Rejected

Rhamnocitrin (RH) is a bioactive flavonoid of Astragali Radix, which exerts a wide variety of pharmacological effects. However, there are no reports focusing on the therapeutical effects and mechanisms of RH against neuropathic pain (NP). In this study, systematic pharmacology and in vivo experimental approaches were employed to identify the potential targets of RH for treating oxaliplatin-induced NP. Our findings indicated that the therapeutical effect of RH might be closely associated with key genes, including MAPK3, MAPK1, SRC, PTGS2, EGFR, MMP9, and MMP2, as well as potential signaling pathways such as PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, and Rap1 signaling pathway. The in vivo experimental findings demonstrated that RH could suppress oxidative stress, inflammatory response, and down-regulate MMP2 and MMP9 expressions to exert its therapeutic effects against NP. This study used network pharmacology and experimental validation to elucidate the potential targets and underlying mechanisms by which RH improves oxaliplatin-induced NP and offer new insight on drug development for NP.

Gaucher disease (GD) is a rare metabolic disorder due to pathogenic variants in the gene. We report the first case of the rare p.Arg87Trp pathogenic variant (formerly known as R48W) of the gene in the Tunisian population. A female Arab patient was assessed at the age of 26 due to abdominal distension, bone pain, and headache since she was 25. Physical examination revealed splenomegaly, rib deformation, lumbar scoliosis, and upper limb tremor. Bone marrow was infiltrated by Gaucher cells. The patient was homozygous for the rare p.Arg87Trp variant which is known to be associated with a mild phenotype. This report highlights the necessity of screening the Tunisian population for this rare variant.

In the later stages of a paramedian forehead flap (PMFF) surgery, the supratrochlear (STN) and branches of the supraorbital nerve (SON) are transected during flap inset above the supraorbital rim. This can lead to either a nerve release if the compression point was previously distal to the transection point or a new nerve compression through neuroma or scar tissue formation. We inferred that PMFF could be a model for understanding the correlation between STN/SON pathology and migraines headaches (MH). We hypothesized that patients undergoing PMFF would experience either a change in severity or an onset of a new headache (HA) or MH.

Most studies reporting posterior pituitary tumors (PPTs) are small case series or single cases.

A growing body of epidemiological evidence suggests increasing misuse of gabapentinoids (gabapentin and pregabalin, calcium channel inhibitors approved to treat some neuropathic pain conditions) in people with opioid use disorder. The number of prescriptions for gabapentinoids has risen rapidly over the past decade, with the majority of these prescriptions being for off-label indications. Over the same period, gabapentinoids have become increasingly prevalent in opioid overdose deaths. Despite these trends little research has evaluated potentially harmful interactions between gabapentinoids and opioids. This study evaluated the effects of gabapentin and pregabalin on the ventilatory depressant effects of heroin, and the reversal of heroin-induced ventilatory depression by naloxone. Five male Sprague Dawley rats were given pregabalin (1-32 mg/kg), gabapentin (10-100 mg/kg), or saline i.v. 30 minutes prior to receiving increasing doses of heroin while ventilation was monitored using whole-body plethysmography. Sessions began with a 30-minute baseline period followed by a test period during which rats received infusions of heroin or saline at minutes 0, 3, and 6 with heroin infusions resulting in cumulative doses of 0.1, 0.32, and 1 mg/kg (i.v.), respectively. Naloxone (0.0056-0.01 mg/kg) or saline was administered i.v. 5 minutes following the final infusion of heroin. Minute volume, the product of tidal volume (mL/inspiration) and respiratory rate (breaths/minute), was the primary outcome of this study. Heroin dose-dependently reduced minute volume with 1.0 mg/kg reducing minute ventilation on average to 42% of baseline. Neither pregabalin nor gabapentin altered the ventilatory depressant effects of heroin. When given 5 minutes following the 1.0 mg/kg cumulative dose of heroin, naloxone dose-dependently reversed heroin-induced decreases in minute volume with 0.0056 and 0.01 mg/kg naloxone restoring ventilation to 95 and 160% of baseline levels, respectively. Interestingly, pretreatment with gabapentin or pregabalin dose-dependently attenuated the ability of naloxone to reverse heroin-suppressed minute volume, with the largest dose of gabapentin and pregabalin almost completely blocking the effects of 0.0056 mg/kg naloxone. Both gabapentin and pregabalin attenuated the ability of naloxone to restore ventilation following administration of heroin in rats but did not alter the effects of heroin alone. These findings suggest that gabapentinoids might diminish the effectiveness of naloxone to reverse opioid overdose in humans, a possible explanation for the prevalence of these drugs in opioid overdose deaths. It will be important to determine whether similar interactions occur between gabapentinoids and naloxone for reversing the effects of other mu opioid receptor agonists such as fentanyl.

