It has been postulated that the G protein-coupled receptor, GPR55, is a third cannabinoid receptor. Given that the ligands at the CB1 and CB2 receptors are effective analgesic and anti-inflammatory agents, the role of GPR55 in hyperalgesia associated with inflammatory and neuropathic pain has been investigated. As there are no well-validated GPR55 tool compounds, a GPR55 knockout (GPR55−/−) mouse line was generated and fully backcrossed onto the C57BL/6 strain. General phenotypic analysis of GPR55−/− mice revealed no obvious primary differences, compared with wild-type (GPR55+/+) littermates. GPR55−/− mice were then tested in the models of adjuvant-induced inflammation and partial nerve ligation. Following intraplantar administration of Freund’s complete adjuvant (FCA), inflammatory mechanical hyperalgesia was completely absent in GPR55−/− mice up to 14 days post-injection. Cytokine profiling experiments showed that at 14 days post-FCA injection there were increased levels of IL-4, IL-10, IFNγ and GM-CSF in paws from the FCA-injected GPR55−/− mice when compared with the FCA-injected GPR55+/+ mice. This suggests that GPR55 signalling can influence the regulation of certain cytokines and this may contribute to the lack of inflammatory mechanical hyperalgesia in the GPR55−/− mice. In the model of neuropathic hypersensitivity, GPR55−/− mice also failed to develop mechanical hyperalgesia up to 28 days post-ligation. These data clearly suggest that the manipulation of GPR55 may have therapeutic potential in the treatment of both inflammatory and neuropathic pain.
aNeurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
bDiscovery Technology Group, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
cMolecular Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
dLaboratory Animal Sciences, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
*Corresponding author. Tel.: +44 (0)1279 622654; fax: +44 (0)1279 622555.
1Present address: Wolfson Centre for Age-Related Diseases, King’s College London, London SE1 1UL, UK.
2Present address: NGI CEDD Cognition and Neurodegeneration Centre, 11 Biopolis Way, The Helios, #03-01/02, Singapore 138667, Singapore.
Submitted September 25, 2007; revised April 2, 2008; accepted April 7, 2008.