Articles: neuropathic-pain.
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Neuropeptide Y (NPY) modulates nociception in the spinal cord, but little is known about its mechanisms of release. We measured NPY release in situ using the internalization of its Y1 receptor in dorsal horn neurons. Y1 receptor immunoreactivity was normally localized to the cell surface, but addition of NPY to spinal cord slices increased the number of neurons with Y1 internalization in a biphasic fashion (EC50s of 1 nM and 1 μM). ⋯ Mechanical stimulation in vivo, with rub or clamp of the hindpaw, elicited robust Y1 receptor internalization in rats with spared nerve injury but not sham surgery. In summary, NPY is released from dorsal horn interneurons or primary afferent terminals by electrical stimulation and by activation of TRPV1, PKA or NMDA receptors in. Furthermore, NPY release evoked by noxious and tactile stimuli increases after peripheral nerve injury.
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We provide an updated review of the pharmacological treatment of neuropathic pain, with emphasis on the latest evidence-based recommendations. Drugs proposed as first line include tricyclic antidepressants (particularly amitriptyline), serotonin-noradrenaline reuptake inhibitors (particularly duloxetine), pregabalin and gabapentin. Second-line treatments include 5% lidocaine medicated plasters and capsaicin 8% patches, only for peripheral neuropathic pain and tramadol; whereas potent opioids and botulinum toxin A (for peripheral neuropathic pain) are considered third-line treatments. Future perspectives include the development of new drugs and a more personalised therapeutic approach, which is made possible by recent progress in the assessment and understanding of neuropathic pain.
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Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K2p 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K 2p 1.1 mRNA and its coding K2p 1.1 protein in the DRG neurons. ⋯ Mechanically, the downregulation of DRG K 2p 1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K2p 1.1 and mimicking this increase reduces DRG K2p 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 2p 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K2p 1.1 may contribute to chemotherapy-induced neuropathic pain.
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Spinal cord stimulation has been shown to improve pain relief and reduce narcotic analgesic use in cases of complex refractory pain syndromes. However, a subset of patients ultimately undergoes removal of the spinal cord stimulator (SCS) system, presumably because of surgical complications or poor efficacy. This retrospective study addresses the paucity of evidence regarding risk factors and underlying causes of spinal cord stimulation failures that necessitate this explantation. ⋯ The authors' findings provide insight regarding the mechanisms of spinal cord stimulation failure that resulted in total removal of the implanted system. The relationship between spinal cord stimulation failure and certain psychiatric disorders, such as PTSD, depression, and anxiety, is highlighted. Ultimately, this work may shed light on potential avenues to reduce morbidity and improve patient outcomes.
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Neurobiology of disease · Oct 2019
Upregulation of tumor necrosis factor-alpha in the anterior cingulate cortex contributes to neuropathic pain and pain-associated aversion.
Injury associated pain involves subjective perception and emotional experience. The anterior cingulate cortex (ACC) is a key area involved in the affective component of pain processing. However, the neuroimmune mechanisms underlying enhanced ACC excitability following peripheral nerve injury are still not fully understood. ⋯ Microinjection of anti-TNF-α antibody into the ACC completely eliminated c-Fos overexpression and greatly attenuated pain aversion and mechanical allodynia induced by SNI, suggesting an important role of ACC TNF-α in the pain aversiveness and pain maintenance. Furthermore, modulating ACC pyramidal neurons via a Gi-coupled human M4 muscarinic receptor (hM4Di) or a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD), greatly changed the ACC TNF-α level and the mechanical paw withdrawal threshold. The positive interactions between TNF-α and ACC neurons might modulate the cytokine microenvironment thus contribute to the neuropathic pain.