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

Abstract

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 (Advillin^CRE/+; CB₂^f/f) and preserved in cKO mice lacking CB₂ receptors in microglia/macrophages expressing C-X3-C Motif Chemokine Receptor 1 (CX3CR1^CRE/+; CB₂^f/f). Intraplantar administration of LY2828360 (30 μg i.pl.) reversed carrageenan-induced mechanical allodynia in CB₂^f/f but not Advillin^CRE/+; CB₂^f/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.

Keywords: CB(2) receptor; Cannabinoid; Dorsal root ganglion; Inflammation; Pain.