- مبلغ: ۸۶,۰۰۰ تومان
- مبلغ: ۹۱,۰۰۰ تومان
Chronic pain after traumatic brain injury (TBI) is very common, but the mechanisms linking TBI to pain and the pain-related interactions of TBI with peripheral injuries are poorly understood. In these studies we pursued the hypothesis that TBI pain sensitization is associated with histone acetylation in the rat lateral fluid percussion model. Some animals received hindpaw incisions in addition to TBI to mimic polytrauma. Neuropathological analysis of brain tissue from sham and TBI animals revealed evidence of bleeding, breakdown of the blood brain barrier, in the cortex, hippocampus, thalamus and other structures related to pain signal processing. Mechanical allodynia was measured in these animals for up to eight weeks post-injury. Inhibitors of histone acetyltransferase (HAT) and histone deacetylase (HDAC) were used to probe the role of histone acetylation in such pain processing. We followed serum markers including glial fibrillary acidic protein (GFAP), neuron-specific enolase 2 (NSE) myelin basic protein (MBP) and S100β to gauge TBI injury severity. Our results showed that TBI caused mechanical allodynia in the hindpaws of the rats lasting several weeks. Hindpaws contralateral to TBI showed more rapid and profound sensitization than ipsilateral hindpaws. The inhibition of HAT using curcumin 50 mg/kg s.c reduced mechanical sensitization while the HDAC inhibitor suberoylanilide hydroxamic acid 50 mg/kg i.p. prolonged sensitization in the TBI rats. Immunohistochemical analyses of spinal cord tissue localized changes in the level of acetylation of the H3K9 histone mark to dorsal horn neurons. Taken together, these findings demonstrate that TBI induces sustained nociceptive sensitization, and changes in spinal neuronal histone proteins may play an important role.
Traumatic brain injury (TBI), most frequently mild, accompanies battlefield, motor vehicle and sports-related injuries, and is often associated with chronic pain. More broadly, over 5 million Americans are living with TBI, many of whom experience chronic pain (Langlois et al., 2006). Chronic pain in the setting of TBI contributes to disability, causes suffering, complicates rehabilitative efforts and poses a significant overall challenge to management teams (Lippa et al., 2015). Unfortunately very little information is available concerning why patients with TBI develop chronic pain, and we have no specific treatments for TBI-related pain. Our studies confirm and extend previous human and animal analyses suggesting that mild traumatic brain injury unassociated with persistent neurological deficits can none-the-less support sensitization to painful or noxious stimuli. Moreover, the persistent nature of pain after TBI as well as recent observations of enhanced BDNF expression in the spinal cords of rats (Feliciano et al., 2014) and non-human primates (Nagamoto-Combs et al., 2007) suggests epigenetic mechanisms might be activated at sites distant from the TBI even after mild injuries. The regulation of histone acetylation in neural tissues is a known mechanism regulating the persistence of nociceptive sensitization after hindpaw incision, inflammation and nerve damage (Chiechio et al., 2009; Bai et al., 2010; Sun et al., 2013; Liang et al., 2014, 2015). Our studies demonstrate that well-characterized pharmacological treatments either diminishing (curcumin) or enhancing (SAHA) the level of histone acetylation are in fact able to regulate nociceptive sensitization after TBI or hindpaw incision. Furthermore, TBI increased the spinal abundance of acetylated H3K9 in spinal cord neurons complementing our earlier findings that hindpaw incision increases acetylated H3K9 in neurons from the same sensory processing regions of the spinal cord (Sun et al., 2013). Our data do not, however, exclude the involvement of glial cells in the spinal response to TBI