Samineni Vijay K, Premkumar Louis S, Faingold Carl L
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA.
Pain. 2017 Jul;158(7):1241-1253. doi: 10.1097/j.pain.0000000000000905.
Neuropathic pain is a debilitating pathological condition that is poorly understood. Recent evidence suggests that abnormal central processing occurs during the development of neuropathic pain induced by the cancer chemotherapeutic agent, paclitaxel. Yet, it is unclear what role neurons in supraspinal pain network sites, such as the periaqueductal gray, play in altered behavioral sensitivity seen during chronic pain conditions. To elucidate these mechanisms, we studied the spontaneous and thermally evoked firing patterns of ventrolateral periaqueductal gray (vlPAG) neurons in awake-behaving rats treated with paclitaxel to induce neuropathic pain. In the present study, vlPAG neurons in naive rats exhibited either excitatory, inhibitory, or neutral responses to noxious thermal stimuli, as previously observed. However, after development of behavioral hypersensitivity induced by the chemotherapeutic agent, paclitaxel, vlPAG neurons displayed increased neuronal activity and changes in thermal pain-evoked neuronal activity. This involved elevated levels of spontaneous firing and heightened responsiveness to nonnoxious stimuli (allodynia) as well as noxious thermal stimuli (hyperalgesia) as compared with controls. Furthermore, after paclitaxel treatment, only excitatory neuronal responses were observed for both nonnoxious and noxious thermal stimuli. Systemic administration of gabapentin, a nonopioid analgesic, induced significant dose-dependent decreases in the elevated spontaneous and thermally evoked vlPAG neuronal firing to both nonnoxious and noxious thermal stimuli in rats exhibiting neuropathic pain, but not in naive rats. Thus, these results show a strong correlation between behavioral hypersensitivity to thermal stimuli and increased firing of vlPAG neurons in allodynia and hyperalgesia that occur in this neuropathic pain model.
神经性疼痛是一种难以理解的使人衰弱的病理状况。最近的证据表明，在由癌症化疗药物紫杉醇诱导的神经性疼痛发展过程中会出现异常的中枢处理。然而，目前尚不清楚诸如导水管周围灰质等脊髓上疼痛网络部位的神经元在慢性疼痛状态下出现的行为敏感性改变中发挥何种作用。为了阐明这些机制，我们研究了用紫杉醇诱导神经性疼痛的清醒行为大鼠中腹外侧导水管周围灰质（vlPAG）神经元的自发和热诱发放电模式。在本研究中，如先前观察到的那样，未用药大鼠的vlPAG神经元对有害热刺激表现出兴奋性、抑制性或中性反应。然而，在化疗药物紫杉醇诱导行为超敏反应出现后，vlPAG神经元显示出神经元活动增加以及热痛诱发的神经元活动发生变化。这包括与对照组相比，自发放电水平升高以及对非有害刺激（痛觉过敏）和有害热刺激（痛觉超敏）的反应性增强。此外，在紫杉醇治疗后，对于非有害和有害热刺激均仅观察到兴奋性神经元反应。全身给予非阿片类镇痛药加巴喷丁，可使表现出神经性疼痛的大鼠中，vlPAG神经元对非有害和有害热刺激的自发和热诱发放电升高显著剂量依赖性降低，但对未用药大鼠则无此作用。因此，这些结果表明，在这种神经性疼痛模型中出现的对热刺激的行为超敏反应与vlPAG神经元在痛觉过敏和痛觉超敏中的放电增加之间存在强烈相关性。
