We have previously shown that the selective CB2 agonist L-768,242 inhibited carrageenan -induced inflammation and hypersensitivity to pain (Clayton et al., 2002). The aim of this study was to investigate the effect of the novel, potent and highly selective CB2 agonist GW842166X ( 2-(2, 4-Dichlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid [(tetrahydropyran-4-yl)methyl]amide; CB2 EC₅₀ =55nM (human), 50nM (rat), CB1 EC₅₀>100µM (human), >10µM (rat)) in models of chronic inflammatory and neuropathic hypersensitivity to pain. Male Random Hooded rats (180-240g) were used in all studies.

In established FCA, 100µl of 1mg/ml Freund’s Complete adjuvant (FCA) was injected intraplantar into the left hind paw and 23hrs later GW842166X (0.03-10mg/kg) was dosed orally. One hr post dose the effect of GW842166X on FCA-induced decrease in weight bearing on the inflamed left hind paw (dual channel weight averager: Clayton et al., 1997) and increase in paw volume (plethysmometer) was determined. In a model of chronic inflammatory joint pain, 150µl of FCA was injected into the left knee joint (intra-articular injection) under gaseous anaesthetic and then allowed to recover. On day 13 when the hypersensitivity (weight bearing) and joint diameter (hand held digital micrometer) was stable, GW842166X (5-15mg/kg, b.i.d. p.o.) was dosed for 5 days and the effect on the FCA induced decrease in weight bearing and increase in joint diameter was determined 1hr after the morning dose on each day. In a model of neuropathic pain (chronic constriction injury, CCI) the sciatic nerve in the left leg was loosely ligated with 4 ligatures of chromic 4.0 gut. On day 22 post surgery, when the hypersensitivity (paw pressure, Randall & Selitto, 1957) was maximal and stable, GW842166X (15mg/kg b.i.d., p.o.) was dosed for 8 days. The effect on the CCI induced decrease in paw pressure was determined as above. Data is presented as mean±s.e. mean. Where appropriate geometric mean and 95% confidence intervals for ED 50 values were calculated. Statistical analysis was carried out to determine whether there was a significant difference (p<0.05) between the vehicle and drug treated group using Student’s unpaired t test (eFCA) or Anova followed by Duncan’ post-hoc comparisons (chronic joint pain). In the FCA model GW842166X produced a dose related reversal of the hypersensitivity (max reversal: 98±10%@0.3mg/kg., p<0.05, ED₅₀=0.07(0.03-0.2)mg/kg) and reduced the paw oedema (max reversal: 25±5%@0.3mg/kg, p<0.05). In chronic joint pain, GW842166X produced a significant reversal of the FCA induced decrease in weight bearing on the ipsilateral limb (max reversal: 50%@15mg/kg) and reduced the joint diameter (p<0.05). The effect was maximal by day 5 of dosing. In CCI, chronic dosing of GW842166X produced a significant reversal of the CCI induced decrease in paw withdrawal threshold (max reversal: 58% on day 8, p<0.05).

In conclusion, the CB2 agonist GW842166X fully reversed established inflammatory hypersensitivity, reduced chronic joint hypersensitivity and reduced the paw oedema and joint diameter respectively. In a model of neuropathic hypersensitivity to pain GW842166X significantly reduced the hypersensitivity to pain. The data suggests that GW842166X may have clinical utility in both chronic inflammatory and neuropathic pain.

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