Articles: neuropathic-pain.
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In the spinal nerve ligation (SNL) model of neuropathic pain, synaptic plasticity shifts the excitation/inhibition balance toward excitation in the spinal dorsal horn. We investigated the deregulation of the synaptogenic neuroligin (NL) molecules, whose NL1 and NL2 isoforms are primarily encountered at excitatory and inhibitory synapses, respectively. In the dorsal horn of SNL rats, NL2 was overexpressed whereas NL1 remained unchanged. ⋯ Expression of the inhibitory scaffolding protein gephyrin remained unchanged, indicating a partial change in NL2 postsynaptic partners in SNL rats. This phenomenon appears to be specific to the NL2(-) isoform. Our data showed unexpected upregulation and pronociceptive effects of the "inhibitory" NL2 in neuropathic pain, suggesting a functional shift of NL2 from inhibition to excitation that changed the synaptic ratio toward higher excitation.
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To systematically identify and appraise the current literature of pregabalin in the treatment of neuropathic pain resulting from cancer or cancer treatment. ⋯ There were limited published data reporting efficacy and safety outcomes for pregabalin in the treatment of neuropathic pain in adult patients with cancer. Due to limitations within the studies included in this review, it is not possible to draw any conclusions on the descriptive summary of pregabalin for the treatment of cancer-related neuropathic pain, and further studies are required.
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Studies of peripheral nerve inflammation (neuritis) suggest that some symptoms of neuropathic pain can be generated from inflamed but otherwise uninjured axons. We have previously inferred a role for inflammation-induced axonal transport disruption in the underlying mechanisms. In the present study, we have investigated the development of sensory hypersensitivities following vinblastine-induced axonal transport disruption. Similar to neuritis, locally applied .1 mM vinblastine caused the rapid development of mechanical hypersensitivity within the first week postsurgery. The same animals did not develop heat hypersensitivity. Because aberrant firing from primary sensory neurons is considered necessary to drive spinal mechanisms that lead to hypersensitivities, the levels of ongoing activity and axonal mechanical sensitivity were examined. Recordings from A- and C-fiber neurons did not reveal differences in the levels of ongoing activity between vinblastine-treated (<5.8%) and saline-treated control animals (<4.6%). However, 28% of C-fiber axons were mechanically sensitive at the vinblastine treatment site. Using kinesin immunohistochemistry, we confirmed a reduction of anterograde axonal transport in vinblastine-treated and neuritis animals. In summary, this study has revealed an alternative pain model, which may be relevant to conditions that are not accompanied by frank nerve injury. ⋯ In this study, we expand our previous reports and demonstrate that focal reduced axonal transport causes distal mechanical hypersensitivity considered consistent with neuropathic pain but in the absence of nerve injury. These findings may inform pain conditions that have a neural inflammatory component.
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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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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.