Involvement of the BLT2 receptor in the itch-associated scratching induced by 12-(S)-lipoxygenase products in ICR mice

Background and purpose: Recently, we reported that 12(S)-HPETE (12(S)-hydroperoxyeicosa-5Z, 8Z, 10E, 14Z-tetraenoic acid) induces scratching in ICR mice. We hypothesized that 12(S)-HPETE might act as an agonist of the low-affinity leukotriene B-4 receptor BLT2. To confirm the involvement of the BLT2 receptor in 12(S)-HPETE-induced scratching, we studied the scratch response using the BLT2 receptor agonists compound A (4'-{[pentanoyl (phenyl) amino] methyl}-1,1'-biphenyl-2-carboxylic acid) and 12(S)-HETE (12(S)-hydroxyeicosa-5Z, 8Z, 10E, 14Z-tetraenoic acid). Experimental approach: A video recording was used to determine whether the BLT2 receptor agonists caused itch-associated scratching in ICR mice. Selective antagonists and several chemicals were used. Key results: Both 12(S)-HETE and compound A dose dependently induced scratching in the ICR mice. The dose-response curve for compound A showed peaks at around 0.005-0.015 nmol per site. Compound A- and 12(S)-HETE-induced scratching was suppressed by capsaicin and naltrexon. We examined the suppressive effects of U75302 (6-[6-(3-hydroxy-1E, 5Z-undecadienyl)-2-pyridinyl]-1,5-hexanediol, the BLT1 receptor antagonist) and LY255283 (1-[5-ethyl-2-hydroxy-4-[[6- methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]phenyl]-ethanone,the BLT2 receptor antagonist) on the BLT2 agonist-induced scratching. LY255283 suppressed compound A- and 12(S)- HETE-induced scratching, but U75302 did not. LY255283 required a higher dose to suppress the compound A- induced scratching than it did to suppress the 12(S)-HETE-induced scratching. One of the BLT2 receptor agonists, 12(R)- HETE (12(R)-hydroxyeicosa-5Z, 8Z, 10E, 14Z-tetraenoic acid), also induced scratching in the ICR mice. Conclusions and implications: Our present results corroborate the hypothesis that the BLT2 receptor is involved in 12(S)-lipoxygenase-product-induced scratching in ICR mice. We also confirmed that this animal model could be a valuable means of evaluating the effects of BLT2 receptor antagonists.