Pain sensation is powerfully modulated by signal processing in the brain, and pain becomes chronic with the dysfunction of the pain modulatory system; however, the underlying mechanisms are unclear. We found that the metabotropic glutamate receptor 5 (mGluR5) in the periaqueductal gray (PAG), the key area of endogenous pain modulation, is persistently active in normal conditions to maintain an appropriate sensory perception. In the neuropathic pain condition, Homer1a, an activity-dependent immediate early gene product, disrupted the persistent mGluR5 activity resulting in chronic pain. Remarkably a single-time blockage of the mGluR5 resulted in chronic neuropathic pain-like symptoms even in the absence of nerve injury. The decline of mGluR5 activity induced the pain modulatory dysfunction with a profound reduction of excitability of PAG neurons. These findings uncover the role of the persistent mGluR5 activity in vivo and provide new insight into how pain becomes chronic with the maladaptive coping of the PAG to pain sensation.

痛觉受到大脑信号处理的强烈调节，随着疼痛调节系统的功能障碍，疼痛变成慢性；然而，潜在的机制尚不清楚。我们发现导水管周围灰质 (PAG) 中的代谢型谷氨酸受体 5 (mGluR5) 是内源性疼痛调节的关键区域，在正常条件下持续活跃以维持适当的感官知觉。在神经性疼痛条件下，Homer1a（一种依赖于活动的即刻早期基因产物）破坏了持续的 mGluR5 活动，导致了慢性疼痛。值得注意的是，即使没有神经损伤，mGluR5 的单次阻断也会导致慢性神经性疼痛样症状。mGluR5 活性的下降导致疼痛调节功能障碍，PAG 神经元的兴奋性显着降低。在体内，并提供新的见解，了解疼痛如何随着 PAG 对疼痛感觉的适应不良而变得慢性。