Brief hypoxic episodes drive neuroplasticity in animal models and humans. Pretreatment with an allosteric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (R) modulator ("ampakine") enables a single hypoxic exposure to induce sustained increases in phrenic motor activity ["phrenic motor facilitation" (pMF)]. Phrenic nerve activity was recorded in anesthetized rats to determine whether the ampakine-hypoxia (A-H) combination is unique in its ability to evoke pMF and to determine its underlying mechanisms. Pairing ampakine CX717 with brief moderate or severe hypercapnia failed to produce pMF. Pairing doxapram, a respiratory stimulant, with hypoxia did not produce pMF. We then sequentially tested the hypotheses that A-H-induced pMF requires spinal serotonin, adenosine, or NMDA receptor activation. Cervical intrathecal delivery of serotonin (methysergide) or adenosine 2 A receptor (MSX-3) antagonists before A-H failed to prevent pMF. In contrast, the NMDA-R blocker MK-801 prevented pMF when administered before but not after A-H. Finally, as a step in the translational pathway, we tested the safety and efficacy of acute A-H exposure in unanesthetized rats with indwelling diaphragm electromyogram (EMG) wires after cervical spinal cord injury (SCI). A-H was well tolerated, and at 3 mo after SCI, increased diaphragm EMG output. We conclude that the mechanism driving sustained increases in phrenic motor output after A-H is independent of spinal adenosine or serotonin receptor activation, but requires spinal NMDA-R activation for the induction, but not maintenance, of A-H pMF. Ampakine pretreatment may be useful to increase the efficacy of hypoxia-based rehabilitation paradigms after SCI, particularly since clinical trials report a substantial number of "low responders."NEW & NOTEWORTHY Rehabilitation paradigms using brief hypoxia exposure can improve recovery after spinal cord injury. A low dose of ampakines, which enhance AMPA neurotransmission, coupled with brief hypoxia (A-H), uniquely evokes respiratory neuroplasticity ("phrenic motor facilitation" or pMF) via a mechanism that requires spinal NMDA, but not serotonin or adenosine receptor activation. A-H also increased diaphragm activation in rats with chronic SCI, suggesting that the A-H pairing may be useful in neurorehabilitation.

Background: Ketamine and magnesium sulfate are commonly used perioperatively to prevent shivering, a frequent and clinically relevant complication of spinal and general anesthesia. Although their hypothermic effects are well documented, the neurotransmitter mechanisms underlying these effects remain insufficiently understood. This study examines whether serotonergic, adrenergic (α2), and GABAergic (GABAA) systems contribute to hypothermia induced by ketamine and a ketamine-magnesium sulfate combination. Methods: Body temperature was measured in Wistar rats after administration of ketamine (10 mg/kg) or the ketamine (5 mg/kg)-magnesium sulfate (5 mg/kg) combination. To assess neurotransmitter involvement, animals received yohimbine (α2 antagonist), methysergide (non-selective 5-HT antagonist), or bicuculline (GABAA antagonist) prior to ketamine or the drug combination. Data were analyzed using two-way repeated measures ANOVA followed by Tukey's post hoc test. Results: Yohimbine at 0.5 and 1 mg/kg significantly potentiated ketamine-induced hypothermia, while only 3 mg/kg enhanced the effect of the ketamine-magnesium sulfate combination. Methysergide had a bidirectional influence: 1 mg/kg methysergide deepened ketamine-induced hypothermia, whereas 0.5 mg/kg methysergide attenuated the hypothermic effect of the ketamine-magnesium sulfate combination. Bicuculline (1-2 mg/kg) did not alter the hypothermic responses to ketamine or the combination. Conclusions: These findings indicate that ketamine- and ketamine-magnesium sulfate-induced hypothermia is primarily modulated by serotonergic and adrenergic mechanisms, whereas GABAA receptor-dependent pathways do not appear to play a major role under the experimental conditions used. These results provide new mechanistic insights into NMDA antagonist-related thermoregulation and may help inform anesthetic strategies for shivering prevention and maintenance of perioperative thermal stability.

