Luo Z D, Calcutt N A, Higuera E S, Valder C R, Song Y-H, Svensson C I, Myers R R
Department of Anesthesiology, University of California San Diego, La Jolla, California 92093-0818, USA.
J Pharmacol Exp Ther. 2002 Dec;303(3):1199-205. doi: 10.1124/jpet.102.041574.
The calcium channel alpha2delta-1 subunit is a structural subunit important for functional calcium channel assembly. In vitro studies have shown that this subunit is the binding site for gabapentin, an anticonvulsant that exerts antihyperalgesic effects by unknown mechanisms. Increased expression of this subunit in the spinal cord and dorsal root ganglia (DRG) has been suggested to play a role in enhanced nociceptive responses of spinal nerve-injured rats to innocuous mechanical stimulation (allodynia). To investigate whether a common mechanism underlies allodynic states derived from different etiologies, and if so, whether similar alpha2delta-1 subunit up-regulation correlates with these allodynic states, we compared DRG and spinal cord alpha2delta-1 subunit levels and gabapentin sensitivity in allodynic rats with mechanical nerve injuries (sciatic nerve chronic constriction injury, spinal nerve transection, or ligation), a metabolic disorder (diabetes), or chemical neuropathy (vincristine neurotoxicity). Our data indicated that even though allodynia occurred in all types of nerve injury investigated, DRG and/or spinal cord alpha2delta-1 subunit up-regulation and gabapentin sensitivity only coexisted in the mechanical and diabetic neuropathies. Thus, induction of the alpha2delta-1 subunit in the DRG and spinal cord is likely regulated by factors that are specific for individual neuropathies and may contribute to gabapentin-sensitive allodynia. However, the calcium channel alpha2delta-1 subunit is not the sole molecular change that uniformly characterizes the neuropathic pain states.
钙通道α2δ-1亚基是功能性钙通道组装的重要结构亚基。体外研究表明，该亚基是加巴喷丁的结合位点，加巴喷丁是一种抗惊厥药，其通过未知机制发挥抗痛觉过敏作用。脊髓和背根神经节（DRG）中该亚基表达增加被认为在脊髓神经损伤大鼠对无害机械刺激（异常性疼痛）的伤害性反应增强中起作用。为了研究不同病因引起的异常性疼痛状态是否存在共同机制，如果存在，类似的α2δ-1亚基上调是否与这些异常性疼痛状态相关，我们比较了机械性神经损伤（坐骨神经慢性压迫损伤、脊髓神经横断或结扎）、代谢紊乱（糖尿病）或化学性神经病（长春新碱神经毒性）所致异常性疼痛大鼠的DRG和脊髓α2δ-1亚基水平及加巴喷丁敏感性。我们的数据表明，尽管在所研究的所有类型神经损伤中均出现了异常性疼痛，但DRG和/或脊髓α2δ-1亚基上调及加巴喷丁敏感性仅在机械性和糖尿病性神经病中同时存在。因此，DRG和脊髓中α2δ-1亚基的诱导可能受个体神经病特异性因素的调节，并可能导致对加巴喷丁敏感的异常性疼痛。然而，钙通道α2δ-1亚基并非统一表征神经病理性疼痛状态的唯一分子变化。
