Departamento de Fisiología, Biofísica y Neurociencias, Cinvestav, Mexico City, Mexico.
Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA.
Physiol Rep. 2021 Aug;9(16):e14984. doi: 10.14814/phy2.14984.
Chronic pain is an incapacitating condition that affects a large population worldwide. Until now, there is no drug treatment to relieve it. The impairment of GABAergic inhibition mediated by GABA receptors (GABA R) is considered a relevant factor in mediating chronic pain. Even though both synaptic and extrasynaptic GABA inhibition are present in neurons that process nociceptive information, the latter is not considered relevant as a target for the development of pain treatments. In particular, the extrasynaptic α GABA Rs are expressed in laminae I-II of the spinal cord neurons, sensory neurons, and motoneurons. In this review, we discuss evidence showing that blockade of the extrasynaptic α GABA Rs reduces mechanical allodynia in various models of chronic pain and restores the associated loss of rate-dependent depression of the Hoffmann reflex. Furthermore, in healthy animals, extrasynaptic α GABA R blockade induces both allodynia and hyperalgesia. These results indicate that this receptor may have an antinociceptive and pronociceptive role in healthy and chronic pain-affected animals, respectively. We propose a hypothesis to explain the relevant role of the extrasynaptic α GABA Rs in the processing of nociceptive information. The data discussed here strongly suggest that this receptor could be a valid pharmacological target to treat chronic pain states.
慢性疼痛是一种使人丧失能力的疾病，影响着全世界的大量人口。到目前为止，还没有药物治疗来缓解这种疾病。GABA 能神经元介导的 GABA 受体（GABA R）抑制作用的损害被认为是介导慢性疼痛的一个相关因素。尽管突触内和突触外 GABA 抑制都存在于处理伤害性信息的神经元中，但后者并不被认为是开发疼痛治疗的相关靶点。特别是，突触外的 α GABA Rs 在脊髓神经元、感觉神经元和运动神经元的 I-II 层中表达。在这篇综述中，我们讨论了一些证据，这些证据表明，阻断突触外的 α GABA Rs 可以减轻各种慢性疼痛模型中的机械性痛觉过敏，并恢复与 Hoffmann 反射的率依赖性抑制丧失相关的疼痛缓解。此外，在健康动物中，突触外 α GABA R 阻断会引起痛觉过敏和痛觉过敏。这些结果表明，该受体在健康和受慢性疼痛影响的动物中可能分别具有抗伤害性和促伤害性作用。我们提出了一个假设来解释突触外 α GABA Rs 在伤害性信息处理中的相关作用。这里讨论的数据强烈表明，该受体可能是治疗慢性疼痛状态的一个有效的药理学靶点。
