Department of Physiology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México.
Universidad Politécnica de Catalunya, BarcelonaTech, Catalonia, Spain.
J Physiol. 2018 May 1;596(9):1747-1776. doi: 10.1113/JP275228. Epub 2018 Mar 26.
The state of central sensitization induced by the intradermic injection of capsaicin leads to structured (non-random) changes in functional connectivity between dorsal horn neuronal populations distributed along the spinal lumbar segments in anaesthetized cats. The capsaicin-induced changes in neuronal connectivity and the concurrent increase in secondary hyperalgesia are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. The effects of both capsaicin and lidocaine are greatly attenuated in spinalized preparations, showing that supraspinal influences play a significant role in the shaping of nociceptive-induced changes in dorsal horn functional neuronal connectivity. We conclude that changes in functional connectivity between segmental populations of dorsal horn neurones induced by capsaicin and lidocaine result from a cooperative adaptive interaction between supraspinal and spinal neuronal networks, a process that may have a relevant role in the pathogenesis of chronic pain and analgesia.
Despite a profusion of information on the molecular and cellular mechanisms involved in the central sensitization produced by intense nociceptive stimulation, the changes in the patterns of functional connectivity between spinal neurones associated with the development of secondary hyperalgesia and allodynia remain largely unknown. Here we show that the state of central sensitization produced by the intradermal injection of capsaicin is associated with structured transformations in neuronal synchronization that lead to an enduring reorganization of the functional connectivity within a segmentally distributed ensemble of dorsal horn neurones. These changes are transiently reversed by the systemic administration of small doses of lidocaine, a clinically effective procedure to treat neuropathic pain. Lidocaine also reduces the capsaicin-induced facilitation of the spinal responses evoked by weak mechanical stimulation of the skin in the region of secondary but not primary hyperalgesia. The effects of both intradermic capsaicin and systemic lidocaine on the segmental correlation and coherence between ongoing cord dorsum potentials and on the responses evoked by tactile stimulation in the region of secondary hyperalgesia are greatly attenuated in spinalized preparations, showing that supraspinal influences are involved in the reorganization of the nociceptive-induced structured patterns of dorsal horn neuronal connectivity. We conclude that the structured reorganization of the functional connectivity between the dorsal horn neurones induced by capsaicin nociceptive stimulation results from cooperative interactions between supraspinal and spinal networks, a process that may have a relevant role in the shaping of the spinal state in the pathogenesis of chronic pain and analgesia.
皮内注射辣椒素引起的中枢敏化状态导致麻醉猫腰骶段背角神经元群体之间的功能连接呈现结构化（非随机）变化。小剂量利多卡因的全身给药可暂时逆转辣椒素诱导的神经元连接变化和继发超敏反应，这是一种治疗神经性疼痛的临床有效方法。在脊髓切断的制剂中，辣椒素和利多卡因的作用都大大减弱，表明脊髓上的影响在塑造背角功能性神经元连接的伤害性诱导变化中起着重要作用。我们的结论是，由辣椒素和利多卡因引起的背角神经元节段群体之间的功能连接变化是由脊髓上和脊髓神经元网络之间的合作适应相互作用引起的，这个过程可能在慢性疼痛和镇痛的发病机制中起重要作用。
尽管有大量关于强烈伤害性刺激引起的中枢敏化所涉及的分子和细胞机制的信息，但与继发超敏反应和感觉异常相关的脊髓神经元之间功能连接模式的变化在很大程度上仍然未知。在这里，我们表明，皮内注射辣椒素引起的中枢敏化状态与神经元同步的结构化转变有关，这些转变导致在背角神经元节段分布的集合内的功能连接发生持久的重新组织。这些变化可通过小剂量利多卡因的全身给药短暂逆转，利多卡因是治疗神经性疼痛的一种临床有效方法。利多卡因还可降低皮内注射辣椒素对皮肤弱机械刺激诱发的脊髓反应的易化作用，但对原发性超敏反应区无影响。在脊髓切断的制剂中，皮内注射辣椒素和全身给予利多卡因对脊髓背角电位和继发性超敏反应区触觉刺激诱发反应之间的节段相关性和相干性的影响都大大减弱，表明脊髓上的影响参与了伤害性诱导的背角神经元连接的结构化模式的重组。我们的结论是，由辣椒素伤害性刺激引起的背角神经元之间的功能连接结构化重组是由脊髓上和脊髓网络之间的合作相互作用引起的，这一过程可能在慢性疼痛和镇痛的发病机制中对脊髓状态的形成起着重要作用。
