Gil Daniel W, Cheevers Cynthia V, Kedzie Karen M, Manlapaz Cynthia A, Rao Sandhya, Tang Elaine, Donello John E
Department of Biological Sciences, Allergan, Inc., Irvine, California 92612, USA.
Anesthesiology. 2009 Feb;110(2):401-7. doi: 10.1097/ALN.0b013e3181943226.
The use of alpha-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist mediated analgesia may identify strategies to separate the analgesic from sedative and cardiovascular effects.
Analgesic activity of brimonidine, clonidine, and tizanidine was investigated in wild-type C57B/6, alpha-2A, and alpha-2C knockout mice with allodynia induced by N-methyl-D-aspartate or sulprostone. The alpha receptor selectivity of the alpha agonists was assessed using functional in vitro recombinant assays.
Brimonidine, clonidine, and tizanidine reduced N-methyl-D-aspartate- and sulprostone-induced allodynia in wild-type mice, but not alpha-2A knockout mice. In alpha-2C knockout mice, brimonidine and tizanidine reduced allodynia in both models, whereas clonidine only reduced N-methyl-D-aspartate-induced allodynia. In vitro, clonidine and tizanidine activated alpha-1 and alpha-2 receptors with similar potencies, whereas brimonidine was selective for alpha-2 receptors. In alpha-2C knockout mice with sulprostone-induced allodynia, blockade of clonidine's alpha-1 receptor agonist activity restored clonidine's analgesic efficacy. In wild-type mice, the analgesic potency of intrathecal clonidine and tizanidine was increased 3- to 10-fold by coadministration with the alpha-1A-selective antagonist 5-methylurapidil without affecting sedation. Following intraperitoneal administration, the therapeutic window was negligible for clonidine and tizanidine, but greater for brimonidine. 5-Methylurapidil enhanced the therapeutic window of intraperitoneal clonidine and tizanidine approximately 10-fold.
Alpha-1A receptor agonist activity can counterbalance alpha-2 receptor agonist-induced analgesia. Greater alpha-2 selectivity may enhance the therapeutic window of alpha-2 agonists in the treatment of pain.
由于治疗窗狭窄，α-2肾上腺素能激动剂在镇痛方面的应用受到限制。明确α受体亚型在α激动剂介导的镇痛中的作用，可能有助于找到将镇痛作用与镇静和心血管作用相分离的策略。
在由N-甲基-D-天冬氨酸或舒前列素诱导产生异常性疼痛的野生型C57B/6、α-2A和α-2C基因敲除小鼠中，研究溴莫尼定、可乐定和替扎尼定的镇痛活性。使用功能性体外重组试验评估α激动剂的α受体选择性。
溴莫尼定、可乐定和替扎尼定可减轻野生型小鼠中由N-甲基-D-天冬氨酸和舒前列素诱导的异常性疼痛，但对α-2A基因敲除小鼠无效。在α-2C基因敲除小鼠中，溴莫尼定和替扎尼定在两种模型中均可减轻异常性疼痛，而可乐定仅能减轻由N-甲基-D-天冬氨酸诱导的异常性疼痛。在体外，可乐定和替扎尼定对α-1和α-2受体的激活效力相似，而溴莫尼定对α-2受体具有选择性。在由舒前列素诱导产生异常性疼痛的α-2C基因敲除小鼠中，阻断可乐定的α-1受体激动剂活性可恢复其镇痛效果。在野生型小鼠中，鞘内注射可乐定和替扎尼定并同时给予α-1A选择性拮抗剂5-甲基乌拉地尔时，镇痛效力提高了3至10倍，且不影响镇静作用。腹腔注射后，可乐定和替扎尼定的治疗窗可忽略不计，而溴莫尼定的治疗窗更大。5-甲基乌拉地尔使腹腔注射可乐定和替扎尼定的治疗窗增大了约10倍。
α-1A受体激动剂活性可抵消α-2受体激动剂诱导的镇痛作用。更高的α-2选择性可能会提高α-2激动剂在疼痛治疗中的治疗窗。