Chronic pain and related stress have been previously linked to the development of mood disorders and dysfunction of peripheral organs such as the kidney. While the underlying neurophysiological mechanisms remain elusive, here we examined the effects of chronic pain on activation of immune-inflammatory responses in the brain and kidney. Male rats were exposed to chronic inflammatory pain for up to 42 days [multiple injections of Freund's adjuvant (CFA) into the hind paw], which produced a state of chronic allodynia and enhanced behavioral emotionality. Biochemical analysis of the hippocampus, a limbic region that regulates mood and stress responses, showed that CFA evoked increases in expression of ionized calcium binding adaptor molecule 1 (IBA1) and NLRP3 inflammasome proteins, known markers of microglial activation and neuroinflammatory responses, respectively. An increase in the neutrophil gelatinase-associated lipocalin (NGAL) and IL-18 are recognized as early diagnostic injury and inflammatory biomarkers of kidney disease. NLRP3 is implicated in the pathogenesis of kidney diseases by regulation of renal inflammation. Analysis via immunocytochemistry demonstrated that CFA also evoked significant increases in NGAL, IL-18 and NLRP3 protein levels in the renal glomeruli and tubules, suggesting that chronic pain and related stress effects induce renal inflammation and possibly a reduction in kidney function. Together, these findings provide new evidence to support a mechanistical understanding of a bidirectional relationship between chronic pain-related stress and kidney dysfunction. Further understanding of this relationship could contribute to the identification of novel treatment strategies to diminish both mental health and renal physiological consequences of chronic pain.

Calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) are peptide hormones and their receptors play a critical role in migraine progression and blood pressure control, respectively. CGRP and AM receptors are structurally related since they are the complex of the calcitonin receptor-like receptor (CLR) with the different types of receptor activity-modifying protein (RAMP); the CLR complex with RAMP1 is the CGRP receptor while the CLR complex with RAMP2 is the AM receptor. The extracellular domain (ECD) of CLR and RAMP provides a binding site for peptide ligands as reported in crystal structures. Several crystal structures of the CGRP and AM receptor ECD used maltose-binding protein (MBP) as a tag protein to facilitate crystallization. Unexpectedly, the recent crystal structures of CGRP receptor ECD showed that the N-terminal MBP tag located in proximity of the bound/mutated peptide ligands. The objective of the current study is to investigate potential chemical interaction between peptide ligands and the MBP tagged to the CGRP receptor ECD. Peptide ligand interaction with purified CGRP receptor ECD was evaluated with fluorescence polarization/anisotropy peptide binding assay with a fluorescent peptide probe. The results of the current study provided evidence that MBP N-terminally tagged to the CGRP receptor ECD formed chemical interaction with mutated peptide ligands. Interestingly, N-glycosylation of the CGRP receptor ECD was predicted to prevent MBP docking to the mutated peptide ligands. The N-glycosylation of CLR ECD N123 was the most critical for inhibiting MBP interaction with the mutated peptide ligands. The MBP tag protein interaction was also dependent on the sequence of the peptide ligands. An endogenous CGRP fragment did not appear to interact with the MBP tag. In contrast to the CGRP receptor, the MBP tag was not involved in peptide ligand binding at AM receptor ECD. Here, I provided evidence that N-glycosylation of the CGRP receptor ECD inhibited the MBP tag protein interaction suggesting an additional role of N-glycosylation in the MBP-tagged CGRP receptor ECD. This study reveals the importance of using a tag protein-free CGRP receptor ECD for the accurate assessment of peptide ligand affinity.

In vivo receptor interactions vary as a function of behavioral endpoint. Our laboratory has begun investigating the effects of D1 dopamine receptor agonists and D1 dopamine/mu opioid receptor interactions. This decision is based on studies that have shown (1) dopamine D1 receptors produce pain relief in rodent models of acute pain, (2) a mixed literature indicating D1 agonists either do or do not possess abuse liability, perhaps due in part to behavioral endpoint selection, and (3) co-localization of D1 and mu receptors in brain. This is the first report of D1/mu receptor interactions using an assay of pain depressed behavior. A multiple-cycle FR10 operant schedule and a simple FR10 schedule were utilized in the presence of (antinociception) and in the absence of (rate suppression / sedation) a lactic acid inflammatory pain-like manipulation, with antinociception defined as the therapeutic effect, and sedation defined as a side effect. SKF82958 and methadone were used as selective/high efficacy D1 dopamine and mu opioid agonists, respectively. Both SKF82958 and methadone alone produced dose-dependent restoration of pain-depressed responding and response rate suppression in the mult-cycle schedule, but SKF82958 was ineffective in restoring pain-depressed responding in the simple FR10 schedule. Equal potency 1:1 SKF82958/methadone mixtures and 1:3 and 3:1 mixtures are currently being tested in both operant schedules to determine the nature of the interaction (additive, superadditive, subadditive). Results will indicate if therapeutic index varies as a function of operant schedule, and the degree to which the addition of SKF82958 produces opioid-sparing effects.

Knee osteoarthritis (OA) is a common and morbid condition. No disease-modifying therapies exist; hence the goals of current treatment are to palliate pain and to retain function. OA pain is significantly influenced by the placebo effect. Nonpharmacologic interventions are essential and have been shown to improve outcomes. Canes, unloading braces, and therapeutic heating/cooling may be valuable. Pharmacotherapy options include topical and oral nonsteroidal anti-inflammatory drugs, duloxetine, and periodic intra-articular glucocorticoids and hyaluronans. Opioids, intra-articular stem cells, and platelet-rich plasma are not recommended. Novel targets such as nerve growth factor are under investigation and may be approved soon for OA pain.