Pain remains a significant clinical challenge and currently available
analgesics are not adequate to meet clinical needs. Emerging evidence suggests the role of
imidazoline I(2) receptors in
pain modulation primarily from studies of the non-selective
imidazoline receptor ligand,
agmatine. However, little is known of the generality of the effect to selective I(2) receptor
ligands. This study examined the antinociceptive effects of two selective I(2) receptor
ligands 2-BFI and
BU224 (>2000-fold selectivity for I(2) receptors over α(2)
adrenoceptors) in a hypertonic (5%) saline-induced writhing test and analyzed their interaction with
morphine using a dose-addition analysis.
Morphine,
2-BFI and
BU224 but not
agmatine produced a dose-dependent antinociceptive effect. Both composite additive curve analyses and isobolographical plots revealed a supra-additive interaction between
morphine and
2-BFI or
BU224, whereas the interaction between
2-BFI and
BU224 was additive. The antinociceptive effect of
2-BFI and
BU224 was attenuated by the I(2) receptor antagonist/α(2)
adrenoceptor antagonist
idazoxan but not by the selective α(2)
adrenoceptor antagonist
yohimbine, suggesting an I(2) receptor-mediated mechanism.
Agmatine enhanced the antinociceptive effect of
morphine,
2-BFI and
BU224 and the enhancement was prevented by
yohimbine, suggesting that the effect was mediated by α(2)
adrenoceptors. Taken together, these data represent the first report that selective I(2) receptor
ligands have substantial antinociceptive activity and produce antinociceptive synergy with
opioids in a rat model of
acute pain. These data suggest that drugs acting on
imidazoline I(2) receptors may be useful either alone or in combination with
opioids for the treatment of
pain.