GABAPENTIN (NEURONTIN) AND S-(-3-ISOBUTYLGABA REPRESENT A NOVEL CLASSOF SELECTIVE ANTIHYPERALGESIC AGENTS())

1 Gabapentin (neurontin) is a novel antiepileptic agent that binds to the alpha(2) delta subunit of voltage-dependent calcium channels. The only other compound known to possess affinity for this recognition sit e is the (S)-(+)-enantiomer of 3-isobutylgaba. However, the correspond ing (R)-(-)-enantiomer is 10 fold weaker. The present study evaluates the activity of gabapentin and the two enantiomers of 3-isobutylgaba i n formalin and carrageenan-induced inflammatory pain models. 2 In the rat formalin test, S-(+)-3-isobutylgaba (1-100 mg kg(-1)) and gabapent in (10-300 mg kg(-1)) dose-dependently inhibited the late phase of the nociceptive response with respective minimum effective doses (MED) of 10 and 30 mg kg(-1), s.c. This antihyperalgesic action of gabapentin was insensitive to naloxone (0.1-10.0 mg kg(-1) s.c.). In contrast, th e R-(-)-enantiomer of 3-isobutylgaba (1-100 mg kg(-1)) produced a mode st inhibition of the late phase at the highest dose of 100 mg kg(-1) H owever, none of the compounds showed any effect during the early phase of the response. 3 The s.c. administration of either S-(+)-3-isobutyl gaba (1-30 mg kg(-1)) or gabapentin (10-100 mg kg(-1)), after the deve lopment of peak carrageenan-induced thermal hyperalgesia, dose-depende ntly antagonized the maintenance of this response with MED of 3 and 30 mg kg(-1), respectively. Similar administration of the two compounds also blocked maintenance of carrageenan-induced mechanical hyperalgesi a with MED of 3 and 10 mg kg(-1), respectively. In contrast, R-(-)-3-i sobutylgaba failed to show any effect in the two hyperalgesia models. 4 The intrathecal administration of gabapentin dose-dependently (1-100 mu g/animal) blocked carrageenan-induced mechanical hyperalgesia. In contrast, administration of similar doses of gabapentin into the infla med paw was ineffective at blocking this response. 5 Unlike morphine, the repeated administration of gabapentin (100 mg kg(-1) at start and culminating to 400 mg kg(-1)) over 6 days did not lead to the inductio n of tolerance to its antihyperalgesic action in the formalin test. Fu rthermore, the morphine tolerance did not cross generalize to gabapent in. The s.c. administration of gabapentin (10-300 mg kg(-1)), R-(-) (3 -100 mg kg(-1)) or S-(+)-3-isobutylgaba (3 100 mg kg(-1)) failed to in hibit gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the three compounds (1-100 mg kg(-1), s.c.) did not generalize to the morphine discriminative stimulus. Gabapentin (3 0-300 mg kg(-1)) and S-(+)-isobutylgaba (1-100 mg kg(-1)) showed sedat ive/ataxic properties only at the highest dose tested in the rota-rod apparatus. 6 Gabapentin (30-300 mg kg(-1), s.c.) failed to show an ant inociceptive action in transient pain models. It is concluded that gab apentin represents a novel class of antihyperalgesic agents.