Repeated administration of the selective cannabinoid CB2 receptor agonist GSK554418A results in maintained analgesia in rodent models of chronic inflammatory pain

Alex Wilson, Nick Clayton, Andy Billinton, Ged Giblin, Iain Chessell, GlaxoSmithKline, Harlow, ESSEX, United Kingdom.

GSK554418A (N-(3-chlorophenyl)-1-methyl-7-(4-morpholinylcarbonyl)-1H-pyrrolo[3,2-c]pyridin-4-amine hydrochloride) is a novel, potent and highly selective agonist at the cannabinoid CB2 receptor (Michel et al. 2007, this meeting). Therapeutic acute oral administration of GSK554418A has been shown to reverse hypersensitivity states induced by Complete Freund’s Aduvant (CFA) which are blocked by a selective CB2 receptor agonist AM630 (Clayton et al. 2007, this meeting). The aim of this study was to further investigate the effects of GSK554418A following repeated administration in an acute CFA model to address tolerance as well as in a model of chronic inflammatory joint pain. Male Random Hooded rats (180-240g, Bantin and Kingman) were used for both studies. For the tolerance study, animals were assessed for naïve weight bearing in a rat incapacitance tester (Linton Instrumentation, UK), followed immediately by an intraplantar injection (using light restraint) of 100μl CFA (containing 1mg.ml-1 heat killed mycobacterium tuberculosis). Weight bearing was repeated 23 hr later to assess the CFA-induced shift in weight bearing (hypersensitivity). Animals received GSK554418A 1mg.kg-1 (a dose previously demonstrated to result in maximal reversal of hypersensitivity in this model), or vehicle b.i.d. for 10 days (n= 7/group) and were assessed for weight bearing 1 hr post dose on each day. GSK554418A resulted in a statistically meaningful reversal of CFA-induced hypersensitivity compared with vehicle (p<0.05) on all days with no significant difference in reversal level across the dosing regimen (reversal ranging from 70.51±10.5 to 97.5±9.0) suggesting a lack of tolerance over this period. In the chronic inflammatory joint pain model animals were assessed for naïve weight bearing followed by intra-articular injection of 150μl CFA under light gaseous anaesthesia. Animals were assessed for weight bearing over the next 10 days to ensure a stable hypersensitivity response, after which animals received either GSK554418 (1-10mg.kg-1), rofecoxib (5mg.kg-1) or vehicle, (p.o., b.i.d.) over days 13-17. GSK554418 resulted in a dose related and significant reversal of CFA-induced hypersensitivity (*** = p<0.001, compared with vehicle) which at 10mg.kg-1 was statistically equivalent to rofecoxib.

These studies demonstrate a lack of tolerance to the analgesic action of the CB2 receptor agonist GSK554418A in models of joint pain. These data strongly suggest significant analgesic potential of CB2 receptor agonists in conditions of chronic inflammatory pain.