INTRATHECAL MK-801 AND LOCAL NERVE ANESTHESIA SYNERGISTICALLY REDUCE NOCICEPTIVE BEHAVIORS IN RATS WITH EXPERIMENTAL PERIPHERAL MONONEUROPATHY
INTRATHECAL MK-801 AND LOCAL NERVE ANESTHESIA SYNERGISTICALLY REDUCE NOCICEPTIVE BEHAVIORS IN RATS WITH EXPERIMENTAL PERIPHERAL MONONEUROPATHY
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DOI：
10.1016/0006-8993(92)90688-6
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发表时间：
1992-04-03
期刊：
影响因子：
2.9
通讯作者：
HAYES, RL
中科院分区：
文献类型：
--
作者：
MAO, J;PRICE, DD;HAYES, RL
周围神经损伤后出现的痛觉过敏和自发性疼痛可能与异常的外周输入或中枢活动改变有关，或两者兼而有之。本实验通过检测非竞争性N-甲基-D-天冬氨酸(NMDA，受体拮抗剂)MK-801和局部麻醉剂布比卡因对痛性单神经痛大鼠的热痛觉过敏和自发伤害性行为的影响来研究这些可能性。周围单神经病是通过松散结扎大鼠的坐骨神经而产生的，这一过程会导致结扎的神经的慢性缩窄性损伤(CCI)。辐射热痛敏和自发伤害性行为分别采用足部退缩试验和自发疼痛行为评定法进行评估。CCI大鼠每日4次腹腔注射(Ip)在神经结扎前15分钟开始注射MK-801(0.03、0.1、0.3 mg/kg)，在神经结扎后3、5、7、10和15天，与注射生理盐水的大鼠相比，痛敏反应较少(即较长的足部撤足潜伏期)。鞘内单次注射MK-801也可减少热痛过敏(I.T.)神经结扎后第3天移植到脊髓腰椎节段。损伤后MK-801的这种作用呈剂量依赖性(2.5-20nmol)，并持续到注射后至少48h。此外，IT。与生理盐水组相比，注射MK-801(10nmol)可靠地降低了CCI大鼠的自发疼痛行为评分。MK-801作用的脊髓部位位于尾侧(可能是腰椎)脊髓内，因为I.T.脊髓胸段注射MK-801(10nmol)对热痛敏无影响。坐骨神经结扎后3天单次注射布比卡因局部麻醉，可明显减轻24 h后的热痛敏反应，提示异常的外周输入有助于神经病理性疼痛的维持。而I.T.神经结扎后第3天给予MK-801(2.5nmoL)或局部神经麻醉可使热痛敏减轻48h以内，联合应用MK-801和布比卡因可使热痛敏减弱持续时间延长至少4d。这些数据表明，中枢阻断NMDA受体和周围神经麻醉协同作用，可减轻与痛性单神经病相关的伤害性行为。结果提示，缩窄性神经损伤后痛觉过敏和自发性疼痛行为可能与异常的外周输入和涉及NMDA受体激活的中枢活动改变有关。这些结果也为创伤后神经病理性疼痛综合征的临床治疗提供了新的方法。
The hyperalgesia and spontaneous pain that occur following peripheral nerve injury may be related to abnormal peripheral input or altered central activity, or both. The present experiments investigated these possibilities by examining the effects of MK-801 (a non-competitive N-methyl-D-aspartate, NMDA, receptor antagonist) and bupivacaine (a local anesthetic agent) on thermal hyperalgesia and spontaneous nociceptive behaviors in rats with painful peripheral mononeuropathy. Peripheral mononeuropathy was produced by loosely ligating the rat's common sciatic nerve, a procedure which causes chronic constrictive injury (CCI) of the ligated nerve. The resulting hyperalgesia to radiant heat and spontaneous nociceptive behaviors was assessed by using a foot-withdrawal test and a spontaneous pain behavior rating method, respectively. CCI rats receiving 4 daily intraperitoneal (i.p.) MK-801 injections (0.03, 0.1, 0.3 mg/kg) beginning 15 min prior to nerve ligation exhibited less hyperalgesia (i.e., longer foot-withdrawal latencies) on days 3, 5, 7, 10, and 15 after nerve ligation as compared to those receiving saline injections. Thermal hyperalgesia also was reduced when a single MK-801 injection was given intrathecally (i.t.) onto the spinal cord lumbar segments on Day 3 after nerve ligation. This effect of postinjury MK-801 treatment was dose-dependent (2.5 - 20 nmol) and lasted for at least 48 h after injection. Moreover, i.t. injection of MK-801 (10 nmol) reliably lowered spontaneous pain behavior rating scores in CCI rats compared to those in the saline group. The spinal site of MK-801 action is situated within the caudal (probably lumbar) spinal cord, since i.t. injection of MK-801 (10 nmol) onto the spinal cord thoracic segments did not affect thermal hyperalgesia. Local anesthesia of the ligated sciatic nerve induced by a single perinerve bupivacaine injection on Day 3 after nerve ligation reliably reduced thermal hyperalgesia when tested 24 h after injection, indicating that abnormal peripheral input contributes to maintenance of neuropathic pain. While i.t. MK-801 (2.5 nmol) or local nerve anesthesia on Day 3 after nerve ligation attenuated thermal hyperalgesia for less than 48 h after injection, the combined application of MK-801 and bupivacaine extended the duration of the attenuation of thermal hyperalgesia for at least 4 days after injection. The data indicate that the central blockade of NMDA receptors and peripheral nerve anesthesia synergistically attenuate nociceptive behaviors associated with painful peripheral mononeuropathy. The results suggest that hyperalgesia and spontaneous pain behaviors following constrictive nerve injury may be related to both abnormal peripheral input and altered central activity involving NMDA receptor activation. These results also suggest novel approaches to the clinical management of postinjury neuropathic pain syndromes.