Pitcher Mark H, Price Theodore J, Entrena Jose M, Cervero Fernando
McGill University, Anesthesia Research Unit, Faculty of Medicine, Faculty of Dentistry and McGill Centre for Research on Pain, Montreal, QC, Canada.
Mol Pain. 2007 Jun 30;3:17. doi: 10.1186/1744-8069-3-17.
The Na+, K+, 2Cl- type I cotransporter (NKCC1) and TRPV1 receptors, at the level of the dorsal horn, have been implicated in mediating allodynia in response to an inflammatory insult. The NKCC1 cotransporter regulates intracellular [Cl-] and thus the magnitude and polarity of GABAA receptor responses in neurons. TRPV1 receptors transduce diverse chemical and natural stimuli in nociceptors and are critical for inflammatory hyperalgesia.
Here we have tested the role of spinal NKCC1 cotransporters and TRPV1 receptors in referred allodynia in a model of visceral hyperalgesia in mice. Intrathecal (IT) injection of the NKCC1 inhibitor bumetanide (BUM, 1 nmol) inhibited referred, abdominal allodynia evoked by an intracolonic capsaicin injection. BUM was effective when injected IT either before or up to 4 hrs after the establishment of referred allodynia. The TRPV1 antagonist AMG 9810 (1 nmol) also inhibited referred allodynia in this model suggesting the involvement of an endogenous TRPV1 agonist in the dorsal horn in referred allodynia. In support of this suggestion, the endovanilloid TRPV1 agonist, narachidonoyl- dopamine (NADA, 1 or 10 nmol, IT) evoked stroking allodynia in the hindpaw that was blocked by co-treatment with AMG 9810 (1 nmol). The TRPV1-dependent stroking allodynia caused by NADA appeared to be functionally linked to NKCC1 because BUM (1 nmol) also inhibited NADA-evoked stroking allodynia.
Our findings indicate that spinal NKCC1 and TRPV1 are critical for referred allodynia mediated by a painful visceral stimulus. Moreover, they suggest that endogenous TRPV1 agonists, released in the CNS in painful conditions, might stimulate TRPV1 receptors on primary afferents that, in turn, play a role in increasing NKCC1 activity leading to allodynia.
在背角水平，钠钾氯同向转运体1型（NKCC1）和瞬时感受器电位香草酸受体1（TRPV1）与介导炎症刺激引起的痛觉过敏有关。NKCC1协同转运蛋白调节细胞内[Cl-]，进而调节神经元中GABAA受体反应的幅度和极性。TRPV1受体转导伤害性感受器中的多种化学和自然刺激，对炎症性痛觉过敏至关重要。
在此，我们在小鼠内脏痛觉过敏模型中测试了脊髓NKCC1协同转运蛋白和TRPV1受体在牵涉性痛觉过敏中的作用。鞘内注射NKCC1抑制剂布美他尼（BUM，1 nmol）可抑制结肠内注射辣椒素诱发的牵涉性腹部痛觉过敏。在牵涉性痛觉过敏建立前或建立后4小时内鞘内注射BUM均有效。TRPV1拮抗剂AMG 9810（1 nmol）在该模型中也能抑制牵涉性痛觉过敏，提示背角内源性TRPV1激动剂参与牵涉性痛觉过敏。支持这一观点的是，内源性类香草酸TRPV1激动剂花生四烯酰多巴胺（NADA，1或10 nmol，鞘内注射）诱发后爪轻触痛觉过敏，与AMG 9810（1 nmol）共同处理可阻断该反应。NADA引起的依赖TRPV1的轻触痛觉过敏似乎在功能上与NKCC1相关，因为BUM（1 nmol）也能抑制NADA诱发的轻触痛觉过敏。
我们的研究结果表明，脊髓NKCC1和TRPV1对由内脏疼痛刺激介导的牵涉性痛觉过敏至关重要。此外，研究结果提示，在疼痛状态下中枢神经系统释放的内源性TRPV1激动剂可能刺激初级传入神经上的TRPV1受体，进而在增加NKCC1活性导致痛觉过敏中发挥作用。
