Opiate analgesics are one of the treatment options for severe chronic pain, including late-stage cancer, chronic back pain and other disorders. The recent resurgence in opioid overdose has highlighted the serious need for alternative medicines for pain management. While a role for potentiators of α2/3-containing GABA_A receptors in the modulation of pain has been known for several years, advancements in this area required data from selective compounds. KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3- yl)oxazole) and analogs selectively potentiate GABA_A receptors containing α2/3 subunits and have recently been shown to attenuate pain behaviors in several acute and chronic pain models in rodents. The present study was designed to ascertain whether KRM-II-81 and the structural analog MP-III-80 (3-ethyl-5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)-1,2,4-oxadiazole) would block chemotherapeutic agent paclitaxel-induced pain in male, C57BL/6 mice. Both compounds significantly inhibited pain behaviors evoked by cold and tactile stimulation in paclitaxel-treated mice as did the neuropathic pain drug gabapentin. Subchronic dosing for 22 days with KRM-II-81 and MP-III-80 demonstrated enduring analgesic efficacy without tolerance development, while the effects of gabapentin showed evidence of tolerance development. KRM-II-81 and MP-III-80 also decreased marble-burying behavior in this mouse strain as did the anxiolytic drug chlordiazepoxide. In contrast to KRM-II-81 and MP-III-80, chlordiazepoxide had motor-impairing effects at anxiolytic-like doses. The data add to the literature documenting that these selective potentiators of α2/3-containing GABA_A receptors are effective in a host of animal models used to detect novel analgesic drugs. The anxiolytic-like efficacy of these compounds fits well with the comorbidity of anxiety in patients with chronic pain and cancer.

阿片类镇痛药是严重的慢性疼痛（包括晚期癌症，慢性背痛和其他疾病）的治疗选择之一。阿片类药物过量的近期复苏表明，迫切需要替代药物来治疗疼痛。尽管几年来已知含α2/ 3的GABA _A受体增强剂在调节疼痛中的作用，但该领域的进展需要选择性化合物的数据。KRM-II-81（5-（8-乙炔基-6-（吡啶-2-基）-4 ] H-苯并[ f ]咪唑并[1,5- a ] [1,4]二氮杂-3--3-基）恶唑）和类似物选择性增强GABA _A含有α2/ 3亚基的受体，最近在啮齿动物的几种急性和慢性疼痛模型中显示出可减轻疼痛的行为。本研究旨在确定KRM-II-81和结构类似物MP-III-80（3-乙基-5-（8-乙炔基-6-（吡啶-2-基）-4H-苯并[ f]咪唑并[1,5-a] [1,4]二氮杂pin-3-基）-1,2,4-恶二唑）会阻止化疗剂紫杉醇引起的雄性C57BL / 6小鼠疼痛。两种化合物均能显着抑制紫杉醇治疗小鼠的感冒和触觉刺激引起的疼痛行为，神经性镇痛药加巴喷丁也是如此。用KRM-II-81和MP-III-80亚慢性给药22天可显示持久的镇痛效果，而不会产生耐受性，而加巴喷丁的作用则显示出耐受性增强的证据。KRM-II-81和MP-III-80也在该小鼠品系中降低了大理石埋藏行为，就像抗焦虑药氯二氮卓一样。与KRM-II-81和MP-III-80相比，氯二氮卓在抗焦虑药样剂量下具有运动损伤作用。数据增加了文献记载，这些含α2/ 3的GABA选择性增效剂_甲受体是有效的用于检测新的镇痛药的动物模型的宿主。这些化合物的抗焦虑药功效与慢性疼痛和癌症患者的焦虑症并存。