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Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain.

Nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase (PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.

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Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain.

Neuroinflammation plays a critical role in the pathological process of multiple neurological disorders and pathological pain conditions. GPR109A, a Gi protein-coupled receptor, has emerged as an important therapeutic target for controlling inflammation in various tissues and organs. In this review, we summarized current data about the role of GPR109A in neuroinflammation. Specifically, we focused on the pharmacological features of GPR109A and signaling pathways used by GPR109A to ameliorate neuroinflammation and symptoms in Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, and pathological pain conditions.

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A case of occult pancreaticobiliary reflux due to endoscopically confirmed relaxation of the Oddi sphincter.

An otherwise healthy 45-year-old woman had been experiencing intermittent right upper abdominal pain for the past 1 year. Computed tomography showed pneumobilia and pancreatic duct emphysema despite a normal duodenal papilla. Magnetic resonance cholangiopancreatography and endoscopic ultrasound confirmed bile duct dilation but without a pancreaticobiliary maljunction. Duodenoscopy detected a slightly sunken, unfixed, and spontaneously enlarged duodenal papilla. During the cholangiogram, the Oddi sphincter was relaxed and the catheter could be easily inserted into the bile duct. Further, no findings suggestive of pancreaticobiliary maljunction were observed, and the contrast medium leaked spontaneously from the duodenal papilla. As biliary amylase level was high, we surmised the occurrence of occult pancreaticobiliary reflux due to relaxation of the Oddi sphincter. However, as there are no guidelines on the management of this condition, we did not offer any treatment. Nevertheless, the patient continued to experience similar symptoms and was retested 1 year later with similar results. As occult pancreaticobiliary reflux was reconfirmed, we suggested that the patient undergo laparoscopic extrahepatic bile duct resection and cholecystectomy, which is the standard treatment for pancreaticobiliary maljunction. Pathological evaluation revealed fibrous thickening of the bile duct wall and chronic cholecystitis, which are typical findings of pancreaticobiliary reflux. Even though pancreaticobiliary reflux is mainly observed in pancreaticobiliary maljunction, it has also been reported in normal patients. Here, we describe a novel mechanism of pancreaticobiliary reflux, namely, a relaxed or defective Oddi sphincter.

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A rare case of inflammatory polyp in the common bile duct with cholangitis.

The diagnosis of bile duct tumors can be difficult at times. A transpapillary bile duct biopsy findings with endoscopic retrograde cholangiopancreatography sometimes contradict diagnostic imaging findings. In bile duct tumors, inflammatory polyps in the extrahepatic bile duct are relatively rare with extrahepatic cholangitis. The disease's clinical relevance, including its natural history and prognosis, is not always clear. We show here a rare case of an inflammatory polyp in the common bile duct. A 69-year-old woman with abdominal pain was diagnosed with cholangitis. The findings of contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography suggested that she had extrahepatic cholangiocarcinoma. The examination and therapy of cholangitis were performed by endoscopic retrograde cholangiopancreatography. The cholangiography revealed a suspected tumor in the hilar bile duct with some common bile duct stones. Then, after endoscopic sphincterotomy to remove tiny common bile duct stones, further detailed examinations were performed at the same time using an oral cholangioscope revealed a papillary raised lesion with a somewhat white surface in the bile duct; a biopsy was conducted on the same spot, and epithelial cells with mild atypia appeared in the shape of a papilla. Since the malignant tumor or the intraductal papillary neoplasm of the bile duct could not be ruled out, extrahepatic bile duct resection was conducted with the patient's informed consent. Bile duct inflammatory polyp was the histopathological diagnosis.

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Protocol for a pilot and feasibility randomized-controlled trial of four weeks of oral γ-aminobutyric acid (GABA) intake and its effect on pain and sleep in middle-to-older aged adults.

Approximately 1.71 billion people globally live with musculoskeletal pain conditions, including low back pain, knee pain, and neck pain Cieza et al. (2020). In the US, an estimated 20.4% of U.S. adult had chronic pain and 8.0% of U.S. adults had high-impact chronic pain, with higher prevalence associated with advancing age Dahlhamer et al. (2018). On the other hand, between 50 and 70 million US adults have a sleep disorder (American Sleep Association). Although the link between sleep and pain is widely established, the neurobiological mechanisms underlying this relationship have yet to be fully elucidated, specifically within an aged population. As currently available sleep and chronic pain therapies are only partially effective, novel treatment approaches are urgently needed. Given the potential mechanistic role of γ-aminobutyric acid (GABA) in both conditions, and the availability of GABA supplements over the counter, the present proposal will determine the feasibility and acceptability of oral GABA administration in middle-to-older aged adults with chronic pain and sleep disorders as well as characterize the potential neurobiological mechanisms involved in both conditions. Results from the present investigation using a parallel, double-blinded, placebo-controlled study will provide novel preliminary information needed for future translational pain and sleep research.

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Membrane cholesterol regulates inhibition and substrate transport by the glycine transporter, GlyT2.

