Hayashida Ken-Ichiro, Clayton Bridgette A, Johnson James E, Eisenach James C
Department of Anesthesiology and Center for the Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Pain. 2008 Jun;136(3):348-355. doi: 10.1016/j.pain.2007.07.014. Epub 2007 Sep 5.
Many treatments for neuropathic pain activate or augment norepinephrine release in the spinal cord, yet these treatments are less effective against acute nociceptive stimuli. We previously showed in mice that peripheral nerve injury results in sprouting of spinal noradrenergic fibers, possibly reflecting the substrate for this shift in drug efficacy. Here, we tested whether such sprouting also occurs in rats after nerve injury and examined one signal for such sprouting. Ligation of L5 and L6 spinal nerves unilaterally in rats resulted in hypersensitivity to tactile stimulation of the ipsilateral paw, and sprouting of noradrenergic fibers in the dorsal horn of the lumbar spinal cord. Brain derived nerve growth factor (BDNF) content increased in L4-L6 dorsal root ganglia ipsilateral to injury and in lumbar spinal cord following nerve injury, and intrathecal infusion of BDNF antiserum prevented spinal noradrenergic sprouting. This treatment also prevented the increased analgesic efficacy of intrathecal clonidine observed after nerve injury. Intraspinal injection of BDNF in non-injured rats mimicked the sprouting of spinal noradrenergic fibers seen after nerve injury. These results suggest that increased BDNF synthesis and release drives spinal noradrenergic sprouting following nerve injury, and that this sprouting may paradoxically increase the capacity for analgesia in the setting of neuropathic pain from drugs which utilize or mimic the noradrenergic pathway.
许多治疗神经性疼痛的方法会激活或增强脊髓中去甲肾上腺素的释放，但这些治疗方法对急性伤害性刺激的效果较差。我们之前在小鼠中发现，外周神经损伤会导致脊髓去甲肾上腺素能纤维的芽生，这可能反映了药物疗效发生这种转变的基础。在此，我们测试了这种芽生在大鼠神经损伤后是否也会发生，并研究了这种芽生的一个信号。大鼠单侧结扎L5和L6脊髓神经会导致同侧爪对触觉刺激过敏，以及腰脊髓背角去甲肾上腺素能纤维的芽生。损伤同侧L4-L6背根神经节和神经损伤后的腰脊髓中脑源性神经生长因子（BDNF）含量增加，鞘内注射BDNF抗血清可防止脊髓去甲肾上腺素能芽生。这种治疗还阻止了神经损伤后观察到的鞘内可乐定镇痛效果的增强。在未受伤的大鼠中脊髓内注射BDNF可模拟神经损伤后所见的脊髓去甲肾上腺素能纤维的芽生。这些结果表明，BDNF合成和释放的增加驱动神经损伤后脊髓去甲肾上腺素能芽生，并且这种芽生可能反常地增加了在利用或模拟去甲肾上腺素能途径的药物所致神经性疼痛情况下的镇痛能力。
