Neuropharmacology最新文献

Bone cancer pain (BCP) is one of the most severe complications faced by patients with cancer; however, current pharmacological options are limited. Curcumin has been demonstrated to possess anti-inflammatory and analgesic properties; however, our preliminary research found that the analgesic efficiency of curcumin is not high in BCP. Consequently, curcumin analogs have emerged as a significant focus of our research. This study aimed to systematically investigate the analgesic effects of C16 in rats with BCP induced by MADB 106 breast cancer cells (MADB 106-induced BCP) and elucidate the underlying molecular mechanisms. A range of experimental methods, including kinase profiling, transcriptome sequencing, behavioral tests, immunofluorescence, and biochemical analyses, were employed to comprehensively assess the role of C16 in the MADB 106-induced BCP model. The results indicated that C16 significantly alleviated bone cancer pain induced by Luciferin-MADB 106 cells (10ˆ6 cells) in a dose-dependent manner. Importantly, kinase profiling and validation experiments identified CaMKIα in spinal dorsal horn neurons as the primary target of C16's analgesic effect on MADB 106-induced BCP. Continuous intrathecal administration of C16 markedly suppressed the expression of CREB and P-CREB and reduced the expression of neuroligin 2 in the spinal cords of BCP rats, thereby clarifying the mechanism of action of C16 in alleviating MADB 106-induced BCP. These findings suggest that C16 possesses significant therapeutic potential for mitigating MADB 106-induced BCP nociceptive hypersensitivity, providing a foundation for the future development of novel drugs targeting MADB 106-induced BCP. This article is part of the Special Issue on "Empathic Pain".

Background: Apathy is a syndrome of decreased goal-directed activity, one of the main features of different brain disorders. Despite its high prevalence and life-threatening potential, there are currently very few options for its pharmacological treatment, which may be related to the lack of valid animal models.

Aims: The vesicular monoamine transporter 2 inhibitor tetrabenazine (TBZ) was used in this study to model apathy-related behavior in pathologies linked to a depletion of dopamine. The atypical dopamine transporter inhibitor CE-123 and the NMDA receptor antagonist MK-801 were evaluated for their effects on goal-directed activity in intact and TBZ-treated rats to compare dopamine and non-dopamine approaches.

Methods: To assess goal-directed behavior, the progressive ratio 3 (PR3) operant schedule of food reinforcement was conducted in adult male rats. To assess the motivational changes underlying the schedule, a model analysis based on the mathematical principles of reinforcement was applied.

Results: Treatment with TBZ (0.3 mg/kg) induced a decrease in response rate as the number of required responses increased. This effect was not accompanied by a decrease in the incentive value of the reinforcer or locomotor disturbances, suggesting that decreased tolerance to high effort demands was the underlying mechanism of the decrease in goal-directed activity. Treatment with MK-801 increased operant activity in both TBZ-treated and pharmacologically naïve rats.

Conclusions: Our results support the previously proposed view that the TBZ-treated rats can be a model of apathy-related behavior in pathologies linked to a depletion of dopamine and suggest that NMDA receptors are a potential therapeutic target for the development of novel approaches to the treatment of apathy in both dopamine-depleted and dopamine-intact states.

The central nervous system is a well-known steroidogenic tissue producing, among others, cholesterol metabolites such as neuroactive steroids, oxysterols and steroid hormones. It is well known that these endogenous molecules affect several receptor classes, including ionotropic GABAergic and NMDA glutamatergic receptors in neurons. It has been shown that also ionotropic purinergic (P2X) receptors are cholesterol metabolites' targets. Among P2X receptors, purinergic P2X4 and P2X7 receptors are expressed in microglia, the innate immune cells involved in the brain inflammatory response. In this study, we explore the ionotropic purinergic receptors modulation by cholesterol metabolites in microglia. Patch-clamp experiments were performed in BV2 cells, a murine microglia cell line, to evaluate effects of cholesterol metabolites using micro- and nanomolar concentrations. About P2X4 receptor, we found that testosterone butyrate (20 μM and 200 nM) and allopregnanolone (10 μM and 100 nM) both potentiated its current, while neither 25-hydroxycholesterol (10 μM and 100 nM) nor 17β-estradiol (1 μM) showed any effects. On the other hand, P2X7 receptor current was potentiated by allopregnanolone (10 μM) and 25-hydroxycholesterol (10 μM and 100 nM). Taken together, our data show that modulation of either P2X4 and P2X7 current is affected differently by cholesterol metabolites, suggesting a structure-activity relationship among these players. Identifying the possible link between purinergic transmission, microglia and cholesterol metabolites will allow to define new targets for drug development to treat neuroinflammation.

