Parada Carlos Amilcar, Vivancos Gustavo Gameiro, Tambeli Claudia Herrera, Cunha Fernando de Queiróz, Ferreira Sérgio Henrique
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, 14049-900, São Paulo, Brazil.
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2923-8. doi: 10.1073/pnas.252777799. Epub 2003 Feb 14.
The present study investigated whether activation of presynaptic N-methyl-d-aspartate (NMDA) receptors in the spinal cord produces a retrograde nociceptor sensitization (hypernociception) to mechanical nonnoxious stimulus. By using an electronic version of the von Frey hair test (pressure meter), s.c. intraplantar administration of prostaglandin E(2) (PGE(2)) (50-400 ng per paw) evoked a dose-related ipsilateral paw hypernociception. In contrast, intrathecal (i.t.) administration of NMDA (5-80 ng) and PGE(2) (15-150 ng) evoked dose-related bilateral paw hypernociception. The s.c. intraplantar administration of dipyrone (80-320 microg per paw) or morphine (3 and 9 microg per paw), usually used to antagonize peripheral PGE(2) (100 ng per paw), induced hypernociception and also antagonized the ipsilateral (without affecting the contralateral) paw hypernociception induced by i.t. injections of NMDA (40 ng) or PGE(2) (50 ng). These doses of drugs did not modify the basal mechanical sensitivity of control paws. This result shows that intraspinal NMDA or PGE(2) produces sensitization of the primary sensory neuron in response to mechanical stimulation. In a second series of experiments it was shown that the i.t. treatment with NaV1.8 (SNS/PN3) sodium channel antisense oligodeoxynucleotides, but not mismatch oligodeoxynucleotides, decreased the mRNA expression of sodium tetrodotoxin-resistant channels on the dorsal root ganglia and abolished the mechanical hypernociception induced by i.t. administration of NMDA. Thus, our results support the suggestion that glutamate release in the spinal cord during inflammation causes retrograde hypernociception of nociceptors associated with sodium tetrodotoxin-resistant channels in primary nociceptive sensory neurons.
本研究调查了脊髓中突触前N-甲基-D-天冬氨酸（NMDA）受体的激活是否会对机械性非伤害性刺激产生逆行性伤害感受器敏化（痛觉过敏）。通过使用电子von Frey毛发测试（压力计），足底皮下注射前列腺素E2（PGE2）（每只爪50 - 400 ng）可诱发剂量相关的同侧爪痛觉过敏。相比之下，鞘内注射NMDA（5 - 80 ng）和PGE2（15 - 150 ng）可诱发剂量相关的双侧爪痛觉过敏。通常用于拮抗外周PGE2（每只爪100 ng）的足底皮下注射安乃近（每只爪80 - 320 μg）或吗啡（每只爪3和9 μg）会诱发痛觉过敏，并且还能拮抗鞘内注射NMDA（40 ng）或PGE2（50 ng）所诱导的同侧爪（不影响对侧爪）痛觉过敏。这些药物剂量并未改变对照爪的基础机械敏感性。该结果表明，脊髓内的NMDA或PGE2会使初级感觉神经元对机械刺激产生敏化。在第二系列实验中表明，鞘内用NaV1.8（SNS/PN3）钠通道反义寡脱氧核苷酸而非错配寡脱氧核苷酸进行处理，可降低背根神经节上对河豚毒素耐药通道的mRNA表达，并消除鞘内注射NMDA所诱导的机械性痛觉过敏。因此，我们的结果支持以下观点：炎症期间脊髓中的谷氨酸释放会导致与初级伤害性感觉神经元中对河豚毒素耐药通道相关的伤害感受器逆行性痛觉过敏。
