Seybold V S
Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church St., S.E., Minneapolis, MN 55455, USA.
Handb Exp Pharmacol. 2009(194):451-91. doi: 10.1007/978-3-540-79090-7_13.
Peptides released in the spinal cord from the central terminals of nociceptors contribute to the persistent hyperalgesia that defines the clinical experience of chronic pain. Using substance P (SP) and calcitonin gene-related peptide (CGRP) as examples, this review addresses the multiple mechanisms through which peptidergic neurotransmission contributes to the development and maintenance of chronic pain. Activation of CGRP receptors on terminals of primary afferent neurons facilitates transmitter release and receptors on spinal neurons increases glutamate activation of AMPA receptors. Both effects are mediated by cAMP-dependent mechanisms. Substance P activates neurokinin receptors (3 subtypes) which couple to phospholipase C and the generation of the intracellular messengers whose downstream effects include depolarizing the membrane and facilitating the function of AMPA and NMDA receptors. Activation of neurokinin-1 receptors also increases the synthesis of prostaglandins whereas activation of neurokinin-3 receptors increases the synthesis of nitric oxide. Both products act as retrograde messengers across synapses and facilitate nociceptive signaling in the spinal cord. Whereas these cellular effects of CGRP and SP at the level of the spinal cord contribute to the development of increased synaptic strength between nociceptors and spinal neurons in the pathway for pain, the different intracellular signaling pathways also activate different transcription factors. The activated transcription factors initiate changes in the expression of genes that contribute to long-term changes in the excitability of spinal and maintain hyperalgesia.
伤害感受器中枢终末在脊髓释放的肽类物质会导致持续性痛觉过敏，这是慢性疼痛临床体验的特征。以P物质（SP）和降钙素基因相关肽（CGRP）为例，本综述探讨了肽能神经传递促进慢性疼痛发生和维持的多种机制。初级传入神经元终末上CGRP受体的激活促进递质释放，脊髓神经元上的受体增加AMPA受体的谷氨酸激活。这两种效应均由cAMP依赖性机制介导。P物质激活神经激肽受体（3种亚型），这些受体与磷脂酶C偶联并产生细胞内信使，其下游效应包括使膜去极化并促进AMPA和NMDA受体的功能。神经激肽-１受体的激活还会增加前列腺素的合成，而神经激肽-3受体的激活会增加一氧化氮的合成。这两种产物均作为跨突触的逆行信使，并促进脊髓中的伤害性信号传导。虽然CGRP和SP在脊髓水平的这些细胞效应有助于疼痛通路中伤害感受器与脊髓神经元之间突触强度增加的发展，但不同的细胞内信号通路也会激活不同的转录因子。激活的转录因子引发基因表达的变化，这些变化有助于脊髓兴奋性的长期改变并维持痛觉过敏。
