The α2,3-selective potentiators of GABAA receptors, KRM-II-81 and MP-III-80, produce anxiolytic-like effects and block chemotherapy-induced hyperalgesia in mice without tolerance development

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2020-09, Vol.196, p.172996-172996, Article 172996
• Main Authors: Biggerstaff, A., Kivell, B., Smith, J.L., Mian, Md Y., Golani, L.K., Rashid, F., Sharmin, D., Knutson, D.E., Cerne, R., Cook, J.M., Witkin, J.M.
• Format: Article
• Language: English
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2020.172996

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 GABAA 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 GABAA 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 GABAA 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. •α2,3-selective potentiators of GABAA receptors, KRM-II-81 and MP-III-80 were studied.•Compounds inhibited pain behaviors in paclitaxel-treated mice.•Compounds demonstrated enduring analgesic efficacy without tolerance development.•KRM-II-81 and MP-III-80 produced anxiolytic-like decreases in marble-burying.