Membrane cholesterol binds to and modulates the function of various SLC6 neurotransmitter transporters, including stabilizing the outward-facing conformation of the dopamine and serotonin transporters. Here, we investigate how cholesterol binds to GlyT2 (SLC6A5), modulates glycine transport rate, and influences bioactive lipid inhibition of GlyT2. Bioactive lipid inhibitors are analgesics that bind to an allosteric site accessible from the extracellular solution when GlyT2 adopts an outward-facing conformation. Using molecular dynamics simulations, mutagenesis, and cholesterol depletion experiments, we show that bioactive lipid inhibition of glycine transport is modulated by the recruitment of membrane cholesterol to a binding site formed by transmembrane helices 1, 5, and 7. Recruitment involves cholesterol flipping from its membrane orientation, and insertion of the 3' hydroxyl group into the cholesterol binding cavity, close to the allosteric site. The synergy between cholesterol and allosteric inhibitors provides a novel mechanism of inhibition and a potential avenue for the development of potent GlyT2 inhibitors as alternative therapeutics for the treatment of neuropathic pain and therapeutics that target other SLC6 transporters.

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White gastric mucosa during endoscopy as a new endoscopic feature of chronic ischemic gastritis: A case report.

Chronic ischemic gastritis (CIG) requires early diagnosis and treatment as complications of thromboembolism can be fatal. Although computed tomography (CT) is useful in the diagnosis of CIG, it is difficult to diagnose from a patient's history, endoscopic findings, and tissue biopsy. Identification of the key findings that motivate computed tomography is an important issue. We report a case of CIG diagnosed by endoscopic findings of white patches of mucosa over time. A 63-year-old man presented with epigastric pain. He had a history of repeated gastric ulcers of an undetermined cause. We performed upper endoscopy and observed the appearance of multiple white patches on the gastric mucosa. Central vessel stenosis was considered, and aortic computed tomography revealed complete occlusion of the superior mesenteric artery and stenosis of the celiac artery. We carried out a surgical bypass and found no postoperative endoscopic mucosal changes or abdominal pain. White patch changes in the gastric mucosa over time during endoscopy may indicate CIG. This finding may help in the future diagnosis of CIG.

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Colonoscopy-assisted percutaneous sigmoidopexy for a complete rectal prolapse: A case report.

Colonoscopy-assisted percutaneous sigmoidopexy is a simple and swift procedure that does not require general anesthesia. While we first developed this procedure for treating sigmoid volvulus, we herein present the first case in which we used it to correct a complete rectal prolapse in an older patient. Existing treatment modalities for rectal prolapses are limited by high recurrence rates, greater invasiveness, and greater complications; thus, there is a need for minimally invasive techniques that are associated with lower recurrence rates and fewer complications. In this case, a woman in her 90s complained of persistent fecal incontinence, dysuria, anal pain, and difficulty in walking. She was diagnosed with a complete rectal prolapse of 15 cm and was treated with colonoscopy-assisted percutaneous sigmoidopexy. The sigmoid colon was tractioned colonoscopically and fixed to the abdominal wall to immobilize the prolapsed rectum. The patient developed no complications intraoperatively and postoperatively and experienced no recurrence during a 5-year postoperative period. This report documents the first case wherein colonoscopy-assisted percutaneous sigmoidopexy was used successfully to correct a complete rectal prolapse.

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Regenerative peripheral nerve interface prevents neuroma formation after peripheral nerve transection.

Neuroma formation after peripheral nerve transection often leads to severe neuropathic pain. Regenerative peripheral nerve interface has been shown to reduce painful neuroma in the clinic. However, no reports have investigated the underlying mechanisms, and no comparative animal studies on regenerative peripheral nerve interface and other means of neuroma prevention have been conducted to date. In this study, we established a rat model of left sciatic nerve transfection, and subsequently interfered with the model using the regenerative peripheral nerve interface or proximal nerve stump implantation inside a fully innervated muscle. Results showed that, compared with rats subjected to nerve stump implantation inside the muscle, rats subjected to regenerative peripheral nerve interface intervention showed greater inhibition of the proliferation of collagenous fibers and irregular regenerated axons, lower expressions of the fibrosis marker α-smooth muscle actin and the inflammatory marker sigma-1 receptor in the proximal nerve stump, lower autophagy behaviors, lower expressions of c-fos and substance P, higher expression of glial cell line-derived neurotrophic factor in the ipsilateral dorsal root ganglia. These findings suggested that regenerative peripheral nerve interface inhibits peripheral nerve injury-induced neuroma formation and neuropathic pain possibly via the upregulation of the expression of glial cell line-derived neurotrophic factor in the dorsal root ganglia and reducing neuroinflammation in the nerve stump.

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Delayed Unilateral Eagle Syndrome with Fractured Styloid Process.

Minor injury to head and neck is usually neglected for potential neurological consequences. We report a woman who suffered left Eagle syndrome due to styloid process fracture two years after a minor motorcycle collision.

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