Vanderah T W, Laughlin T, Lashbrook J M, Nichols M L, Wilcox G L, Ossipov M H, Malan T P, Porreca F
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson 85724, USA.
Pain. 1996 Dec;68(2-3):275-81. doi: 10.1016/s0304-3959(96)03225-3.
Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.
神经病理性疼痛状态伴随着对伤害性和非伤害性感觉刺激的敏感性增加，分别表现为痛觉过敏和异常性疼痛。在神经病理性疼痛的动物模型中，痛觉过敏和异常性疼痛的存在伴随着神经可塑性变化，包括脊髓中P物质、胆囊收缩素（CCK）和强啡肽水平的升高。N-甲基-D-天冬氨酸（NMDA）受体似乎参与维持导致神经病理性疼痛的中枢敏感性。除了其阿片样活性外，强啡肽还被认为作用于NMDA受体复合物。为了模拟在神经病理性疼痛动物模型中观察到的脊髓强啡肽水平升高，大鼠通过留置导管接受鞘内（i.t.）单次注射强啡肽A（1-17）、强啡肽A（1-13）、强啡肽A（2-17）或强啡肽A（2-13）。通过测量对用von Frey细丝探测的反应阈值来确定触觉异常性疼痛。给予强啡肽A（1-17）诱发显著且持久的触觉异常性疼痛（即>60天）。同样，鞘内给予强啡肽A（1-13）、强啡肽A（2-17）或强啡肽A（2-13）也产生持久的触觉异常性疼痛。用MK-801进行鞘内预处理而非后处理可预防强啡肽A（1-17）诱导的异常性疼痛的发展；单独鞘内给予MK-801对触觉刺激反应无影响。相反，用纳洛酮进行鞘内预处理不影响强啡肽A（1-17）诱导的触觉异常性疼痛的发展，单独给予时也不改变感觉阈值。这些结果表明，单剂量的强啡肽A或其去酪氨酸片段会产生持久的异常性疼痛，这在大鼠中可能是不可逆的。此外，这种作用似乎是通过NMDA而非阿片样受体的激活介导的。虽然异常性疼痛发生和维持的精确机制尚不清楚，但强啡肽可能在脊髓中产生变化，这可能导致出现类似于“神经病理性”状态的体征。鉴于神经损伤后强啡肽水平升高，推测强啡肽在神经病理性疼痛状态中可能具有病理相关作用似乎是合理的。
