Chronic Cannabinoid Receptor 2 Activation Reverses Paclitaxel Neuropathy Without Tolerance or Cannabinoid Receptor 1–Dependent Withdrawal

Background Mixed cannabinoid receptor 1 and 2 (CB 1 and CB 2 ) agonists such as Δ 9 -tetrahydrocannabinol (Δ 9 -THC) can produce tolerance, physical withdrawal, and unwanted CB 1 -mediated central nervous system side effects. Whether repeated systemic administration of a CB 2 -preferring agonist engages CB 1 receptors or produces CB 1 -mediated side effects is unknown. Methods We evaluated antiallodynic efficacy, possible tolerance, and cannabimimetic side effects of repeated dosing with a CB 2 -preferring agonist AM1710 in a model of chemotherapy-induced neuropathy produced by paclitaxel using CB 1 knockout (CB 1 KO), CB 2 knockout (CB 2 KO), and wild-type (WT) mice. Comparisons were made with the prototypic classic cannabinoid Δ 9 -THC. We also explored the site and possible mechanism of action of AM1710. Results Paclitaxel-induced mechanical and cold allodynia developed to an equivalent degree in CB 1 KO, CB 2 KO, and WT mice. Both AM1710 and Δ 9 -THC suppressed established paclitaxel-induced allodynia in WT mice. In contrast to Δ 9 -THC, chronic administration of AM1710 did not engage CB 1 activity or produce antinociceptive tolerance, CB 1 -mediated cannabinoid withdrawal, hypothermia, or motor dysfunction. Antiallodynic efficacy of systemic administration of AM1710 was absent in CB 2 KO mice and WT mice receiving the CB 2 antagonist AM630, administered either systemically or intrathecally. Intrathecal administration of AM1710 also attenuated paclitaxel-induced allodynia in WT mice, but not CB 2 KO mice, implicating a possible role for spinal CB 2 receptors in AM1710 antiallodynic efficacy. Finally, both acute and chronic administration of AM1710 decreased messenger RNA levels of tumor necrosis factor-α and monocyte chemoattractant protein 1 in lumbar spinal cord of paclitaxel-treated WT mice. Conclusions Our results highlight the potential of prolonged use of CB 2 agonists for managing chemotherapy-induced allodynia with a favorable therapeutic ratio marked by sustained efficacy and absence of tolerance, physical withdrawal, or CB 1 -mediated side effects.