Abstract
CB(2) cannabinoid receptor agonists suppress pathological pain in animal models and lack unwanted side effects commonly associated with direct activation of CB(1) receptors. However, the types of pain most responsive to CB(2) agonists are incompletely understood and cell types which underlie CB(2)-mediated therapeutic efficacy remain largely unknown. We previously reported that the CB(2) 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 CB(1) knock out (KO) mice but absent in CB(2) KO mice. The anti-allodynic efficacy of LY2828360 was absent in conditional KO (cKO) mice lacking CB(2) receptors in peripheral sensory neurons (Advillin(CRE/+); CB(2)(f/f)) and preserved in cKO mice lacking CB(2) receptors in microglia/macrophages expressing C-X3-C Motif Chemokine Receptor 1 (CX3CR1(CRE/+); CB(2)(f/f)). Intraplantar administration of LY2828360 (30 μg i.pl.) reversed carrageenan-induced mechanical allodynia in CB(2)(f/f) but not Advillin(CRE/+); CB(2)(f/f) mice of both sexes. Thus, CB(2) 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 CB(2)-dependent mechanism that requires peripheral sensory neuron CB(2) receptors and suggest that the clinical applications of LY2828360 as an anti-hyperalgesic agent should be re-evaluated.