Distinct sensitizing effects of the cAMP-PKA second messenger cascade on rat dural mechanonociceptors
Distinct sensitizing effects of the cAMP-PKA second messenger cascade on rat dural mechanonociceptors
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DOI：
10.1113/jphysiol.2001.013175
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发表时间：
2002-01-15
影响因子：
5.5
通讯作者：
Strassman, AM
中科院分区：
文献类型：
--
作者：
Levy, D;Strassman, AM
cAMP/蛋白激酶A（PKA）第二信使级联的激活与炎症介质诱导的机械性痛觉过敏有关。我们研究了这一级联反应在支配脑膜的伤害性神经元的机械致敏中的作用，这一过程被认为与头痛综合征（如偏头痛）的病理生理学有关。分别用伺服力控制刺激器或von Frey单丝刺激硬脑膜时，记录了40个机械敏感性硬脑膜传入（传导速度：0.3-6.6 m s（-1））和9个机械不敏感性硬脑膜传入（MIA）（传导速度：0.3-2.8 m s（-1））的三叉神经节单单位活动。二丁酰腺苷3 '，5'-环一磷酸（dbcAMP，100，妈妈），一个稳定的膜渗透cAMP类似物的硬脑膜的局部应用程序，在大多数机械敏感单位（19/29，66%）产生机械敏化。观察到两种不同的机械致敏模式。38%的单位仅表现出阈值降低（TH组），而28%的单位仅表现出阈上反应增加（STH组）。dbcAMP还在大多数MIA单位中诱导机械敏感性（6/9，67%）。dbcAMP诱导的致敏作用被PKA抑制剂Rp-cAMP（1 mm）和H-89（100 pin）阻断。在大多数测试的机械敏感单位中，炎症介质的混合物诱导了两种致敏成分。然而，在每个单元中，PKA抑制剂仅阻断两种效应中的一种（TH或STH）。被归类为TH或STH的单位在基线刺激反应斜率、阈值和传导速度方面也不同。这些研究结果牵连cAMP-PKA级联在致敏硬脑膜mechanonociceptor，并表明，该级联可能产生致敏通过至少两种不同的机制，在不同的神经元群体。
Activation of the cAMP/protein kinase A (PKA) second messenger cascade has been implicated in the induction of mechanical hyperalgesia by inflammatory mediators. We examined the role of this cascade in mechanical sensitization of nociceptive neurons that innervate the meninges, a process thought to be involved in the pathophysiology of headache syndromes such as migraine. Single unit activity was recorded in the trigeminal ganglion from 40 mechanosensitive dural afferents (conduction velocitity: 0.3-6.6 m s(-1)) and nine mechanically insensitive dural afferents (MIAs) (conduction velocitity: 0.3-2.8 m s(-1)) while stimulating the dura with a servo force-controlled stimulator or von Frey monofilaments, respectively. Local application to the dura of dibutyryl adenosine 3',5'-cyclic monophosphate (dbcAMP, 100,mum), a stable membrane-permeant cAMP analogue, produced mechanical sensitization in the majority of mechanosensitive units (19/29, 66%). Two distinct patterns of mechanical sensitization were observed. Thirty-eight per cent of the units exhibited only a decrease in threshold (TH group), while 28% showed only an increase in suprathreshold responses (STH group). dbcAMP also induced mechanosensitivity in the majority of MIA units (6/9, 67%). dbcAMP-induced sensitization was blocked by the PKA inhibitors, Rp-cAMP (1 mm) and H-89 (100 pin). A mixture of inflammatory mediators induced both components of sensitization in the majority of mechanosensitive units tested. However, in each unit, PKA inhibitors blocked only one of the two effects (either TH or STH). Units that were classified as TH or STH also differed in their baseline stimulus-response slopes, thresholds and conduction velocities. These findings implicate the cAMP-PKA cascade in sensitization of dural mechanonociceptors and suggest that this cascade may produce sensitization through at least two different mechanisms operating in separate neuronal populations.