Loss of diffuse noxious inhibitory control after traumatic brain injury in rats: A chronic issue.

Chronic pain is one of the most challenging and debilitating symptoms to manage after traumatic brain injury (TBI), yet the underlying mechanisms remain elusive. The disruption of normal endogenous pain control mechanisms has been linked to several forms of chronic pain and may play a role in pain after TBI. We hypothesized therefore that dysfunctional descending noradrenergic and serotonergic pain control circuits may contribute to the loss of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, weeks to months after TBI. For these studies, the rat lateral fluid percussion model of mild TBI was used along with a DNIC paradigm involving a capsaicin-conditioning stimulus. We observed sustained failure of the DNIC response up to 180-days post injury. We confirmed, that descending α2 adrenoceptor-mediated noradrenergic signaling was critical for endogenous pain inhibition in uninjured rats. However, augmenting descending noradrenergic signaling using reboxetine, a selective noradrenaline reuptake inhibitor, failed to restore DNIC after TBI. Furthermore, blocking serotonin-mediated descending signaling using selective spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine was also unsuccessful at restoring endogenous pain modulation after TBI. Unexpectedly, increasing descending serotonergic signaling using the selective serotonin reuptake inhibitor escitalopram and the serotonin-norepinephrine reuptake inhibitor duloxetine restored the DNIC response in TBI rats at both 49- and 180- days post injury. Consistent with these observations, spinal serotonergic fiber depletion with 5, 7-dihydroxytryptamine eliminated the effects of escitalopram. Intact α2 adrenoceptor signaling, however, was not required for the serotonin-mediated restoration of DNIC after TBI. These results suggest that TBI causes maladaptation of descending nociceptive signaling mechanisms and changes in the function of both adrenergic and serotonergic circuits. Such changes could predispose those with TBI to chronic pain.

Curcumin treatment attenuates pain and enhances functional recovery after incision.

BACKGROUND: Acute pain after surgery remains moderate to severe for 20% to 30% of patients despite advancements in the use of opioids, adjuvant drugs, and regional anesthesia. Depending on the type of surgery, 10% to 50% of patients experience persistent pain postoperatively, and there are no established methods for its prevention. Curcumin (diferuloylmethane) is one of the phenolic constituents of turmeric that has been used in Eastern traditional medicine as an antiseptic, antioxidant, anti-inflammatory, and analgesic agent. It may be effective for treating postoperative pain. METHODS: We used the hindpaw incision model with C57BL/6 mice. Sensitization to mechanical and thermal stimuli as well as effects on edema and temperature were measured up to 7 days after surgery. Spontaneous pain after incision was assessed by using conditioned place preference (CPP), and alterations in gait function were assessed using multiparameter digital gait analysis. RESULTS: Curcumin (50 mg/kg) significantly reduced the intensity of mechanical and heat sensitization after hindpaw incision in mice. No effects of curcumin on baseline nociceptive thresholds were observed. Curcumin also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. In addition, perioperative curcumin treatment attenuated hyperalgesic priming due to incision when mice were subsequently challenged with hindpaw prostaglandin E2 application. Furthermore, while vehicle-treated mice had evidence of spontaneous pain 48 hours after incision in the CPP paradigm, no evidence of ongoing pain was observed in the mice treated with curcumin. Likewise, hindpaw incision caused changes in several gait-related indices, but most of these were normalized in the curcumin-treated animals. The peri-incisional levels of several pronociceptive immune mediators including interleukin (IL)-1ß, IL-6, tumor necrosis factor α, and macrophage inflammatory protein-1α were either not reduced or were even augmented 1 and 3 days after incision in curcumin-treated mice. The anti-inflammatory cytokine IL-10 was unchanged, while transforming growth factor-ß levels were enhanced under the same conditions. CONCLUSIONS: Our studies suggest that curcumin treatment is effective in alleviating incision-induced inflammation, nociceptive sensitization, spontaneous pain, and functional gait abnormalities. Augmented transforming growth factor-ß production provides one possible mechanism. These preclinical findings demonstrate curcumin's potential as a preventative strategy in postoperative pain treatment.

Effects of methyl donor diets on incisional pain in mice.

BACKGROUND: Dietary supplementation with methyl donors can influence the programming of epigenetic patterns resulting in persistent alterations in disease susceptibility and behavior. However, the dietary effects of methyl donors on pain have not been explored. In this study, we evaluated the effects of dietary methyl donor content on pain responses in mice. METHODS: Male and female C57BL/6J mice were treated with high or low methyl donor diets either in the perinatal period or after weaning. Mechanical and thermal nociceptive sensitivity were measured before and after incision. RESULTS: Mice fed high or low methyl donor diets displayed equal weight gain over the course of the experiments. When exposed to these dietary manipulations in the perinatal period, only male offspring of dams fed a high methyl donor diet displayed increased mechanical allodynia. Hindpaw incision in these animals caused enhanced nociceptive sensitization, but dietary history did not affect the duration of sensitization. For mice exposed to high or low methyl donor diets after weaning, no significant differences were observed in mechanical or thermal nociceptive sensitivity either at baseline or in response to hindpaw incision. CONCLUSIONS: Perinatal dietary factors such as methyl donor content may impact pain experiences in later life. These effects, however, may be specific to sex and pain modality.