Acute intoxication by toluene usually follows intentional inhalation to achieve a "high", which may lead to repeated use due to toluene's reinforcing properties. In both acute and chronic intoxication brain function is primarily affected. Neuronal and glial elements participate in toluene's reinforcing properties and chronic toxicity, yet the targets underlying acute toxicity remain unknown. Many signs of toluene's acute toxicity overlap with those of brain ischemia. Moreover, two studies in humans who abused toluene reveal brain hypoperfusion in middle cerebral artery (MCA) territories. Hypoperfusion, however, may result from either excessive vasoconstriction/increased vasodilation. Using rat and mouse models, we demonstrate that toluene at concentrations reached during recreational inhalation (8000 ppm) significantly decreases (-8%) MCA diameter in vivo in male and female animals. Using GC-MS, we determined toluene blood levels from inhalation (0.09-127 mM) and then show that <1 mM toluene constricts ex vivo-pressurized MCA independently of endothelium. Toluene action is blunted by deletion of KCNMA1, which codes for BK channels, key regulators of MCA diameter, and upon selective channel blockade by 1 μM paxilline. Lastly, when applied onto an isolated membrane patch several minutes after patch-excision from the SM cell, submM toluene reduces mildly yet statistically significantly (P < 0.05) both steady-state activity (-15%) and unitary current amplitude (-20%) of MCA myocyte BK channels. Thus, BK channels themselves and their immediate proteolipid microenvironment suffice for these drug actions. Collectively, data unveil a direct inhibition of MCA myocyte BK currents by intoxicating levels of toluene, which determines, or at least contributes to, MCA constriction by toluene levels reached during inhalation by humans who suffer acute brain intoxication.

Parkinson's disease (PD) is a neurodegenerative disorder typified by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) leading to motor symptoms including resting tremor, rigidity, akinesia, and postural instability. DA replacement therapy with levodopa (L-DOPA) remains the gold-standard treatment for the motor symptoms of PD. Unfortunately, chronic use of L-DOPA leads to the development of side effects known as L-DOPA-induced dyskinesia (LID). The mechanisms underlying LID are multifaceted, but accumulating research has strongly implicated maladaptive neuroplasticity within the raphe-striatal serotonin (5-HT) circuit. The 5-HT transporter (SERT) has emerged as an intriguing therapeutic target as it is upregulated in the brains of dyskinetic patients and animal models of LID, and pharmacological blockade of SERT alters L-DOPA's effects. Therefore, the current study employed an interventional genetic knockdown of SERT (SERT-KD) to investigate its role in LID expression and LID-associated transcription factors. To do so, hemiparkinsonian, stably dyskinetic rats (N = 68) received adeno-associated virus 9 (AAV9) expressing either a short-hairpin RNA against SERT (SERT-shRNA) or a scrambled control shRNA (SCR-shRNA) after which LID reinstatement and motor performance were assayed over 2 weeks. Dorsal raphe and striatal tissue were collected for the expression analyses of known parkinsonian and LID-associated genes. Results demonstrated that SERT-KD significantly and durably reduced LID and L-DOPA-induced striatal cFOS mRNA without altering L-DOPA efficacy. Such findings point to SERT-mediated adaptations as a 5-HT mechanism by which L-DOPA exerts its actions and therapeutic target for LID.