Activation of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) in the spinal cord contributes to neuropathic pain; however, its role at supraspinal sites remains unexplored. Ozanimod is a new FDA-approved S1PR1 antagonist for multiple sclerosis. Here, we show that systemic ozanimod administration reverses behavioral hypersensitivities in male rodents induced by chronic sciatic nerve constriction and chemotherapy (oxaliplatin and paclitaxel). Moreover, bilateral ozanimod injection in the rostral ventral medulla (RVM) reversed behavioral hypersensitivities in a time-dependent manner, evincing a role for S1PR1 in the descending pain modulatory system. RNA-Seq analysis of the RVM revealed that traumatic nerve injury downregulated type I interferons (IFN-I) signaling. Intra-RVM ozanimod administration normalized IFN-I-associated gene expression levels, suggesting that S1PR1 activation mediated IFN-I signaling downregulation that, in turn, may regulate RVM descending pain pathways. In the RVM, engagement of noradrenergic and serotonergic inhibitory circuits suppressed spinal nociception. Intrathecal injection of an α2 antagonist (yohimbine) or a serotonin antagonist (methysergide) prevented the antinociceptive effects of ozanimod in both models of neuropathic pain implicating these descending inhibitory projections in S1PR1 antagonism. In contrast to the disease state, intra-RVM injection of the S1PR1 agonist SEW2871 to uninjured animals did not cause behavioral hypersensitivities, underscoring a state-dependent role of S1PR1 in nociception. Our results establish a role for S1PR1 in descending facilitation and suggest that this function may inhibit IFN-I signaling pathways. Our findings support repurposing FDA-approved functional S1PR1 antagonists as nonopioid treatments for neuropathic pain.

Cortical spreading depolarization (CSD) describes a slow, sustained depolarization within the cerebral gray matter that renders neurons unable to fire action potentials, resulting in widespread neuronal depression. CSD has been observed in stroke, subarachnoid hemorrhage, epilepsy, traumatic brain injury, and migraines and is a potential indicator of imminent neuronal death. Therefore, the identification, monitoring, and treatment of CSD are crucial in both neurointensive care and neurosurgical settings. Such measures are paramount for optimizing outcomes among patients with neurological injuries. However, this slow-spreading depolarization at high amplitudes presents challenges to identifying and monitoring CSD in clinical settings. We aim to identify various current and potential techniques for monitoring CSD in neurocritical care and neurosurgical settings, alongside exploring available treatment modalities. We also analyze current limitations in the detection of CSD, including the identification of potential biomarkers. A brief comprehensive scoping review of available literature utilizing search engines such as PubMed and Google Scholar was conducted using key search terms such as "cortical spreading depression", "CSD", "spreading depolarization", and "CSD monitoring". Eligibility for this review was restricted to full-text, English, peer-reviewed literature articles. There were no restrictions on publication dates. Around 450 articles discussing CSD were reviewed and ultimately 65 articles were included in the analysis. Electrocorticography (ECoG), an invasive modality that involves placing electrodes on the brain tissue directly, remains the primary modality to detect CSD, both in the neurosciences intensive care unit (NSICU) and during neurosurgical procedures. However, there are other potential modalities for detection such as Electroencephalogram (EEG), pressure reactivity index (PRx), magnetoencephalography (MEG), MRI/fMRI, and laser speckle imaging (LSI). These methods have been tested in animal models and/or in clinical practice but each has drawbacks that render these modalities not readily available or nonfunctional as independent detection methods in the NSICU. Nevertheless, a multimodal monitoring approach utilizing a combination of monitoring modalities such as ECoG in conjunction with tools that measure cerebral vascular response such as cerebral perfusion pressure, cerebral blood flow, and PRx could provide timely measurements of CSD. There are potential biomarkers being studied for early detection of CSD which include adenosine, GFAP, lactate, IL-6, or TNF-alpha. Some treatment modalities that have been studied that inhibit or halt CSD include: topiramate, valproate, propranolol, amitriptyline, methysergide, Propofol, and glutamate receptor inhibitors. Although several methods have been studied, invasive ECoG remains the gold standard for CSD detection. There are currently no reliable non-invasive modalities for CSD detection. Nevertheless, a multimodal approach that utilizes ECoG in conjunction with different methods of monitoring, could prove a useful tool in NSICU as well as neurosurgical procedures. Further research is needed to not only determine the utility and application of other monitoring methods in the clinical setting but also explore non-invasive monitoring methods.

Psychologic stress induces behavioral and autonomic responses such as acceleration of respiration. The lateral habenula (LHb) is noted to be involved in stress-induced behavioral responses. However, its involvement in stress-induced respiratory responses is unknown. In this study, we aimed to analyze whether and how the LHb regulates respiration. Electrical stimulation of the LHb of anesthetized Wistar male rats increased respiratory frequency and minute ventilation, calculated by respiratory frequency × thoracic movement amplitude. Systemic administration of a dopaminergic receptor antagonist, clozapine, suppressed the LHb-induced respiratory responses. On the other hand, administration of a serotonergic receptor antagonist, methysergide, significantly accelerated the LHb-induced increase in respiratory frequency, together with suppressing the thoracic movement amplitude. To clarify the source of dopaminergic modulation, we inhibited the ventral tegmental area (VTA), which contains dopaminergic neurons and receives inputs from the LHb, by administering microinjections of a GABAA agonist, muscimol. The bilateral inhibition of the VTA almost abolished the LHb-induced respiratory responses. These results suggest that LHb activation causes respiration acceleration, mainly mediated by dopaminergic neurons in the VTA and suppressively modulated by the serotonergic system. Neural circuits originating in the LHb may be a key modulator for respiration during psychological stress.

