In mouse the
cannabinoid receptor 2 (CB2) agonists L768242 and (+)-
AM1241, at doses of 30 mg/kg i.p. and 1 and 3 mg/kg i.v., respectively, reduced the second phase of nocifensive behaviors elicited by
formalin intraplantar injection. This effect was counteracted by the selective CB2 antagonist
SR144528 (1 mg/kg i.p.). In rat (+)-
AM1241 (3 and 6 mg/kg i.v.) and L768242 (30 mg/kg i.p.) reduced
allodynia elicited by L5-L6 spinal nerve
ligation.
SR144528 reverted these effects, supporting a CB2-mediated action. To clarify the mechanisms underlying these effects we investigated CB2 gene expression and function in the nervous system. CB2
mRNA was expressed in spinal cord and dorsal root ganglia (DRG) of both
sham and neuropathic rats and was up-regulated in the ipsilateral spinal cord of neuropathic rats. Expression studies demonstrated the presence of CB2
mRNA in culture of spinal cord microglia. A
biomarker, CGRP, was used to investigate modulation of DRG primary afferents by CB2 agonists. Both L768242 and (+)-
AM1241 dose dependently (EC50 of 3.6 and 4.5 nM, respectively) reduced
capsaicin-induced
calcitonin gene-related peptide (CGRP) release. Coadministration of
SR144528 resulted in a rightforward shift (pKB 8.1 and 8.2 for (+)-
AM1241 and L768242, respectively) of the dose-response curve. Experiments on
capsaicin-induced CGRP release in tissue from CB1-/- mice ruled out a CB1-mediated effect. These results confirm that CB2 is present in the central nervous system and suggest that CB2 agonists may elicit their
analgesic effect by acting not only at non-neuronal peripheral sites but also at neural level, making CB2 an attractive target for
chronic pain treatment.