Study of peripheral mechanism of hyperalgesia in neuropathic pain

我们已经报道了在某些病理条件下，拟交感神经刺激皮肤多模态受体（CPRs）。然而，目前尚不清楚交感动作是否会增强心肺复苏术对其他类型刺激的反应。为了澄清这一问题，我们利用皮肤隐神经体外制备研究了去甲肾上腺素（NE）对CPRs热和缓激素（BK）反应的影响。在深度麻醉下，解剖切除与正常SD大鼠后爪皮肤连续的隐神经。将已确定的单个CPR单元的感受野与化学溶液混合或在堆芯侧进行斜坡加热。BK （1-10 μ m）反应的模式和程度存在很大的个体间差异，并且在重复BK灌注（间隔10分钟）后观察到明显的快速反应。在BK或热刺激之前，NE （1-10 μ m）本身没有激活cpr。相比之下，经过几次BK或加热试验后，一些心肺复苏术单位对NE感到兴奋。NE （1-10 uM）使BK反应增敏，而无论NE诱导的兴奋是否存在，它都抑制了热反应。这些结果提示了ne修饰对CPRs BK和热响应的不同机制。接下来，我们将重点研究ne致敏对BK反应的机制，并确定a_2-肾上腺素受体是否介导这种作用。用BK （1 ~ 10 μ m）在堆芯侧灌注已鉴定的单个CPRs感受野60秒，间隔10 μ m。施用NE后，BK反应增强，且持续到第2天。NE应用后BK响应（N=10）。然而，NE联合a_2拮抗剂yohinibine （1-10 μ m）或CH-38083 （1-10 μ m）未能使BK反应增敏（N=7）。这些结果表明ne诱导的BK反应增敏是通过a_2-肾上腺素受体介导的。

We have reported that sympathomimetics excites cutaneous polymodal receptors (CPRs) in some pathological conditions. However, it remains obscure whether sympathetic action augments the CPR responses to other types of stimulus. To clarify this issue, the effects of norepinephrine (NE) on the heat and bradykinin (BK) responses of CPRs were studied using skin-saphenous nerve in vitro preparation. Under deep anesthesia, the saphenous nerve in continuity with the hind paw skin of normal SD rats was sabcutaneously dissected and excised. Receptive fields of identified single CPR units were superfused with chemical solutions or ramp-heated at the corium side. There was a large inter-individual variability in pattern and magnitude of the BK (1-10 uM) response, and a marked tachyphylaxis upon repeated BK superfusion (10-min interval) was observed. NE (1-10 uM) by itself did not excite CPRs before BK or heat stimulations. In contrast, after a few trials of BK or heat, some CPR units were excited by NE.NE (1-10 uM) sensitized the BK responses, while it suppressed the heat responses regardless of the presence of NE-induced excitation. These results suggest different mechanisms of NE-modification on BK and heat responses of CPRs.Next we have focused on the mechanism of NE-sensitization on BK response and determined if an a_2-adrenoceptor mediates this effect. Receptive fields of identified single CPRs were superfused with BK (1-10 uM) at the corium side for 60 sec with 10-mm intervals. BK responses increased after NE application, and this effect lasted till the 2nd.BK response after NE application (N=10). NE combined with a_2-antagonists, yohinibine (1-10 uM) or CH-38083 (1-10 uM), however, failed to sensitize the BK responses (N=7). These results suggest that NE-induced sensitization of BK response was mediated through a_2-adrenoceptors.