Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
Gastroenterology. 2012 Jan;142(1):165-173.e2. doi: 10.1053/j.gastro.2011.09.041. Epub 2011 Oct 1.
BACKGROUND & AIMS: The chronic, persistent pain associated with chronic pancreatitis (CP) has many characteristics of neuropathic pain, initiated and maintained by the activation of spinal microglia. We investigated whether activated microglia in the thoracic spinal cord contribute to chronic pain in a rat model of CP.
CP was induced in Sprague-Dawley rats by an intraductal injection of 2% trinitrobenzene sulfonic acid. Hyperalgesia was assessed by the measurement of mechanical sensitivity of the abdomen and nocifensive behavior to electrical stimulation of the pancreas. Three weeks after induction of CP, spinal samples were analyzed by immunostaining and immunoblot analyses for levels of CD11 (a marker of microglia, determined with the antibody OX42) and phosphorylated p38 (P-p38, a marker of activation of p38 mitogen-activated protein kinase signaling). We examined the effects of minocycline (inhibitor of microglia) and fractalkine (microglia-activating factor) on visceral hyperalgesia in rats with CP.
Rats with CP had increased sensitivity and nociceptive behaviors to mechanical probing of the abdomen and electrical stimulation of the pancreas. The dorsal horn of the thoracic spinal cords of rats with CP contained activated microglia (based on increased staining with OX42), with an ameboid appearance. Levels of P-p38 increased in rats with CP and colocalized with OX42-positive cells. Intrathecal injection of minocycline reversed and prevented the increase of nocifensive behaviors and levels of P-p38 in rats with CP. Fractalkine induced hyperalgesia in rats without CP, which was blocked by minocycline.
Activated spinal microglia have important roles in maintaining and initiating chronic pain in a rat model of CP. Microglia might be a target for treatment of hyperalgesia caused by pancreatic inflammation.
慢性胰腺炎（CP）相关的持续性慢性疼痛具有许多神经病理性疼痛的特征，由脊髓小胶质细胞的激活引发和维持。我们研究了胸段脊髓中激活的小胶质细胞是否会导致 CP 大鼠模型中的慢性疼痛。
通过胰管内注射 2%三硝基苯磺酸诱导 Sprague-Dawley 大鼠 CP。通过测量腹部机械敏感性和胰腺电刺激的伤害性行为来评估痛觉过敏。CP 诱导 3 周后，通过免疫染色和免疫印迹分析脊髓样本，检测 CD11（小胶质细胞标志物，用 OX42 抗体测定）和磷酸化 p38（p38 丝裂原活化蛋白激酶信号转导激活标志物）的水平。我们研究了米诺环素（小胶质细胞抑制剂）和 fractalkine（小胶质细胞激活因子）对 CP 大鼠内脏痛觉过敏的影响。
CP 大鼠对腹部机械探查和胰腺电刺激的敏感性和伤害性行为增加。CP 大鼠的胸段脊髓背角含有激活的小胶质细胞（基于 OX42 染色增加），呈阿米巴样外观。CP 大鼠的 P-p38 水平升高，并与 OX42 阳性细胞共定位。鞘内注射米诺环素可逆转并预防 CP 大鼠伤害性行为和 P-p38 水平的增加。在没有 CP 的大鼠中， fractalkine 诱导痛觉过敏，米诺环素可阻断其作用。
激活的脊髓小胶质细胞在 CP 大鼠模型中维持和引发慢性疼痛方面具有重要作用。小胶质细胞可能是治疗胰腺炎症引起的痛觉过敏的靶点。
