Search Results (41)

Background: Burning Mouth Syndrome (BMS) is a nociplastic pain condition characterized by altered central nervous system pain processing, significantly impacting patient quality of life. Pharmacological management often involves amitriptyline (monotherapy) and aripiprazole (for refractory cases) in Japan. However, the therapeutic efficacy of these drugs in BMS frequently exhibits a non-sigmoid (U-shaped or bell-shaped) dose–response relationship, indicating a clinically effective dose that is often considerably lower than those used for their primary indications and challenging conventional pharmacological assumptions. Method: This paper synthesizes existing pharmacological knowledge to elucidate the mechanisms underlying the non-dose-dependent actions of amitriptyline and aripiprazole in BMS. It focuses on their specific interactions with key neurotransmitter systems and receptors, particularly N-methyl-D-aspartate (NMDA) receptors and dopamine D2 receptors, to explain the observed non-linear dose–response and the importance of identifying a personalized therapeutic window. Result: Amitriptyline demonstrates efficacy in BMS at low doses (e.g., 25 mg), primarily through its action as an NMDA receptor antagonist via calcium-dependent desensitization and open-channel block, addressing central sensitization. Its effects are distinct from its antidepressant actions, and the “serotonin paradox” highlights the complexity of serotonin’s role in pain. Aripiprazole, utilized for refractory BMS, acts as a dopamine D2 receptor partial agonist, leading to a non-linear dose–response where sustained therapeutic effect is observed at specific low doses (e.g., 1.7–1.8 mg/day). This non-linearity is attributed to partial agonism, alongside interactions with serotonin 5-HT1A and 5-HT2A receptors. The general non-dose-dependency for both drugs is further explained by phenomena such as multiple binding sites with differing affinities, receptor desensitization/downregulation, activation of counter-regulatory mechanisms, and hormesis. Discussion: The observed non-linear dose–response curves for amitriptyline and aripiprazole in BMS underscore the inadequacy of a “one-size-fits-all” treatment approach. This necessitates a shift towards personalized medicine, which considers individual patient factors including pharmacogenomics, comorbidities, age, organ function, and psychological/social profiles. The true “personalized therapeutic window” is a balance between achieving significant pain relief and minimizing adverse effects, emphasizing careful titration and patient-centered care. Conclusions: The pharmacological actions of amitriptyline and aripiprazole in BMS are not linearly dose-dependent, but rather exhibit a personalized therapeutic window driven by complex interactions with NMDA and D2 receptors and adaptive physiological responses. This intricate pharmacological landscape mandates a personalized medicine approach to optimize treatment outcomes, improve patient adherence, and enhance the quality of life for individuals suffering from this challenging nociplastic pain condition. Full article

Gepirone, a selective 5-hydroxytryptamine (serotonin) 1A (5-HT_1A) receptor agonist, offers a promising strategy for treating mood and anxiety disorders. The therapeutic importance of 5-HT_1A modulation is well established, as these receptors regulate serotonergic neurotransmission both presynaptically, in the somatodendritic regions of raphe neurons, and postsynaptically, in structures including the hippocampus, neocortex, septum, amygdala, and hypothalamus. Gepirone exhibits a distinctive pharmacological profile, acting as a full agonist at presynaptic autoreceptors and a partial agonist at postsynaptic receptors, with high affinity for 5-HT_1A and much lower affinity for 5-HT_2A receptors. Its effects on serotonergic signaling are time-dependent. Acute administration suppresses serotonergic firing through autoreceptor activation, while chronic treatment induces autoreceptor desensitization, leading to enhanced 5-HT release in projection areas. This process is complemented by partial agonism at postsynaptic 5-HT_1A receptors, which further supports long-term neuromodulation. This article provides an integrated overview of gepirone’s mechanism of action, bridging receptor pharmacology, neurophysiological adaptations, and therapeutic implications. Particular emphasis is placed on the compound’s unique dual role in regulating serotonergic tone over time, a feature that differentiates it from other 5-HT_1A-targeting agents. By linking molecular mechanisms to clinical outcomes, we highlight gepirone’s potential advantages in efficacy, safety, and tolerability compared with conventional antidepressants. This comprehensive perspective underscores gepirone as a paradigmatic example of selective 5-HT_1A modulation and offers novel insights into the development of targeted treatments for depression and anxiety. Full article

