Mol Pain
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Neuropathic pain is a difficult to treat disorder arising from central or peripheral nervous system lesions. The etiology of neuropathic pain consists of several overlapping pathways converging into an exaggerated pain state with symptoms such as allodynia and hyperalgesia. One of these pathways involves activation of spinal cord microglia and astrocytes, which drive and maintain the inflammatory response following the lesion. These cells are a potential target for drugs for neuropathic pain relief. In this current study, we investigated the dose-effect relationship of the tissue protective peptide ARA 290, derived from the tertiary structure of erythropoietin, on allodynia and concurrent spinal cord microglia and astrocytes. ⋯ The erythropoietin-analogue ARA290 dose-dependently reduced allodynia coupled to suppression of the spinal microglia response, suggestive of a mechanistic link between ARA290-induced suppression of central inflammation and relief of neuropathic pain symptoms.
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Paclitaxel, a widely-used antineoplastic drug, produces a painful peripheral neuropathy that in rodents is associated with peripheral-nerve mitochondrial alterations. The sigma-1 receptor (σ1R) is a ligand-regulated molecular chaperone involved in mitochondrial calcium homeostasis and pain hypersensitivity. This receptor plays a key role in paclitaxel-induced neuropathic pain, but it is not known whether it also modulates mitochondrial abnormalities.In this study, we used a mouse model of paclitaxel-induced neuropathic pain to test the involvement of the σ1R in the mitochondrial abnormalities associated with paclitaxel, by using genetic (σ1R knockout mice) and pharmacological (σ1R antagonist) approaches. ⋯ These results suggest that activation of the σ1R is necessary for development of the sensory nerve mitochondrial damage and neuropathic pain produced by paclitaxel. Therefore, σ1R antagonists might have therapeutic value for the prevention of paclitaxel-induced neuropathy.
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Leukocytes containing opioid peptides locally control inflammatory pain. In the early phase of complete Freund's adjuvant (CFA)-induced hind paw inflammation, formyl peptides (derived e.g. from Mycobacterium butyricum) trigger the release of opioid peptides from neutrophils contributing to tonic basal antinociception. In the later phase we hypothesized that toll-like-receptor-(TLR)-4 activation of monocytes/macrophages triggers opioid peptide release and thereby stimulates peripheral opioid-dependent antinociception. ⋯ Endogenous opioids from monocytes/macrophages mediate endogenous antinociception in the late phase of inflammation. Peripheral TLR4 stimulation acts as a transient counter-regulatory mechanism for inflammatory pain in vivo, and increases the release of opioid peptides from monocytes in vitro. TLR4 antagonists as new treatments for sepsis and neuropathic pain might unexpectedly transiently enhance pain by impairing peripheral opioid analgesia.