ABT-594 [(R)-5-(2-AZETIDINYLMETHOXY)-2-CHLOROPYRIDINE] - A NOVEL, ORALLY EFFECTIVE ANTINOCICEPTIVE AGENT ACTING VIA NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTORS - II - IN-VIVO CHARACTERIZATION

The antinociceptive effects of ABT-594, a novel nicotinic acetylcholin e receptor (nAChR) ligand, were examined in rats in models of acute th ermal (hot box) and persistent chemical (formalin test) pain. Also, th e effects of ABT-594 treatment on motor function and electroencephalog ram (EEG) were determined. In the hot box and formalin test (i.e., pha se 1 and 2), acute treatment with ABT-594 (0.03, 0.1 and 0.3 mu mol/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 retaine d significant efficacy (0.3 mu mol/kg i.p.) when administered after fo rmalin injection. The antinociceptive effects of ABT-594 in the hot bo x and formalin tests were attenuated by pretreatment with the nAChR an tagonist, mecamylamine, and in animals treated with the nAChR antagoni st, chlorisondamine, given centrally (10 mu g/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 re peatedly (5 days b.i.d.) with ABT-594. Also, acute treatment with ABT- 594 decreased body temperature and decreased the amount of time the an imals could maintain balance in an edge-balance test. These effects we re no longer present in animals dosed repeatedly with ABT-594. At anti nociceptive doses, ABT-594 produced activation of free running EEG in contrast to the sedative-like effects of morphine. Full antinociceptiv e 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 po tent antinociceptive agent with full efficacy in models of acute and p ersistent pain and that these effects are mediated predominately by an action at central neuronal nAChRs. In addition, antinociceptive effec ts were maintained after repeated dosing, whereas effects of ABT-594 o n motor and temperature measures were attenuated in animals treated re peatedly with ABT-594. Thus, compounds acting at nAChRs may represent a novel approach for the treatment of a variety of pain states.