Background/Objectives: Fibromyalgia is a chronic pain syndrome with unclear etiology, meaning that it is difficult to treat effectively. The stimulation of cannabinoid receptor 1 (CB1) suppresses neuronal excitability and synaptic transmission in nociceptive pathways via reducing activity in the calcium channel and promoting the opening of the potassium channel. Methods: In this study, we examined whether CB1 activity contributes to the antinociceptive efficacy of electroacupuncture (EA) in a mouse fibromyalgia (FM) pain model established using intermittent cold stress (ICS). The model mice demonstrated both mechanical and thermal hyperalgesia measured using the von Frey and Hargreaves tests, respectively. Results: Electroacupuncture effectively reduced both forms of hyperalgesia and enhanced CB1 expression in the dorsal root ganglia, spinal cord, hypothalamus, and periaqueductal gray. In addition, EA attenuated the fibromyalgia-associated reactive transformation of microglia and astrocytes and the activation of the pain-related TLR4–MyD88–TRAF6 signaling pathway. The effects of ICS were also mitigated by the deletion of Trpv1, the gene encoding the transient receptor potential cation channel TRPV1 (capsaicin channel) implicated in nociceptive and inflammatory signaling. Further, the antinociceptive efficacy of EA was partially recapitulated by the acupoint injection of a CB1 agonist and abolished by the injection of a CB1 antagonist, suggesting that activating CB1 is essential for this therapeutic effect. Conclusions: Electroacupuncture can effectively alleviate mechanical and thermal hyperalgesia in a mouse model affected by fibromyalgia pain by activating the CB1 pathway, highlighting the therapeutic potential of CB1 agonism as a therapeutic strategy. Full article

Aripiprazole is a third-generation antipsychotic, approved in 2002, notable for its partial agonism of the Dopamine D2 receptor and lower risk of metabolic and extrapyramidal adverse effects. It is available in a long-acting injectable formulation, which is very useful for maintaining medication compliance, which is crucial for preventing recurrent psychotic episodes in patients. Additionally, the aripiprazole long-acting injectable is frequently combined with other antipsychotic medications in acute settings to manage refractory symptoms. However, there is limited literature regarding the psychopharmacology, efficacy, and adverse effect profiles of augmenting aripiprazole long-acting injectable with other antipsychotic medications. This narrative review intends to synthesize the existing literature on aripiprazole, its comparative affinity to the dopamine D2 receptor versus other antipsychotics, and the efficacy and side effect profiles of combining aripiprazole with other antipsychotics in the context of acute inpatient treatment for psychosis. Current literature on K_i values indicates that fluphenazine, pimozide, thiothixene, trifluoperazine, and perphenazine bind more strongly to dopamine D2 receptors than aripiprazole. However, there is a knowledge gap regarding antipsychotic polypharmacy with aripiprazole and these first generation antipsychotics, limiting the discussion of these drug combinations to theory. Additionally, the muscarinic effects of aripiprazole suggest the possibility of augmentation with clozapine or xanomeline-trospium, albeit the peer-reviewed literature on this was also limited. Overall, it is difficult to draw conclusions regarding best clinical practices for these scenarios, as the existing literature is contradictory. Nonetheless, the application of the dopamine and muscarinic pathway theories for schizophrenia opens venues for future research and consideration. Full article

Background/Objectives: Diseases associated with inflammatory processes continue to grow steadily throughout the world. Unfortunately, prolonged use of drugs induces adverse effects ranging from hypersensitivity reactions to damage to the digestive system. These negative effects open the possibility of continuing the search for anti-inflammatory compounds with less toxicity. The aim of this research was to isolate and evaluate the anti-inflammatory activity of a mixture of two enantiomeric labdanes isolated from Gymnosperma glutinosum by in vivo, in vitro, and in silico methods. Methods: A brief description of the main methods or treatments applied. This can include any relevant preregistration or specimen information. The structure of the labdanes enantiomers was elucidated by X-ray crystallography and spectroscopies methods. The anti-inflammatory effect was evaluated on a mouse model of ear edema induced with 12-O-tetradecanoyl phorbol-13-acetate; the pro-inflammatory mediators, nitric oxide (NO) and interleukin (IL-6), were quantified on macrophages stimulated with lipopolysaccharide, and the interaction between labdanes and diana was studied by molecular docking. Results: We identified the chemical structures of two new labdane enantiomers: a-gymglu acid and b-ent-gymglu acid. The enantiomer mixture, named gymglu acid, diminished ear edema at doses of 1 and 2 mg/ear by 36.07% and 41.99%, respectively. A concentration of 155.16 µM of gymglu acid inhibited the production of NO by 78.06% and IL-6 by 71.04%. The in silico results suggest two routes by which these labdanes reduce inflammation: partial agonism toward the corticosteroid receptors and inhibition of nitric oxide synthases. Conclusions: These results show that the gymglu acid enantiomers have promising anti-inflammatory activity. Full article

