AN OVERVIEW OF SOME HERBAL ANTIDEPRESSANT PLANTS

There are numerous ways to categorize and treat depression, which is a diverse mood disease. The illness is caused by factors such as 5-HT, NA, and MAO-A inhibition and stimulation. Reduced curiosity about pleasure, feelings of inappropriate guilt or worthlessness, a drop in hunger and sexual desire, sleeplessness, and persistent suicidal thoughts are some of the symptoms. There are several synthetic medications used to treat depression, but not all of them make patients happy, and some of them may have negative side effects. Many have turned to well-liked traditional herbal remedies to avoid the negative effects of allopathic therapy. Due to their broad application, therapeutic efficacy, and little to negligible adverse effects, herbal medications are currently used worldwide. Several medicinal plants and medicines derived from these plants have shown antidepressant properties by the combined effect of their medicinal constituents. We discuss promising novel medicinal products targets for the management of major depressive illness in this review. We address the potential antidepressant benefits of selectively targeting receptors, including opioid, G-protein-coupled, and metabotropic glutamate receptors. Since they may also have therapeutic value, we also talk about substances that target biological processes, including inflammation, the gut microbiota, the cholesterol biosynthesis pathway, and the hypothalamic-pituitary-adrenal axis. Lastly, we offer a synopsis of all the plants displayed in graphical format, together with an overview of the antidepressant plants which currently are widely accessible.