The antinociceptive effects of
ABT-594, a novel
nicotinic acetylcholine receptor (nAChR)
ligand, were examined in rats in models of acute thermal (hot box) and persistent chemical (
formalin test)
pain. Also, the effects of
ABT-594 treatment on motor function and electroencephalogram (EEG) were determined. In the hot box and
formalin test (i.e., phase 1 and 2), acute treatment with
ABT-594 (0.03, 0.1 and 0.3 mumol/kg i.p.) produced significant dose-dependent antinociceptive effects. In the hot box, the efficacy of
ABT-594 was maintained after a repeated dosing paradigm (5 days b.i.d.i.p.).
ABT-594 was fully efficacious in the
formalin test when administered before
formalin, and also retained significant efficacy (0.3 mumol/kg i.p.) when administered after
formalin injection. The antinociceptive effects of
ABT-594 in the hot box and
formalin tests were attenuated by pretreatment with the nAChR antagonist,
mecamylamine, and in animals treated with the nAChR antagonist
chlorisondamine, given centrally (10 micrograms/rat i.c.v. 5 days before), but not in animals pretreated with the
opioid receptor antagonist,
naltrexone. Acute treatment with
ABT-594 produced an initial decrease in open-field locomotor activity, which was absent in animals dosed repeatedly (5 days b.i.d.) with
ABT-594. Also, acute treatment with
ABT-594 decreased body temperature and decreased the amount of time the animals could maintain balance in an edge-balance test. These effects were no longer present in animals dosed repeatedly with
ABT-594. At antinociceptive doses,
ABT-594 produced activation of free running EEG in contrast to the
sedative-like effects of
morphine. Full antinociceptive efficacy was maintained in both the hot box and
formalin tests after
oral administration, whereas the effects on motoric performance were attenuated. In conclusion, these data demonstrate that
ABT-594 is a potent antinociceptive agent with full efficacy in models of acute and persistent
pain and that these effects are mediated predominately by an action at central neuronal nAChRs. In addition, antinociceptive effects were maintained after repeated dosing, whereas effects of
ABT-594 on motor and temperature measures were attenuated in animals treated repeatedly with
ABT-594. Thus, compounds acting at nAChRs may represent a novel approach for the treatment of a variety of
pain states.