Cannabinoid CB ₂ receptors in primary sensory neurons are implicated in CB ₂ agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance

Cannabinoid CB ₂ agonists show therapeutic efficacy without the unwanted side effects commonly associated with direct activation of CB ₁ receptors. The G protein-biased CB ₂ receptor agonist LY2828360 attenuates the maintenance of chemotherapy-induced neuropathic nociception in male mice and blocks the development of morphine tolerance in this model. However, the specific cell types involved in this phenomenon have never been investigated and whether this therapeutic profile is observed in female mice remains poorly understood. We used conditional deletion of CB ₂ receptors from specific cell populations to determine the population(s) mediating the anti-allodynic and morphine-sparing effects of CB ₂ agonists. Anti-allodynic effects of structurally distinct CB ₂ agonists (LY2828360 and AM1710) were present in paclitaxel-treated CB ₂ ^f/f mice of either sex. The anti-allodynic effect of the CB ₂ agonists were absent in conditional knockout (KO) mice lacking CB ₂ receptors in peripheral sensory neurons (Advillin ^CRE/+ ; CB ₂ ^f/f ) but preserved in mice lacking CB ₂ receptors in CX3CR1 expressing microglia/macrophages (CX3CR1 ^CRE/+ ; CB ₂ ^f/f ). The morphine-sparing effect of LY28282360 occurred in a sexually-dimorphic manner, being present in male mice but absent in female mice of any genotype. In mice with established paclitaxel-induced neuropathy, prior LY2828360 treatment (3 mg/kg per day i.p. x 12 days) blocked the subsequent development of morphine tolerance in male CB ₂ ^f/f mice but was absent in male (or female) Advillin ^CRE/+ ; CB ₂ ^f/f mice. LY2828360-induced sparing of morphine tolerance was preserved in male CX3CR1 ^CRE/+ ; CB ₂ ^f/f mice, but this effect was not observed in female CX3CR1 ^CRE/+ ; CB ₂ ^f/f mice. Similarly, co-administration of morphine with a low dose of LY2828360 (0.1 mg/kg per day i.p. x 6 days) reversed tolerance to the anti-allodynic efficacy of morphine in paclitaxel-treated male CB ₂ ^f/f mice, but this effect was absent in female CB ₂ ^f/f mice and Advillin ^CRE/+ ; CB ₂ ^f/f mice of either sex. Additionally, LY2828360 (3 mg/kg per day i.p. x 8 days) delayed, but did not prevent, the development of paclitaxel-induced mechanical and cold allodynia in either CB ₂ ^f/f or CX3CR1 ^CRE/+ ; CB ₂ ^f/f mice of either sex. Our studies reveal that CB ₂ receptors in primary sensory neurons are required for the anti-allodynic effects of CB ₂ agonists in a mouse model of paclitaxel-induced neuropathic nociception. We also find that CB ₂ agonists acting on primary sensory neurons produce a sexually-dimorphic sparing of morphine tolerance in males, but not female, paclitaxel-treated mice.