Chronic pain is the most prevalent and complex clinical disorder,affecting approximately 30% of people globally. Various intricate alterations in nociceptive pathways responsible for chronic pain are linked to long-term tissue damage or injury to the peripheral or central nervous systems. These include remolding in the phenotype of cells and fluctuations in the expression of proteins such as ion channels, neurotransmitters, and receptors. Heat shock proteins are important molecular chaperone proteins in cell responses to stress, including inflammation, neurodegeneration, and pain signaling. They play a key role in activating glial and endothelial cells and in the production of inflammatory mediators and excitatory amino acids in both peripheral and central nervous systems. In particular, they contribute to central sensitization and hyperactivation within the dorsal horn of the spinal cord. The expression of some HSPs plays a remarkable role in upregulating pain response by acting as scavengers of ROS, controlling inflammatory cytokines. Different HSPs act by different mechanisms and several important pathways have been implicated in targeting HSPs for the treatment of neuropathic pain including p38-mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), brain-derived neurotrophic factors (BDNF). We summarize the role of HSPs in various preclinical and clinical studies and the crosstalk of HSPs with various nociceptors and other pain models. We also highlighted some artificial intelligence tools and machine learning-assisted drug discovery methods for rapid screening of HSPs in various diseases. Focusing on HSPs could lead to the development of new therapeutics that modulate pain responses and enhance our understanding of pain in various pathological conditions and neurological disorders.

Although angiotensin 1-7 (Ang 1-7) and its role as a part of the "protective" axis of the renin-angiotensin system are well described in the literature, the mechanisms of its angiotensin II-like pressor and tachycardic effects following its acute central administration are not fully understood. It was the aim of the present study to examine which receptors contribute to the aforementioned cardiovascular effects. Ang 1-7 and antagonists for glutamate, GABA, vasopressin, thromboxane A₂ (TP), α₁-adrenergic, and P2X purinoceptors or modulators of oxidative stress were injected into the paraventricular nucleus of the hypothalamus (PVN) of urethane-anesthetized male Wistar rats. Acute injection of Ang 1-7 into the PVN increased blood pressure (BP) by about 15 mmHg and heart rate (HR) by about 14 beats/min. After preinjection with bicuculline (GABA_A receptor antagonist), CNQX + D-AP5 (AMPA/kainate and NMDA receptor antagonists) and SQ29548 (TP receptor antagonist) the BP and HR reactions to Ang 1-7 were attenuated or abolished. The vasopressin V_1A and V_1B receptor antagonists conivaptan and nelivaptan, and the NADPH oxidase inhibitor apocynin even reversed the pressor and tachycardic effects of Ang 1-7. Antagonists of P2X (PPADS) and α₁-adrenergic receptors (prazosin), the free radical scavenger tempol and the superoxide dismutase inhibitor DETC did not modify the cardiovascular effects of Ang 1-7. The (Mas receptor-related) rise in BP and HR evoked by Ang 1-7 administered to the rat PVN is linked to glutamate, vasopressin, GABA_A and thromboxane receptors, and to oxidative stress, but does not seem to involve α₁-adrenergic or P2X receptors.

There is renewed interest in psychedelics, such as psilocybin, as therapies for multiple difficult-to-treat psychiatric disorders. Even though psychedelics can induce highly pleasant or aversive experiences, depending on multiple personal and environmental factors, there is little research into how such experiences impact post-acute mood-altering actions. Here we aimed at offsetting this gap. First, we tested whether acute psilocybin effects differed between sexes. Adult male and female C57BL/6J mice received saline or psilocybin (5 mg/kg; i.p.), and head-twitch response (HTR) frequency was quantified. Notably, while psilocybin increased HTR frequency in both sexes, the effect was greater in females. We then tested if stress exposure during acute drug effects impacted post-acute psilocybin actions. Following drug treatment, mice were returned to their homecage or restrained for 1 h. Anxiety- and depression-like behaviors were assessed starting 24 h following drug administration, using the marble burying, novelty-suppressed feeding, and splash tests. Psilocybin induced anxiolytic-, but not antidepressant-like, which were fully blocked by stress in males, but only partially so in females. Lastly, we assessed the acute stress-psilocybin interaction on plasma corticosterone levels in a separate cohort of mice, treated as above. Both stress and psilocybin independently increased corticosterone levels, without additive or interactive effects being observed for either sex. Our data reveals the role of sex and peri-acute negative experiences in the acute and post-acute actions of psilocybin. These findings underline the importance of non-pharmacological factors, such as the quality of the psychedelic experience, in the mood-altering effects of psychedelics, holding significant for both their therapeutic and recreational use.

