The management of neuropathic pain is still a major challenge because of its unresponsiveness to most common treatments. Curcumin has been reported to play an active role in the treatment of various neurological disorders, such as neuropathic pain. Curcumin has long been recognized as a p300/CREB-binding protein (CBP) inhibitor of histone acetyltransferase (HAT) activity. However, this mechanism has never been investigated for the treatment of neuropathic pain with curcumin. The aim of the present study was to investigate the anti-nociceptive role of curcumin in the chronic constriction injury (CCI) rat model of neuropathic pain. Furthermore, with this model we investigated the effect of curcumin on P300/CBP HAT activity-regulated release of the pro-nociceptive molecules, brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (Cox-2). Treatment with 40 and 60 mg/kg body weight curcumin for 7 consecutive days significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia, whereas 20 mg/kg curcumin showed no significant analgesic effect. Chromatin immunoprecipitation analysis revealed that curcumin dose-dependently reduced the recruitment of p300/CBP and acetyl-Histone H3/acetyl-Histone H4 to the promoter of BDNF and Cox-2 genes. A similar dose-dependent decrease of BDNF and Cox-2 in the spinal cord was also observed after curcumin treatment. These results indicated that curcumin exerted a therapeutic role in neuropathic pain by down-regulating p300/CBP HAT activity-mediated gene expression of BDNF and Cox-2.

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Obesity is associated with increased risk for chronic pain. Basic mechanisms for this association are poorly understood. Using a milder version of a radicular pain model, local inflammation of the dorsal root ganglion (DRG), we observed marked increases in mechanical and cold allodynia in rats of both sexes that were maintained on a high-fat diet (HFD) for 6 weeks prior to DRG inflammation. Notably, this increase in pain-related behaviors occurred in both Long-Evans and Sprague-Dawley rats despite the fact that the 6-week HFD exposure induced obesity (e.g., increased insulin, leptin, weight, and percent body fat) in the Long-Evans, but not Sprague-Dawley, strains. This suggested that HFD, rather than obesity per se, increased pain behaviors. Increased pain behaviors were observed even after a much shorter (1 week) exposure to the HFD but the effect was smaller. HFD also increased behavioral responses and paw swelling to paw injection of complete Freund’s adjuvant, a model of peripheral inflammatory pain. No change was detected in plasma cytokine levels in HFD rats. However, increased macrophage infiltration of the DRG was observed in response to the HFD, absent any pain model. The results suggest that HFD can increase pain even when it does not cause obesity.