Behavioural and pharmacological effects of cannabidiol (CBD) and the cannabidiol analogue KLS-13019 in mouse models of pain and reinforcement

Br J Pharmacol. 2021 Aug;178(15):3067-3078. doi: 10.1111/bph.15486. Epub 2021 May 15.


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.

Keywords: Cannabidiol; KLS-13019; morphine; neuropathic pain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cannabidiol* / pharmacology
  • Disease Models, Animal
  • Mice
  • Morphine
  • Nociceptive Pain*
  • Reinforcement, Psychology


  • Cannabidiol
  • Morphine