Articles: neuralgia.
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Review
Mechanisms of spinal cord stimulation for the treatment of pain: Still in the dark after 50 years.
Despite the value of spinal cord stimulation (SCS) in treating some patients with focal neuropathic pain, technological advances in stimulator design and treatment protocols have not correlated with significant improvements in clinical outcomes. This may be because incomplete understanding of the mechanisms underlying SCS precludes improvement in clinical efficacy. In this brief review, we (a) review phenomenological effects of SCS, (b) review the literature on proposed spinal sites of action of SCS and (c) propose a novel hypothesis of mechanism of action. ⋯ We review possible spinal mechanisms of action of spinal cord stimulation for neuropathic pain, proposing that direct modulation of dorsal horn neurons is crucial. We suggest that mechanistic insights are needed for translation into more favourable clinical outcomes.
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Activation of cannabinoid CB1 receptors suppresses pathological pain but also produces unwanted side effects, including tolerance and physical dependence. Inhibition of fatty-acid amide hydrolase (FAAH), the major enzyme catalyzing the degradation of anandamide (AEA), an endocannabinoid, and other fatty-acid amides, suppresses pain without unwanted side effects typical of direct CB1 agonists. However, FAAH inhibitors have failed to show efficacy in several clinical trials suggesting that the right partnership of FAAH inhibition and pathology has yet to be identified. ⋯ Both FAAH inhibitors synergized with paclitaxel to reduce 4T1 and HeyA8 tumor cell line viability without reducing viability of non-tumor HEK293 cells. Neither FAAH inhibitor reduced viability of non-tumor HEK293 cells in either the presence or absence of paclitaxel, suggesting that nonspecific cytotoxic effects were not produced by the same treatments. Our results suggest that FAAH inhibitors reduce paclitaxel-induced allodynia without the occurrence of CB1-dependence in vivo and may, in fact, enhance the anti-tumor actions of paclitaxel in vitro.
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Tumor necrosis factor (TNF) is a proinflammatory cytokine, which is involved in physiological and pathological processes and has been found to be crucial for pain development. In the current study, we were interested in the effects of blocking Tumor necrosis factor receptor 1 (TNFR1) signaling on neuropathic pain after peripheral nerve injury with the use of transgenic mice and pharmacological inhibition. We have previously shown that TNFR1 mice failed to develop neuropathic pain and depressive symptoms after chronic constriction injury (CCI). ⋯ In male mice, XPro1595 treatment reduces elevated NMDA receptor levels in the brain after injury, whereas in female mice, NMDA receptor levels decrease after CCI. We further show that estrogen inhibits the therapeutic response of XPro1595 in females. Our results suggest that TNFR1 signaling plays an essential role in pain induction after CCI in males but not in females.
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Peripheral nerve injury downregulates the expression of the μ-opioid receptor (MOR) and voltage-gated potassium channel subunit Kv1.2 by increasing their DNA methylation in the dorsal root ganglion (DRG). Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) causes DNA demethylation. Given that DRG MOR and Kv1.2 downregulation contribute to neuropathic pain genesis, this study investigated the effect of DRG TET1 overexpression on neuropathic pain. ⋯ Mechanistically, TET1 microinjection rescued the expression of MOR and Kv1.2 by reducing the level of 5-methylcytosine and increasing the level of 5-hydroxymethylcytosine in the promoter and 5' untranslated regions of the Oprml1 gene (encoding MOR) and in the promoter region of the Kcna2 gene (encoding Kv1.2) in the DRG ipsilateral to SNL. These findings suggest that DRG TET1 overexpression mitigated neuropathic pain likely through rescue of MOR and Kv1.2 expression in the ipsilateral DRG. Virus-mediated DRG delivery of TET1 may open a new avenue for neuropathic pain management.
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Molecular neurobiology · Apr 2019
Pain-Relieving Effects of mTOR Inhibitor in the Anterior Cingulate Cortex of Neuropathic Rats.
The anterior cingulate cortex (ACC) is a well-known brain area that is associated with pain perception. Previous studies reported that the ACC has a specific role in the emotional processing of pain. Chronic pain is characterized by long-term potentiation that is induced in pain pathways and contributes to hyperalgesia caused by peripheral nerve injury. ⋯ A behavioral test was performed to evaluate mechanical allodynia, and optical imaging was conducted to observe the neuronal responses of the ACC to peripheral stimulation. Inhibition of mTOR by rapamycin reduced mechanical allodynia, down-regulated mTOR signaling in the ACC, and diminished the expressions of synaptic proteins which are involved in excitatory signaling, thereby reducing neuropathic pain-induced synaptic plasticity. These results suggest that inhibiting mTOR activity by rapamycin in the ACC could serve as a new strategy for treating or managing neuropathic pain before it develops into chronic pain.