The beta-3 adrenergic receptor (β3-AR), whose expression is modulated by oxygen levels, was found to play a key role in organ maturation, and its agonism was reported to mitigate hyperoxia-induced large bowel damage by preventing organ hypoplasia, preserving epithelial integrity, vascularization, and the neurochemical coding in the colonic myenteric plexus. This study explored the effects of β3-AR agonism in preventing hyperoxia-related alterations on the ileal enteric nervous system (ENS). Sprague–Dawley rat pups were reared under normoxia or hyperoxia (85%) during the first two weeks after birth and treated or not with the β3-AR agonist BRL37344 at 1, 3, or 6 mg/kg. Hyperoxia caused an imbalance of inhibitory nitrergic and excitatory cholinergic neurons in both the myenteric and submucosal plexuses and decreased the amounts of neurons in the submucosal plexus and that of S100β⁺ and GFAP⁺ glial cells in the myenteric plexus. Administration of 3 mg/kg BRL37344 preserved the neuronal chemical coding and partially prevented the loss of myenteric GFAP⁺ glial cells, while it did not counteract submucosal neuronal loss. Our findings indicate the potential of β3-AR agonism as a new therapeutic strategy for hyperoxia-induced ileal ENS alterations. Full article

The cholinergic pathways in the central nervous system (CNS) play a pivotal role in different cognitive functions of the brain, such as memory and learning. This review takes a dive into the pharmacological side of this important part of CNS function, taking into consideration muscarinic receptors and cholinesterase enzymes. Targeting a specific subtype of five primary muscarinic receptor subtypes (M1-M5) through agonism or antagonism may benefit patients; thus, there is a great pharmaceutical research interest. Inhibition of AChE and BChE, orthosteric or allosteric, or partial agonism of M1 mAChR are correlated with Alzheimer’s disease (AD) symptoms improvement. Agonism or antagonism on different muscarinic receptor subunits may lessen schizophrenia symptoms (especially positive allosteric modulation of M4 mAChR). Selective antagonism of M4 mAChR is a promising treatment for Parkinson’s disease and dystonia, and the adverse effects are limited compared to inhibition of all five mAChR. Additionally, selective M5 antagonism plays a role in drug independence behavior. M3 mAChR overexpression is associated with malignancies, and M3R antagonists seem to have a therapeutic potential in cancer, while M1R and M2R inhibition leads to reduction of neoangiogenesis. Depending on the type of cancer, agonism of mAChR may promote cancer cell proliferation (as M3R agonism does) or protection against further tumor development (M1R agonism). Thus, there is an intense need to discover new potent compounds with specific action on muscarinic receptor subtypes. Chemical structures, chemical modification of function groups aiming at action enhancement, reduction of adverse effects, and optimization of Drug Metabolism and Pharmacokinetics (DMPK) will be further discussed, as well as protein–ligand docking. Full article

Bipolar disorder (BD) is characterized by recurrent episodes of mania, hypomania, and depression and is often complicated by comorbid substance use disorders (SUDs). Up to 60% of individuals with BD experience SUDs, which exacerbate mood instability and increase the risk of rapid cycling, suicide, and poor clinical outcomes. Current treatment strategies, including lithium and valproate, show limited efficacy in treating both BD and SUD. Psychotherapeutic approaches such as cognitive behavioral therapy (CBT) offer benefits but lack a specific focus on substances such as cannabis and cocaine. Since there is still debate on how to treat this comorbidity, there is a need to find new therapeutic options; this mini-review examines the pharmacological properties of cariprazine and its emerging role in the treatment of comorbid BD and SUD. Cariprazine, an atypical antipsychotic with partial agonism at dopamine D2 and D3 receptors, has shown promise in treating both mood symptoms and cognitive dysfunction in BD. Its unique affinity for D3 receptors, which are involved in motivation and reward processing, may offer advantages in reducing drug craving. Clinical trials indicate that cariprazine effectively treats manic, depressive, and mixed episodes in BD with a favorable side effect profile, particularly at lower doses. Preliminary results suggest its potential to reduce craving and substance use in individuals with co-occurring BD and SUD. Therefore, cariprazine, with its unique pharmacodynamic mechanism, could be further studied for the treatment of BD in comorbidity with SUD. However, evidence on the role of cariprazine in the treatment of SUDs remains limited, based primarily on case reports and animal studies. Further research, including large-scale clinical trials, is needed to determine its full efficacy in this dual diagnosis. Full article

