Wilkerson_2016_Br.J.Pharmacol_173_1678

BACKGROUND AND PURPOSE: Inhibition of diacylglycerol lipase (DGL)beta prevents LPS-induced pro-inflammatory responses in mouse peritoneal macrophages. Thus, the present study tested whether DGLbeta inhibition reverses allodynic responses of mice in the LPS model of inflammatory pain, as well as in neuropathic pain models. EXPERIMENTAL APPROACH: Initial experiments examined the cellular expression of DGLbeta and inflammatory mediators within the LPS-injected paw pad. DAGL-beta (-/-) mice or wild-type mice treated with the DGLbeta inhibitor KT109 were assessed in the LPS model of inflammatory pain. Additional studies examined the locus of action for KT109-induced antinociception, its efficacy in chronic constrictive injury (CCI) of sciatic nerve and chemotherapy-induced neuropathic pain (CINP) models. KEY
RESULTS: Intraplantar LPS evoked mechanical allodynia that was associated with increased expression of DGLbeta, which was co-localized with increased TNF-alpha and prostaglandins in paws. DAGL-beta (-/-) mice or KT109-treated wild-type mice displayed reductions in LPS-induced allodynia. Repeated KT109 administration prevented the expression of LPS-induced allodynia, without evidence of tolerance. Intraplantar injection of KT109 into the LPS-treated paw, but not the contralateral paw, reversed the allodynic responses. However, i.c.v. or i.t. administration of KT109 did not alter LPS-induced allodynia. Finally, KT109 also reversed allodynia in the CCI and CINP models and lacked discernible side effects (e.g. gross motor deficits, anxiogenic behaviour or gastric ulcers). CONCLUSIONS AND IMPLICATIONS: These findings suggest that local inhibition of DGLbeta at the site of inflammation represents a novel avenue to treat pathological pain, with no apparent untoward side effects.