Conditional deletion of CB2 cannabinoid receptors from peripheral sensory neurons eliminates CB2-mediated antinociceptive efficacy in a mouse model of carrageenan-induced inflammatory pain

CB2 cannabinoid receptor agonists suppress pathological pain in animal models and lack unwanted side effects commonly associated with direct activation of CB1 receptors. However, the types of pain most responsive to CB2 agonists are incompletely understood and cell types which underlie CB2-mediated therapeutic efficacy remain largely unknown. We previously reported that the CB2 receptor agonist LY2828360 reduced neuropathic nociception induced by toxic challenge with chemotherapeutic and anti-retroviral agents in mice. Whether these findings generalize to models of inflammatory pain is not known. Here we show that LY2828360 (10 mg/kg i.p.) reversed the maintenance of carrageenan-induced mechanical allodynia in female mice. Anti-allodynic efficacy was fully preserved in global CB1 knock out (KO) mice but absent in CB2 KO mice. The anti-allodynic efficacy of LY2828360 was absent in conditional KO (cKO) mice lacking CB2 receptors in peripheral sensory neurons (AdvillinCRE/+; CB2f/f) and preserved in cKO mice lacking CB2 receptors in microglia/macrophages expressing C-X3-C Motif Chemokine Receptor 1 (CX3CR1CRE/+; CB2f/f). Intraplantar administration of LY2828360 (30 μg i.pl.) reversed carrageenan-induced mechanical allodynia in CB2f/f but not AdvillinCRE/+; CB2f/f mice of both sexes. Thus, CB2 receptors in peripheral sensory neurons likely underlie the therapeutic effects of LY2828360 injection in the paw. Lastly, qRT-PCR analyses revealed that LY2828360 reduced carrageenan-induced increases in IL-1β and IL-10 mRNA in paw skin. Our results suggest that LY2828360 suppresses inflammatory nociception in mice through a neuronal CB2-dependent mechanism that requires peripheral sensory neuron CB2 receptors and suggest that the clinical applications of LY2828360 as an anti-hyperalgesic agent should be re-evaluated.