Perioperative neurocognitive disorders (PND) is one of the most common postoperative complications, which can lead to a harmful impact on self-dependence, longer hospital stays, increased medical costs, morbidity, and mortality amongst older adults. Microglia can modulate synapse elimination involved in the complement component protein 1q (C1q) pathway to induce cognitive dysfunction, which is significantly improved by short chain fatty acids (SCFAs) treatment. Here we investigate the effects of SCFAs treatment on PND via mediating C1q complement pathway. High-throughput sequencing of 16S rDNA from fecal samples of male SD rats was applied to assess the changes in gut microbiota. Fecal microbiota transplantation (FMT) was performed to investigate whether gut microbiota from PND rats could alter cognitive impairment. The blood from the rat tail vein was collected to measure the SCFAs concentrations. Hippocampal and brain tissue samples were obtained to perform Western blots, Golgi and immunofluorescence staining. Primary microglia treated with SCFAs or Histone deacetylase inhibitor were cultured to measure microglial activation states and the expression of acetylated histone. The 16S rDNA sequencing results showed that PND rats had the significant changes in the species diversity of the gut microbiota and the metabolite of specifc species. Gut microbiota from PND rats could alter spatial learning and memory, and meanwhile, the changed SCFAs concentrations in plasma were involved. The synapse elimination in PND rats was strikingly reversed by SCFAs treatment involved in modulation complement C1q via suppressing neuroinflammation. This suggests that a link between gut microbiota dysbiosis and cognitive function impairment is involved in synapse elimination via mediating complement C1q pathway. SCFAs treatment can alleviate PND, the mechanisms of which may be associated with regulating complement C1q pathway.

During the transition to motherhood, complex brain adaptations occur to ensure adequate maternal responses to offspring' needs accompanied by reduced anxiety. Among others, the corticotropin-releasing factor (CRF) and oxytocin (OXT) systems have emerged as crucial regulators of these essential postpartum adaptations. Here, we investigated their roles within the nucleus accumbens shell (NAcSh), a central region of the reward and maternal circuits, in maternal neglect of lactating rats. Furthermore, we assessed the contribution of the local CRF system to anxiety-like behaviour, comparing lactating female, virgin female and male rats to evaluate potential sex-differences. Increasing CRF receptor (CRF-R) 1 transmission via local CRF infusion in the NAcSh led to maternal neglect, reducing nursing and increasing self-directed behaviours. In turn, local CRF-R1 inhibition impaired maternal motivation. Intra-NAcSh Urocortin3 infusion did not promote maternal neglect but increased anxiety-like behaviour in lactating and virgin female rats, whereas CRF infusion had anxiogenic effects only in male rats. Crh-r1 mRNA expression was higher in male and lactating rats compared to virgin females; furthermore, male rats had increased Crh-bp mRNA expression compared to virgin female rats, only. Lastly, pharmacological manipulations of the OXT system did not affect maternal responses. In conclusion, finely balanced CRF-R1 signalling in the NAcSh is required for the proper expression of maternal behaviours. Dampened CRF-R2 signalling prevents the onset of anxiety-like behaviour in female rats, whereas CRF-R1 plays a more prominent role in males, highlighting complex sex-differences of the CRF system's regulation of anxiety within the NAcSh.