Partridge B J, Chaplan S R, Sakamoto E, Yaksh T L
Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0818, USA.
Anesthesiology. 1998 Jan;88(1):196-205. doi: 10.1097/00000542-199801000-00028.
The authors sought to characterize the pharmacologic characteristic and site of action of gabapentin (Neurontin) in a model of thermal hyperalgesia induced by intrathecal substance P administration.
Rats were prepared with long-term lumbar intrathecal catheters. Hind paw withdrawal latency was determined using a radiant heat stimulus focused through a glass surface onto the plantar surface of the paw.
Within 5 min after intrathecal injection of substance P (30 nmol), hind paw withdrawal latency fell from 11 to 8 s. Gabapentin given intrathecally or intraperitoneally produced dose-dependent reversal of the thermal hyperalgesia, with complete reversal (ED100) occurring at 163 microg for intrathecal and 185 mg/kg for intraperitoneal administration. S(+)-3-isobutyl-gamma aminobutyric acid, but not R(-)-3-isobutyl-gamma aminobutyric acid, also produced dose-dependent reversal of the intrathecal substance P-induced thermal hyperalgesia (intrathecal ED100, 65 microg and intraperitonal ED100, 31 mg/kg). The effects of intraperitoneally administered gabapentin and 3-isobutyl-gamma aminobutyric acid were reversed by intrathecal pretreatment with D-serine (100 microg) but not by L-serine. All effects were observed at doses that had little effect on motor function or spontaneous activity. Intrathecal N-methyl-D-aspartate (2 nmol) induced thermal hyperalgesia, which was blocked by gabapentin (100 mg/kg intraperitoneally) and S(+)-3-isobutyl-gamma aminobutyric acid (30 mg/kg intraperitoneally).
The structure-activity relationship and the stereospecificity noted after intrathecal delivery suggest that gabapentin and S(+)-3-isobutyl-gamma aminobutyric acid act at a common spinal locus to modulate selectively a facilitated state of nociceptive processing.
作者试图在鞘内注射P物质诱导的热痛觉过敏模型中，描述加巴喷丁（Neurontin）的药理特性和作用部位。
给大鼠制备长期腰段鞘内导管。使用通过玻璃表面聚焦到爪足底表面的辐射热刺激来测定后爪缩足潜伏期。
鞘内注射P物质（30 nmol）后5分钟内，后爪缩足潜伏期从11秒降至8秒。鞘内或腹腔内给予加巴喷丁可产生剂量依赖性的热痛觉过敏逆转，鞘内给药163微克和腹腔内给药185毫克/千克时出现完全逆转（ED100）。S(+)-3-异丁基-γ-氨基丁酸而非R(-)-3-异丁基-γ-氨基丁酸也可产生剂量依赖性的鞘内P物质诱导的热痛觉过敏逆转（鞘内ED100为65微克，腹腔内ED100为31毫克/千克）。腹腔内给予加巴喷丁和3-异丁基-γ-氨基丁酸的作用可被鞘内预先注射D-丝氨酸（100微克）逆转，但不能被L-丝氨酸逆转。所有效应均在对运动功能或自发活动影响极小的剂量下观察到。鞘内注射N-甲基-D-天冬氨酸（2 nmol）诱导热痛觉过敏，这被加巴喷丁（腹腔内100毫克/千克）和S(+)-3-异丁基-γ-氨基丁酸（腹腔内30毫克/千克）阻断。
鞘内给药后观察到的构效关系和立体特异性表明，加巴喷丁和S(+)-3-异丁基-γ-氨基丁酸在共同的脊髓部位起作用，以选择性调节伤害性感受处理的易化状态。
