Cannabinoid CB2 receptors in primary sensory neurons are implicated in CB2 agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance

Abstract

Cannabinoid CB₂ agonists show therapeutic efficacy without unwanted CB₁-mediated side effects. The G protein-biased CB₂ receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks development of morphine tolerance in this model. However, the cell types involved in this phenomenon are unknown and whether this therapeutic profile is observed in female mice has never been investigated. We used conditional deletion of CB₂ receptors to determine the cell population(s) mediating the anti-allodynic and morphine-sparing effects of CB₂ agonists. Anti-allodynic effects of structurally distinct CB₂ agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB₂^f/f mice and in mice lacking CB₂ receptors in CX3CR1 expressing microglia/macrophages (CX3CR1^CRE/+; CB₂^f/f), but were absent in mice lacking CB₂ receptors in peripheral sensory neurons (Advillin^CRE/+; CB₂^f/f). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male, but not female, mice. LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the development of morphine tolerance in male CB₂^f/f and CX3CR1^CRE/+; CB₂^f/f mice with established paclitaxel-induced neuropathy but was absent in male (or female) Advillin^CRE/+; CB₂^f/f mice. Co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed morphine tolerance in paclitaxel-treated male CB₂^f/f mice, but not Advillin^CRE/+; CB₂^f/f mice of either sex. LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical or cold allodynia in either CB₂^f/f or CX3CR1^CRE/+; CB₂^f/f mice of either sex. Our findings have potential clinical implications.

Keywords: CB2; Cancer; Chemotherapy-induced peripheral neuropathy; Dorsal root ganglion; Opioid tolerance.