Generalized Anxiety Disorder (GAD) is a common psychiatric condition characterized by persistent and excessive worry, often accompanied by dysautonomic symptoms that significantly impact patients’ well-being. Cannabidiol (CBD), a non-psychoactive compound derived from cannabis, has shown potential as an anxiolytic through its partial agonism of the 5HT-1A receptor and its negative allosteric modulation of CB1 receptors, which may help mitigate the anxiogenic effects of tetrahydrocannabinol (THC). This study evaluates the impact of CBD on individuals diagnosed with various anxiety disorders, comparing its effects to placebo and conventional pharmaceutical treatments through a systematic review of randomized controlled trials (RCTs). A systematic search of RCTs published between 2013 and 2023 was conducted across three databases using the terms “cannabidiol” and “anxiety”. Out of the 284 articles identified, 11 met the eligibility criteria. The studies reviewed varied widely in terms of the types of anxiety disorders and CBD dosages examined, leading to results that were often contradictory. Despite these conflicting outcomes, the data suggest that CBD may reduce anxiety with minimal adverse effects when compared to a placebo. However, further RCTs with improved methodologies, encompassing a broad range of doses and continuous CBD administration across specific anxiety disorders, are needed. Unlike previous studies and meta-analyses, this review encompasses a broader spectrum of anxiety disorders and a variety of study designs and dosages, providing a more nuanced understanding of CBD’s potential efficacy across different conditions. Full article

Trace amine-associated receptor 1 (TAAR1) is a negative regulator of dopamine (DA) release. The partial TAAR1 agonist RO5263397 promotes wakefulness and suppresses NREM and REM sleep in rodents and non-human primates. We tested the hypothesis that the TAAR1-mediated effects on sleep/wake regulation were due, in part, to DA release. Male C57BL6/J mice (n = 8) were intraperitoneally administered the D1R antagonist SCH23390, the D2R antagonist eticlopride, a combination of D1R + D2R antagonists, or saline at ZT5.5, followed 30 min later by RO5263397 or vehicle per os. EEG, EMG, subcutaneous temperature, and activity were recorded across the 8 treatments and sleep architecture was analyzed for 6 h post-dosing. As described previously, RO5263397 increased wakefulness and delayed NREM and REM sleep onset. D1, D2, and D1 + D2 pretreatment reduced RO5263397-induced wakefulness for 1–2 h after dosing but only the D1 antagonist significantly reduced the TAAR1-mediated increase in NREM latency. Neither the D1 nor the D2 antagonist affected the TAAR1-mediated suppression of REM sleep. These results suggest that, whereas the TAAR1 effects on wakefulness are mediated, in part, through the D2R, D1R activation plays a role in reversing the TAAR1-mediated increase in NREM sleep latency. In contrast, the TAAR1-mediated suppression of REM sleep appears not to involve D1R or D2R mechanisms. Full article

For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR. Full article

The heterogeneity of etiology may serve as a crucial factor in the challenges of treatment, including the low response rate and the delay in establishing therapeutic effect. In the present study, we examined whether social experience since early life is one of the etiologies, with the involvement of the 5-HT1A receptors, and explored the potentially therapeutic action of the subchronic administration of buspirone, a partial 5-HT1A agonist. Rats were isolation reared (IR) since their weaning, and the depressive profile indexed by the forced-swim test (FST) was examined in adulthood. Nonspecific locomotor activity was used for the IR validation. Buspirone administration (1 mg/kg/day) was introduced for 14 days (week 9–11). The immobility score of the FST was examined before and after the buspirone administration. Tissue levels of serotonin (5-HT) and its metabolite 5-HIAA were measured in the hippocampus, the amygdala, and the prefrontal cortex. Efflux levels of 5-HT, dopamine (DA), and norepinephrine (NE) were detected in the hippocampus by brain dialysis. Finally, the full 5-HT1A agonist 8-OH-DPAT (0.5 mg/kg) was acutely administered in both behavioral testing and the dialysis experiment. Our results showed (i) increased immobility time in the FST for the IR rats as compared to the social controls, which could not be reversed by the buspirone administration; (ii) IR-induced FST immobility in rats receiving buspirone was corrected by the 8-OH-DPAT; and (iii) IR-induced reduction in hippocampal 5-HT levels can be reversed by the buspirone administration. Our data indicated the 5-HT1A receptor-linked early life social experience as one of the mechanisms of later life depressive mood. Full article

