Department of Anesthesiology, School of Medical Science, Kumamoto University, Kumamoto, Japan.
Mol Pain. 2021 Jan-Dec;17:17448069211052167. doi: 10.1177/17448069211052167.
Mirogabalin is a novel αδ ligand approved in Japan for the treatment of peripheral neuropathic pain. However, the sites of action of αδ ligands to produce analgesic effects on inflammatory pain remain unclear. In this study, we investigated the analgesic effect and site of action of mirogabalin using the rat formalin test, an acute inflammatory pain model. Mirogabalin was administered orally, intrathecally, and intracerebroventricularly. Open field tests were performed to evaluate the effect of oral-, intrathecally, and intracerebroventricularly administered mirogabalin on locomotor activity and orientation ability. Oral mirogabalin produced an analgesic effect when the formalin test was performed 4 h, but not 1 or 2 h, after oral administration. Intrathecal, but not intracerebroventricular, administration of mirogabalin produced analgesic effects when mirogabalin was administered 10 min before formalin injection. These analgesic effects were not antagonized by idazoxan, an α2 adrenergic antagonist; WAY100135, a 5-HT antagonist; or naloxone, an opioid receptor antagonist. Mirogabalin attenuated moving distances 1 and 2 h after oral administration and 10 min after intracerebroventricular administration, but not 10 min after intrathecal administration. In the oral administration group, the time course of the analgesic effect was different from that of moving distance. In the intracerebroventricular group, mirogabalin attenuated moving distances but did not produce an analgesic effect. In the intrathecal group, mirogabalin produced an analgesic effect but did not affect moving distances. These findings suggest that the analgesic effect of mirogabalin on the rat formalin test is mediated by spinal action and not by the activation of α2, 5-HT, or opioid receptors, and that the inhibitory effect of mirogabalin on moving distances is mediated by the supraspinal brain.
米拉Gabalin 是一种新型的 δ 配体在日本批准用于治疗周围神经性疼痛。然而，δ 配体作用部位产生镇痛作用的炎性疼痛仍然不清楚。在这项研究中，我们使用大鼠福尔马林试验，一种急性炎症性疼痛模型，研究米拉Gabalin 的镇痛作用和作用部位。米拉 Gabalin 口服，鞘内和脑室给药。旷场试验用于评估口服、鞘内和脑室给予米拉 Gabalin 对运动活动和定向能力的影响。口服米拉 Gabalin 在口服后 4 小时进行福尔马林试验时产生镇痛作用，但在 1 小时或 2 小时后不产生镇痛作用。鞘内但不是脑室给予米拉 Gabalin 在福尔马林注射前 10 分钟给予米拉 Gabalin 时产生镇痛作用。这些镇痛作用不能被伊达唑兰，一种 α2 肾上腺素能拮抗剂；WAY100135，5-HT 拮抗剂；或纳洛酮，一种阿片受体拮抗剂。米拉 Gabalin 减弱口服后 1 和 2 小时和脑室给药后 10 分钟的移动距离，但鞘内给药后 10 分钟不减慢移动距离。在口服给药组，镇痛作用的时程与移动距离的时程不同。在脑室给药组，米拉 Gabalin 减弱了移动距离，但没有产生镇痛作用。在鞘内给药组，米拉 Gabalin 产生了镇痛作用，但没有影响移动距离。这些发现表明米拉 Gabalin 对大鼠福尔马林试验的镇痛作用是由脊髓作用介导的，而不是由 α2、5-HT 或阿片受体的激活介导的，而米拉 Gabalin 对移动距离的抑制作用是由大脑的脊髓上部位介导的。
