Pogatzki Esther M, Niemeier Jan S, Sorkin Linda S, Brennan Timothy J
Department of Anesthesia, University of Iowa, 200 Hawkins Drive 6 JCP, Iowa City, IA 52242, USA.
Pain. 2003 Sep;105(1-2):97-107. doi: 10.1016/s0304-3959(03)00169-6.
Secondary mechanical hyperalgesia has been demonstrated in postoperative patients indicating that central sensitization occurs after surgery. However, the underlying mechanisms are unknown. Here, we studied the role of spinal N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate receptors for pain behaviors indicating secondary hyperalgesia caused by gastrocnemius incision in the rat. We further determined if Ca(2+) permeable AMPA/kainate receptors are important for secondary hyperalgesia after gastrocnemius incision and for pain behaviors indicating primary hyperalgesia and guarding behavior after plantar incision. Withdrawal thresholds (WTs) to punctate mechanical stimuli were assessed by applying calibrated monofilaments to the plantar hind paw before gastrocnemius incision. WTs were tested again 2 h after gastrocnemius incision and again after intrathecal (IT) injection of either dizocilpine maleate (MK-801), 2-amino-5-phosphonovaleric acid (AP5), 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX), or Joro spider toxin (JSTX). The doses used were: MK-801 (vehicle, 15, 30, 40 nmol), AP5 (vehicle, 10, 30 nmol), NBQX (vehicle, 5, 10 nmol), and JSTX (vehicle, 2, 5, 9 nmol). In the same rats, WTs were tested on postoperative day 2 before and after the same drugs were injected again. In other rats, WTs to monofilaments and response frequencies to a non-punctate mechanical stimulus or guarding behaviors were determined before, 1 h after plantar incision was made, and assessed again after JSTX (9 nmol or vehicle) was administered IT. Secondary mechanical hyperalgesia after gastrocnemius incision was dose-dependently blocked by NBQX but was only marginally affected by AP5 or MK-801. Only secondary mechanical hyperalgesia was reversed by JSTX; primary mechanical hyperalgesia and guarding behavior were unchanged. These results indicate that spinal sensitization contributing to behaviors for secondary hyperalgesia after incision requires Ca(2+) permeable AMPA/kainate receptors. The data further demonstrate that behaviors for secondary mechanical hyperalgesia after incision can be inhibited without affecting behaviors for primary mechanical hyperalgesia and guarding. Mechanisms for central sensitization causing secondary hyperalgesia in postoperative patients may therefore be separated from spontaneous pain and hyperalgesia that arises adjacent to the area of the incision.
术后患者已证实存在继发性机械性痛觉过敏，这表明手术后会发生中枢敏化。然而，其潜在机制尚不清楚。在此，我们研究了脊髓 N-甲基-D-天冬氨酸和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/海人藻酸受体在大鼠腓肠肌切开引起的继发性痛觉过敏相关疼痛行为中的作用。我们进一步确定 Ca(2+) 通透性 AMPA/海人藻酸受体对于腓肠肌切开后的继发性痛觉过敏以及足底切开后的原发性痛觉过敏和保护性行为相关疼痛行为是否重要。在腓肠肌切开前，通过将校准的单丝施加于后足底来评估对点状机械刺激的撤针阈值（WTs）。在腓肠肌切开后 2 小时以及鞘内注射马来酸氯氮平（MK-801）、2-氨基-5-膦酰戊酸（AP5）、1,2,3,4-四氢-6-硝基-2,3-二氧代[f]喹喔啉-7-磺酰胺（NBQX）或乔罗蜘蛛毒素（JSTX）后再次测试 WTs。所用剂量为：MK-801（溶剂，15、30、40 nmol）、AP5（溶剂，10、30 nmol）、NBQX（溶剂，5、10 nmol）和 JSTX（溶剂，2、5、9 nmol）。在同一批大鼠中，在再次注射相同药物前后的术后第 2 天测试 WTs。在其他大鼠中，在足底切开前、切开后 1 小时以及鞘内注射 JSTX（9 nmol 或溶剂）后再次评估对单丝的 WTs 以及对非点状机械刺激的反应频率或保护性行为。腓肠肌切开后的继发性机械性痛觉过敏被 NBQX 剂量依赖性阻断，但仅受到 AP5 或 MK-801 的轻微影响。只有 JSTX 能逆转继发性机械性痛觉过敏；原发性机械性痛觉过敏和保护性行为未改变。这些结果表明，脊髓敏化对切开后继发性痛觉过敏行为的影响需要 Ca(2+) 通透性 AMPA/海人藻酸受体。数据进一步表明，切开后继发性机械性痛觉过敏行为可被抑制，而不影响原发性机械性痛觉过敏和保护性行为。因此，术后患者中导致继发性痛觉过敏的中枢敏化机制可能与切口区域附近出现的自发疼痛和痛觉过敏相分离。