Even slight structural differences between phytocannabinoid isomers are usually enough to cause a change in their biological properties. In this study, we used in vitro CB1 agonism/antagonism assays to compare the receptor binding functionality of THCV (tetrahydrocannabivarin) and HHC (hexahydrocannabinol) isomers and applied molecular docking to provide an explanation for the difference in the activities. No CB1 agonism was observed for ∆9- and ∆8-THCV. Instead, both isomers antagonized CP 55940, with ∆9-THCV being approximately two times more potent than the ∆8 counterpart (IC₅₀ = 52.4 nM and 119.6 nM for ∆9- and ∆8-THCV, respectively). Docking simulations found two binding poses for THCV isomers, one very similar to ∆9-THC and one newly discovered pose involving the occupation of side pocket 1 of the CB1 receptor by the alkyl chain of the ligand. We suggested the latter as a potential antagonist pose. In addition, our results established 9R-HHC and 9S-HHC among partial agonists of the CB1 receptor. The 9R-HHC (EC₅₀ = 53.4 nM) isomer was a significantly more potent agonist than 9S (EC₅₀ = 624.3 nM). ∆9-THC and 9R-HHC showed comparable binding poses inside the receptor pocket, whereas 9S-HHC adopted a new and different binding posture that can explain its weak agonist activity. Full article

Integrins are heterodimeric cell-surface receptors that regulate cell–cell adhesion and cellular functions through bidirectional signaling. On the other hand, anomalous trafficking of integrins is also implicated in severe pathologies as cancer, thrombosis, inflammation, allergies, and multiple sclerosis. For this reason, they are attractive candidates as drug targets. However, despite promising preclinical data, several anti-integrin drugs failed in late-stage clinical trials for chronic indications, with paradoxical side effects. One possible reason is that, at low concentration, ligands proposed as antagonists may also act as partial agonists. Hence, the comprehension of the specific structural features for ligands’ agonism or antagonism is currently of the utmost interest. For α4β1 integrin, the situation is particularly obscure because neither the crystallographic nor the cryo-EM structures are known. In addition, very few potent and selective agonists are available for investigating the mechanism at the basis of the receptor activation. In this account, we discuss the physiological role of α4β1 integrin and the related pathologies, and review the few agonists. Finally, we speculate on plausible models to explain agonism vs. antagonism by comparison with RGD-binding integrins and by analysis of computational simulations performed with homology or hybrid receptor structures. Full article

Although traditional opioids such as morphine and oxycodone are commonly used in the management of acute postoperative pain, novel opioids may play a role as alternatives that provide potent pain relief while minimizing adverse effects. In this review, we discuss the mechanisms of action, findings from preclinical studies and clinical trials, and potential advantages of several novel opioids. The more established include oliceridine (biased ligand activity to activate analgesia and downregulate opioid-related adverse events), tapentadol (mu-opioid agonist and norepinephrine reuptake inhibitor), and cebranopadol (mu-opioid agonist with nociceptin opioid peptide activity)—all of which have demonstrated success in the clinical setting when compared to traditional opioids. On the other hand, dinalbuphine sebacate (DNS; semi-synthetic mu partial antagonist and kappa agonist), dual enkephalinase inhibitors (STR-324, PL37, and PL265), and endomorphin-1 analog (CYT-1010) have shown good efficacy in preclinical studies with future plans for clinical trials. Rather than relying solely on mu-opioid receptor agonism to relieve pain and risk opioid-related adverse events (ORAEs), novel opioids make use of alternative mechanisms of action to treat pain while maintaining a safer side-effect profile, such as lower incidence of nausea, vomiting, sedation, and respiratory depression as well as reduced abuse potential. Full article