Abstract
Background Mounting evidence has shown that sirtuin 1 (SIRT1), a class III histone deacetylase, alleviated several types of neuropathic pain in the spinal cord and dorsal root ganglion and regulated some aberrant behaviors in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Methods In this context, the effect of SIRT1 on neuropathic pain in the VTA-NAc pathway was investigated in the model of chronic constrictive injury (CCI). Results SIRT1 was localized in the VTA neurons in naive mice. The expression of SIRT1 was decreased in the contralateral VTA of CCI mice. After microinjection of SRT1720 (an activator of SIRT1) in the contralateral VTA of CCI mice, the established thermal hyperalgesia was attenuated. However, it was further exacerbated by EX-527 (an inhibitor of SIRT1). The elevated level of acetyl-histone 3 was reduced by SRT1720 but further elevated by EX-527 in the contralateral VTA of CCI mice. The increased expression of Fos in both VTA and NAc was downregulated by SRT1720 but further upregulated by EX-527 in CCI mice. Conclusions The discovery of the effect of SIRT1 on neuropathic pain in the VTA represents an important step forward in understanding the analgesic mechanisms of the VTA-NAc pathway.
Highlights
Chronic pain is a highly prevalent and intractable disease in the world, leading patients to wind up in a constant state of pain and contributing to high costs of health care and productivity loss [1,2,3,4,5]
Glial fibrillary acidic protein (GFAP), Iba-1, and NeuN are regarded as the markers of the astrocyte, microglia, and neuron, respectively. e results showed that sirtuin 1 (SIRT1) was almost colocalized with NeuN in the ventral tegmental area (VTA)
Coimmunoprecipitation analysis revealed that the level of acetyl-histone 3, a substrate of SIRT1, was elevated in the contralateral VTA of constrictive injury (CCI) mice, and the degree of elevation was decreased by SRT1720 (Figure 3(c))
Summary
Chronic pain is a highly prevalent and intractable disease in the world, leading patients to wind up in a constant state of pain and contributing to high costs of health care and productivity loss [1,2,3,4,5]. E nucleus accumbens (NAc), a key projectional region of VTA DA neurons, plays an analgesic role in neuropathic pain [19, 20, 28,29,30]. In this context, the effect of SIRT1 on neuropathic pain in the VTA-NAc pathway was investigated in the model of chronic constrictive injury (CCI). After microinjection of SRT1720 (an activator of SIRT1) in the contralateral VTA of CCI mice, the established thermal hyperalgesia was attenuated. It was further exacerbated by EX-527 (an inhibitor of SIRT1). Conclusions. e discovery of the effect of SIRT1 on neuropathic pain in the VTA represents an important step forward in understanding the analgesic mechanisms of the VTA-NAc pathway
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