Pruritus in the elderly, particularly those cases without skin dryness or other identifiable causes, makes treatment challenging due to the lack of evidence regarding the therapeutic effects of antipruritics. This study proposes an age-related alloknesis mouse model for an evaluation system for such cases, and aimed to investigate the effectiveness and mechanisms of action of several drugs commonly used as antipruritics in Japan, utilizing this model. Mice 69-80 weeks old were used as aged mice, and the level of mechanical alloknesis was counted as the number of scratching behaviours in response to innocuous stimuli. Bepotastine, neurotropin, pregabalin, baricitinib, and abrocitinib were used as antipruritics, and yohimbine and methysergide as inhibitors of the descending inhibitory pathway. The findings suggest that mechanical alloknesis in aged mice is a suitable animal model for assessing pruritus in the elderly without xerosis, and pregabalin, neurotropin, baricitinib, and abrocitinib may be effective antipruritics in the elderly through activating both the noradrenergic and serotonergic descending inhibitory pathways. These findings may be useful for the selection of antipruritics for pruritus in the elderly without skin lesions or dryness.

Though microdosing psychedelics has become increasingly popular, its long-term effects on cardiac health remain unknown. Microdosing most commonly involves ingesting sub-threshold doses of lysergic acid diethylamide (LSD), psilocybin, or other psychedelic drugs 2-4 times a week for at least several weeks, but potentially months or years. Concerningly, both LSD and psilocybin share structural similarities with medications which raise the risk of cardiac fibrosis and valvulopathy when taken regularly, including methysergide, pergolide, and fenfluramine. 3,4-Methylenedioxymethamphetamine, which is also reportedly used for microdosing, is likewise associated with heart valve damage when taken chronically. In this review, we evaluate the evidence that microdosing LSD, psilocybin, and other psychedelics for several months or more could raise the risk of cardiac fibrosis. We discuss the relationship between drug-induced cardiac fibrosis and the 5-HT2B receptor, and we make recommendations for evaluating the safety of microdosing psychedelics in future studies.

Cleomin, a 1,3-oxazolidine-2-thione, was recently isolated from Neocalyptrocalyx longifolium, a species traditionally used for treating painful conditions. Reports about the pharmacological activities of cleomin are lacking. Here, the antinociceptive effects of cleomin were investigated using mice models of pain, namely the formalin, the cold plate, and the tail flick tests. Motor integrity was assessed in the rota-rod test. Antagonism assays and in silico docking analyses were performed to investigate the putative mechanisms of action. Cleomin (12.5-25 mg/kg), at doses that did not induce motor impairment, induced dose-dependent antinociception in both early and late phases of the formalin test and reduced nociceptive behaviors in both the cold plate and tail flick tests. Pretreatments with phaclofen and atropine attenuated the antinociceptive effects of cleomin, implicating the involvement of GABAB and muscarinic receptors. In silico docking studies suggested satisfactory coupling between cleomin and GABAB and M2 receptors, hence corroborating their role in cleomin's activity. Pretreatments with naloxone, yohimbine, bicuculline, and methysergide did not affect the antinociception of cleomin. In silico pharmacokinetics prediction showed a good drug ability profile of cleomin. In conclusion, cleomin promoted antinociception mediated by GABAB and muscarinic receptors. These findings support further investigation of the analgesic potential of cleomin.

Pseudospondias microcarpa is used in ethnomedicine to manage central nervous system diseases. The hydroethanolic extract (PME) from the leaves of the plant has shown anxiolytic-like properties in mice anxiety models. However, its effects in chronic anxiety models and possible mechanism(s) of action were not studied. Therefore, the current study evaluated the anxiolytic-like mechanisms of PME in zebrafish models of anxiety. The zebrafish light dark test (LDT) and novel tank test (NTT) were employed to assess the anxiolytic-like effects of PME (0.1, 0.3, 1.0 mg mL[-1]), fluoxetine (3 × 10[-5] mg mL[-1]) and diazepam (1.5 × 10[-7] mg mL[-1]). The chronic unpredictable stress (CUS) test was used to further evaluate the extract's anxiolytic-like properties. The potential mechanisms of anxiolytic action of the extract was evaluated after pre-treated with flumazenil, granisetron, methysergide, or pizotifen, all at 1 × 10[-3] mg mL[-1]. The extract significantly decreased anxiety behaviours in the NT and LD tests. These observed effects of the extract were however counteracted by flumazenil, granisetron, methysergide and pizotifen pre-treatment. In addition, PME treatment significantly reversed CUS-induced anxiety behaviours in zebrafish. Results show that PME possesses anxiolytic-like effects possibly through interaction with serotonergic and gamma-aminobutyric acid mediated pathways.