Articles: neuropathic-pain.
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Comparative Study
Reversible inhibition of the glycine transporter GlyT2 circumvents acute toxicity while preserving efficacy in the treatment of pain.
Available medications for chronic pain provide only partial relief and often cause unacceptable side effects. There is therefore a need for novel molecular targets to develop new therapeutics with improved efficacy and tolerability. Despite encouraging efficacy data in rodents with inhibitors of the neuronal glycine transporter-2 (GlyT2), there are also some reports of toxicity and their development was discontinued. ⋯ Our pharmacological comparison of two closely related GlyT2 inhibitors with different modes of inhibition provides important insights into their safety and efficacy profiles, uncovering that in the presence of a GlyT2 mechanism-based toxicity, reversible inhibitors might allow a tolerable balance between efficacy and toxicity. These findings shed light into the drawbacks associated with the early GlyT2 inhibitors and describe a new mechanism that might serve as the starting point for new drug development.
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SUMMARY Neuropathic pain is a complex pain syndrome that remains difficult to treat. Patients fail to obtain satisfactory relief despite receiving pharmacological agents. ⋯ Preventative, nonpharmacological and pharmacological treatments are suggested in the management of neuropathic pain. Interventional options, such as spinal cord stimulation, intrathecal drug delivery, intravenous infusions therapies, and sympathetic nerve block, should be considered in patients with refractory neuropathic pain.
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Case Reports
Evidence of pancreatic neuropathy and neuropathic pain in hereditary chronic pancreatitis.
Increased neural density and neural hypertrophy are characteristic features of pancreatic neuropathy in chronic pancreatitis. Here, we present the extraordinary case of prominent pancreatic neuropathy in a 21-year-old female patient with hereditary chronic pancreatitis and intractable pain who underwent total pancreatectomy. ⋯ These histological alterations, including nerve hypertrophy and increased neural density, are known for different aetiologies of chronic pancreatitis, e.g. alcoholic, idiopathic and tropic pancreatitis. However, this is the first report of a patient with hereditary chronic pancreatitis demonstrating the characteristic features of pancreatic neuropathy and neuropathic pain.
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There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain and other indications. In continuation of our ongoing program aiming for the development of new small molecule cannabinoid ligands, we have synthesized a novel series of carbazole and γ-carboline derivatives. The affinities of the newly synthesized compounds were determined by a competitive radioligand displacement assay for human CB2 cannabinoid receptor and rat CB1 cannabinoid receptor. ⋯ Other potent and CB2 receptor-selective compounds, including compounds 63 and 68, and a selective CB1 agonist, compound 74 were also discovered. In addition, we identified the CB2 ligand 35 which failed to promote CB2 receptor internalization and inhibited compound CP55,940-induced CB2 internalization despite a high CB2 receptor affinity. The present study provides novel tricyclic series as a starting point for further investigations of CB2 pharmacology and pain treatment.
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Previous studies have shown that the morphology and number of cells in the spinal cord dorsal horn could change following peripheral nerve injury and that the Hippo signaling pathway plays an important role in cell growth, proliferation, apoptosis, and dendritic remolding. In the present study, we examined whether the expression of YAP and TAZ, two critical components regulated by Hippo signaling, in the spinal cord dorsal horn would be altered by chronic constriction sciatic nerve injury (CCI). ⋯ These findings indicate that peripheral nerve injury induced time-dependent and region-specific changes in the spinal YAP and TAZ expression. A role for Hippo signaling in synaptic and structural plasticity is discussed in relation to the cellular mechanism of neuropathic pain.