Riley R C, Trafton J A, Chi S I, Basbaum A I
Departments of Anatomy and Physiology and W. M. Keck Foundation Center for Integrative Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA.
Neuroscience. 2001;103(3):725-37. doi: 10.1016/s0306-4522(00)00571-6.
Internalization of spinal cord neurokinin-1 receptors following noxious stimulation provides a reliable measure of tachykinin signaling. In the present study, we examined the contribution of GABAergic mechanisms to the control of nociceptor processing involving tachykinins. Spinal administration of the GABA(B) receptor agonist R(+)-baclofen in the rat, at antinociceptive doses, significantly reduced the magnitude of neurokinin-1 receptor internalization in neurons of lamina I in response to acute noxious mechanical or thermal stimulation. By contrast, administration of even high doses of the GABA(A) receptor agonists, muscimol or isoguvacine, were without effect. CGP55845, a selective GABA(B) receptor antagonist, completely blocked the effects of baclofen, but failed to increase the incidence of internalization when administered alone. These results provide evidence for a presynaptic control of nociceptive primary afferent neurons by GABA(B) but not GABA(A) receptors in the superficial laminae of the spinal cord, limiting tachykinin release. Because CGP5584 alone did not increase the magnitude of neurokinin-1 receptor internalization observed following noxious stimulation, there appears to be little endogenous activation of GABA(B) receptors on tachykinin-releasing nociceptors under acute stimulus conditions. The contribution of pre- and postsynaptic regulatory mechanisms to GABA(B) receptor-mediated antinociception was also investigated by comparing the effect of baclofen on Fos expression evoked by noxious stimulation to that induced by intrathecal injection of substance P. In both instances, baclofen reduced Fos expression not only in neurons that express the neurokinin-1 receptor, but also in neurons that do not. We conclude that baclofen acts at presynaptic sites to reduce transmitter release from small-diameter nociceptive afferents. Presynaptic actions on non-tachykinin-containing nociceptors could similarly account for the reduction by baclofen of noxious stimulus-induced Fos expression in neurokinin-1 receptor-negative neurons. However, the inhibition of Fos expression induced by exogenous substance P indicates that actions at sites postsynaptic to tachykinin- and/or non-tachykinin-containing primary afferent terminals must also contribute to the antinociceptive actions of GABA(B) receptor agonists.
伤害性刺激后脊髓神经激肽-1受体的内化提供了速激肽信号传导的可靠测量方法。在本研究中，我们研究了γ-氨基丁酸（GABA）能机制在涉及速激肽的伤害感受器处理控制中的作用。以抗伤害感受剂量向大鼠脊髓给予GABA(B)受体激动剂R(+)-巴氯芬，可显著降低I层神经元中神经激肽-1受体对急性伤害性机械或热刺激的内化程度。相比之下，给予高剂量的GABA(A)受体激动剂蝇蕈醇或异鹅膏蕈氨酸则没有效果。选择性GABA(B)受体拮抗剂CGP55845完全阻断了巴氯芬的作用，但单独给药时未能增加内化发生率。这些结果为脊髓浅层中GABA(B)而非GABA(A)受体对伤害性初级传入神经元的突触前控制提供了证据，从而限制了速激肽的释放。由于单独使用CGP5584不会增加伤害性刺激后观察到的神经激肽-1受体内化程度，在急性刺激条件下，速激肽释放性伤害感受器上的GABA(B)受体似乎几乎没有内源性激活。通过比较巴氯芬对伤害性刺激诱发的Fos表达与鞘内注射P物质诱导的Fos表达的影响，还研究了突触前和突触后调节机制对GABA(B)受体介导的抗伤害感受的作用。在这两种情况下，巴氯芬不仅降低了表达神经激肽-1受体的神经元中的Fos表达，也降低了不表达该受体的神经元中的Fos表达。我们得出结论，巴氯芬作用于突触前位点以减少小直径伤害性传入纤维的递质释放。对不含速激肽的伤害感受器的突触前作用可能同样解释了巴氯芬对神经激肽-1受体阴性神经元中伤害性刺激诱导的Fos表达的降低作用。然而，外源性P物质诱导的Fos表达的抑制表明，在含有速激肽和/或不含速激肽的初级传入终末的突触后位点的作用也必须有助于GABA(B)受体激动剂的抗伤害感受作用。
