BACKGROUND AND PURPOSE: Cannabidiol (CBD) is a non-euphorigenic component of Cannabis sativa that prevents the development of paclitaxel-induced mechanical sensitivity in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). We recently reported that the CBD structural analogue KLS-13019 shows efficacy in an in vitro model of CIPN. The present study was to characterize the behavioural effects of KLS-13019 compared to CBD and morphine in mouse models of CIPN, nociceptive pain and reinforcement. EXPERIMENTAL APPROACH: Prevention or reversal of paclitaxel-induced mechanical sensitivity were assessed following intraperitoneal or oral administration of CBD, KLS-13019 or morphine. Antinociceptive activity using acetic acid-induced stretching and hot plate assay, anti-reinforcing effects on palatable food or morphine self-administration and binding to human opioid receptors were also determined. KEY RESULTS: Like CBD, KLS-13019 prevented the development of mechanical sensitivity associated with paclitaxel administration. In contrast to CBD, KLS-13019 was also effective at reversing established mechanical sensitivity. KLS-13019 significantly attenuated acetic acid-induced stretching and produced modest effects in the hot plate assay. KLS-13019 was devoid of activity at μ-, δ- or κ-opioid receptors. Lastly, KLS-13019, but not CBD, attenuated the reinforcing effects of palatable food or morphine. CONCLUSIONS AND IMPLICATIONS: KLS-13019 like CBD, prevented the development of CIPN, while KLS-13019 uniquely attenuated established CIPN. Because KLS-13019 binds to fewer biological targets, this will help to identifying molecular mechanisms shared by these two compounds and those unique to KLS-13019. Lastly, KLS-13019 may possess the ability to attenuate reinforced behaviour, an effect not observed in the present study with CBD.
BACKGROUND AND PURPOSE:Cannabidiol (CBD) is a non-euphorigenic component of Cannabis sativa that prevents the development of paclitaxel-induced mechanical sensitivity in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). We recently reported that the CBD structural analogue KLS-13019 shows efficacy in an in vitro model of CIPN. The present study was to characterize the behavioural effects of KLS-13019 compared to CBD and morphine in mouse models of CIPN, nociceptive pain and reinforcement. EXPERIMENTAL APPROACH: Prevention or reversal of paclitaxel-induced mechanical sensitivity were assessed following intraperitoneal or oral administration of CBD, KLS-13019 or morphine. Antinociceptive activity using acetic acid-induced stretching and hot plate assay, anti-reinforcing effects on palatable food or morphine self-administration and binding to human opioid receptors were also determined. KEY RESULTS: Like CBD, KLS-13019 prevented the development of mechanical sensitivity associated with paclitaxel administration. In contrast to CBD, KLS-13019 was also effective at reversing established mechanical sensitivity. KLS-13019 significantly attenuated acetic acid-induced stretching and produced modest effects in the hot plate assay. KLS-13019 was devoid of activity at μ-, δ- or κ-opioid receptors. Lastly, KLS-13019, but not CBD, attenuated the reinforcing effects of palatable food or morphine. CONCLUSIONS AND IMPLICATIONS: KLS-13019 like CBD, prevented the development of CIPN, while KLS-13019 uniquely attenuated established CIPN. Because KLS-13019 binds to fewer biological targets, this will help to identifying molecular mechanisms shared by these two compounds and those unique to KLS-13019. Lastly, KLS-13019 may possess the ability to attenuate reinforced behaviour, an effect not observed in the present study with CBD.
Authors: Douglas E Brenneman; William A Kinney; Mark E McDonnell; Pingei Zhao; Mary E Abood; Sara Jane Ward Journal: J Mol Neurosci Date: 2022-07-02 Impact factor: 2.866