Selective activation of nociceptor sub-groups by slow depolarizing electrical stimuli

电刺激范式的最新发展使无髓伤害性感受器的特异性评估成为可能。一个半正弦波形状(0.2-1 mA，500ms)的单一脉冲在“多模式”伤害性感受器中诱发动作电位(AP)的抽射样放电(“爆发”)。振荡的正弦波刺激(0.05-0.2 mA，4赫兹)还会激活“机械不敏感”(“沉默”)的C-痛觉感受器。在持续的正弦波刺激(1分钟，4赫兹)下，大约50%的小纤维神经病患者报告疼痛增加，而健康对照组的患者表现出显著的疼痛适应。这项拟议的研究项目旨在确定使“多模式”伤害性感受器在AP爆发时放电的神经生物学机制。持续的伤害性感受器在连续正弦波刺激时无调节放电的机制将被评估。在神经病理性疼痛患者中，伤害性感受器敏化作为持续自发性疼痛的潜在来源以及局部止痛治疗的临床相关性将被记录下来。将在猪体内进行单一神经纤维记录和体外记录复合动作电位(CAP)，以探讨无髓传入神经元对强度-持续时间依赖性半正弦波脉冲(时轴)的兴奋性。伤害性感受器对持续正弦波刺激的适应性将在猪中波神经支配区域的UVB炎症皮肤中进行评估。我们将探讨低阈值电压门控钙通道和钙激活氯通道在缓慢增加斜坡电流的伤害性感受器去极化中的作用。类似于在猪的单个神经纤维记录，在人类心理物理学中，我们将在健康志愿者和神经病理性疼痛患者中评估在连续正弦波和强度-时程(时轴)半正弦波刺激下无髓传入的神经元兴奋。将探讨患者的兴奋性测试作为局部止痛治疗和患者分层的预测价值。在NGF敏感的皮肤上，将研究在持续的伤害性感受器刺激过程中，“多模式”和“沉默的”伤害性感受器对疼痛适应的不同贡献。它们对继发性痛觉过敏和皮肤中不同部位的作用将被确定。从这些发现中，我们期待有迹象表明导致持续的伤害性感受器兴奋和放电爆发的机制，以及参与继发性痛觉过敏发展的特定伤害性感受器类别。从慢性神经性疼痛患者中获得的结果为更好的患者分层和局部止痛治疗的可能性提供了前景。

Recent development of electrical stimulation paradigms enables specific assessment of unmyelinated nociceptors. A single pulse of halfsine wave shape (0.2 – 1 mA, 500 ms) induces in „polymodal“ nociceptors a volley-like discharge (“burst”) of action potentials (APs). Oscillating sine wave stimuli (0.05 – 0.2 mA, 4 Hz) additionally activate „mechano-insensitive“ („silent“) C-nociceptors. Upon continuous sine wave stimulation (1 min, 4 Hz), about 50% of patients with small-fiber neuropathy report increasing pain whereas healthy control subjects reveal a substantial pain accommodation. The proposed research project targets to identify the neurobiological mechanisms that enable „polymodal“ nociceptors to discharge with AP bursts. Mechanisms for ongoing nociceptor discharges without accommodation upon continuous sine wave stimulation will be assessed. Clinically relevant nociceptor sensitization as potential source for ongoing spontaneous pain together with local analgetic therapy will be recorded in neuropathic pain patients. Nociceptor classes contributing to secondary hyperalgesia will be identified.Single nerve fiber recordings will be performed in pig in vivo and compound action potentials (CAP) recorded ex vivo to explore the excitability of unmyelinated afferent neurons to strength-duration dependent halfsine wave pulses (chronaxie). Accommodation of nociceptors to continuous sine wave stimulation will be assessed in UVB inflamed skin of the N.saphenous innervation territory in pigs. The functional role of low-threshold voltage-gated calcium channels and calcium-activated chloride channels in nociceptor depolarization upon slowly increasing ramp currents will be explored.Similar to single nerve fiber recordings in pig, in human psycho-physics we will assess in healthy volunteers and neuropathic pain patients the neuronal excitation of unmyelinated afferents during continuous sine wave and strength-duration (chronaxie) halfsine wave stimulation. Excitability tests in patients serving as predictive value for local analgesic therapy and patient stratification will be explored. The differential contribution of „polymodal“ and „silent“ nociceptors on pain accommodation during ongoing nociceptor stimulation will be investigated in NGF-sensitized skin. Their contribution to secondary hyperalgesia and differential location in the skin will be identified. From the findings we expect indications on the mechanisms leading to sustained nociceptor excitation and discharge bursts, as well as the specific nociceptor classes involved in secondary hyperalgesia development. The results obtained from chronic neuropathic pain patients allow perspectives for a better patient stratification and the potential of a local analgesic treatment therapy.