Behavioral and pharmacological effects of cannabidiol (CBD) and the CBD analogue KLS-13019 in mouse models of pain and reinforcement
Background and purpose: Cannabidiol (CBD) is a non-euphorigenic component of Cannabis sativa which 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 goal of the present study was to characterize the behavioral pharmacological effects of KLS-13019 in comparison 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 IP or oral administration of CBD, KLS-13019, or morphine. Antinociceptive activity using acetic acid-induced stretching and hot plate, anti-reinforcing effects on palatable food or morphine self-administration, and binding to human opioid receptors were also determined.
Key results: Like CBD, IP or oral 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 also 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.
Conclusion: KLS-13019 shares CBD’s ability to prevent the development of CIPN, while KLS-13019 uniquely attenuated established CIPN. Because KLS-13019 binds to fewer biological targets, these findings can bring us closer to identifying molecular mechanisms shared by the two compounds as well as those unique to KLS-13019. Lastly, KLS-13019 may possess the ability to attenuate reinforced behavior, an effect not observed in the present study with CBD.