The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat

We have examined the effects of a novel GABA(B) agonist, CGP35024, in model s of chronic neuropathic (partial sciatic ligation) and inflammatory (Freun d's complete adjuvant) pain in the rat, and its inhibitory action on spinal transmission in vitro. The effects of CGP35024 were compared with L-baclof en and gabapentin. CGP35024 and L-baclofen reversed neuropathic mechanical hyperalgesia following single subcutaneous or intrathecal administration, b ut did not affect inflammatory mechanical hyperalgesia. Gabapentin only mod erately affected neuropathic hyperalgesia following a single administration by either route, but produced significant reversal following daily adminis tration for 5 days. It was only weakly active against inflammatory hyperalg esia following single or repeated administration. The antihyperalgesic effe cts of L-baclofen and CGP35024, but not gabapentin, were blocked by the sel ective GABA(B) receptor antagonist CGP56433A. CGP35024 was seven times more potent against neuropathic hyperalgesia than in the rotarod test for motor co-ordination, whilst L-baclofen was approximately equipotent in the two t ests. In the isolated hemisected spinal cord from the rat, CGP35024, L-bacl ofen and gabapentin all inhibited capsaicin-evoked ventral root potentials (VRPs). CGP35024 and L-baclofen, but not gabapentin, also inhibited the pol ysynaptic and monosynaptic phases of electrically-evoked VRPs, as well as t he 'wind-up' response to repetitive stimulation. These data indicate that C GP35024 and L-baclofen modulate nociceptive transmission in the spinal cord to inhibit neuropathic hyperalgesia, and that CGP35024 has a therapeutic w indow fur antihyperalgesia over spasmolysis. (C) 2001 International Associa tion For the Study of Pain. Published by Elsevier Science B.V. All rights r eserved.