Antagonists of metabotropic glutamate receptors (mGluRs) have the potential to act as analgesic drugs that may help alleviate chronic pain. This study was done to look at the possible rewarding properties of the mGluR5 antagonist, fenobam, in a cognitive assay. Analgesic conditioned place preference (aCPP) was used to examine the effects of fenobam (30 mg/kg) and the prototypical mGluR5 antagonist, MPEP, and these effects were compared to those of a drug with known analgesic properties, morphine (10 mg/kg). In each experiment, one group of mice received spared nerve injury (SNI) surgery to model chronic pain; the other group received a control sham surgery. Both fenobam and MPEP induced preference in the SNI mice, such that SNI mice spent significantly more time in the mGluR5 antagonist-paired chamber compared to a vehicle-paired chamber. No such preference developed for sham mice. Morphine induced preference in male and female mice in both the SNI and sham groups. The results showed that fenobam and MPEP likely reduced on-going distress in the SNI mice, causing them to prefer the chamber paired with the drug compared to the vehicle-paired chamber. Since sham animals did not prefer the drug-paired chamber, these data demonstrate that mGluR5 antagonism is non-rewarding in the absence of pain-like injury.

Context Marine cyanobacteria offer a robust resource for natural products drug discovery due to the secondary metabolites they produce. Objective To identify novel cyanobacterial compounds that exhibit CNS psychoactive effects. Materials and methods Cyanobacteria were collected from Las Perlas Archipelago, Panama and subjected to dichloromethane/methanol extraction and fractionation by column chromatography before being screened for affinity against a panel of CNS targets. A 50:50 ethyl acetate:methanol fraction of one cyanobacterial extract (2064H) was subjected to HPLC and the major peak was isolated (2064H3). At a dose of 20 μg per animal, 2064H and 2064H3 were tested in mice using behavioral assays that included the forced swim, open field, and formalin tests. Results 2064H was shown to bind to the serotonin 2C (5-HT2C) receptor, a known target for depression and pain treatment. 2064H showed 59.6% inhibition of binding of [3H]-mesulergine with an IC50 of 179 ng/mL and did not show inhibition of binding greater than 45% with any other receptors tested. Both 2064H and 2064H3 decreased immobility time in the first min of the tail suspension test. 2064H increased time, distance and number of entries in the center region in the first half of the open field test. 2064H increased overall nocifensive behaviors in the formalin test. Discussion and Conclusion Overall, manipulating the 5-HT2C receptor with these receptor-specific ligands derived from cyanobacteria altered pain, depression and anxiety-like behaviors, illustrating the importance of this receptor in affective behaviors. These results demonstrate the potential of cyanobacteria as a source for CNS active compounds.

INTRODUCTION: Spontaneous pneumothorax, pneumomediastinum, and subcutaneous emphysema have been described as rare life-threatening complications of COVID-19. Reports of pneumoperitoneum or pneumoretroperitoneum are extremely rare. We present a patient with COVID-19 pneumonia who developed spontaneous pneumomediastinum and subcutaneous emphysema with subsequent progression to pneumoretroperitoneum, without evidence of pneumothorax. CASE PRESENTATION:A 61 year old man with HIV and Addison's disease presented to the emergency department with worsening dyspnea, cough, and diarrhea. On admission, his oxygen saturation was 80% on room air, and he had diffuse bilateral lung rhonchi. Nasopharyngeal swab was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Chest x-ray showed bilateral interstitial opacities. He was treated with dexamethasone, remdesivir, enoxaparin and supplemental oxygen. On hospital day three, he developed worsening hypoxia with pO2 of 41mmHg on 15L non-rebreather oxygen. He was transferred to the intensive care unit (ICU) and placed on non-invasive positive pressure ventilation but was quickly weaned to high-flow oxygen. On hospital day 17, he developed worsening hypoxia and reported neck swelling and tenderness. Computed tomography (CT) of the neck and chest confirmed extensive subcutaneous emphysema and pneumomediastinum and diffuse granular lung opacities without any normally aerated lung parenchyma, without evidence of pneumothorax. He was placed on mechanical ventilation after failing non-invasive positive pressure ventilation. Despite supportive care and lung protective ventilation, he remained hypoxic with worsening subcutaneous emphysema. CT of the chest, abdomen and pelvis showed development of pneumoperitoneum and pneumoretroperitoneum. Due to the patient's refractory hypoxia with progression to multi-system organ failure, his family opted for compassionate extubation and he expired on hospital day 34.DISCUSSION: Common causes of pneumoretroperitoneum include perforated viscous or iatrogenic introduction of air. As this patient had neither surgical procedures or evidence of perforation, his pneumoretroperitoneum was likely due to prolonged positive end expiratory pressure (PEEP) in setting of acute respiratory distress syndrome due to COVID-19. Mechanical ventilation likely acted as a shearing force intensifying air leak into the mediastinum which tracked inferiorly into the retroperitoneum. CONCLUSIONS:In conclusion, pneumomediastinum is a possible complication of COVID-19 pneumonia that can progress to pneumoretroperitoneum despite lung protective ventilation causing acute decompensation that can worsen patient prognosis.