We have examined the effects of a novel
GABA(B) agonist, CGP35024, in models of chronic neuropathic (partial sciatic
ligation) and inflammatory (Freund's complete adjuvant)
pain in the rat, and its inhibitory action on spinal transmission in vitro. The effects of CGP35024 were compared with L-
baclofen and
gabapentin. CGP35024 and L-
baclofen reversed neuropathic
mechanical hyperalgesia following single subcutaneous or intrathecal administration, but did not affect inflammatory
mechanical hyperalgesia.
Gabapentin only moderately affected neuropathic
hyperalgesia following a single administration by either route, but produced significant reversal following daily administration for 5 days. It was only weakly active against inflammatory
hyperalgesia following single or repeated administration. The antihyperalgesic effects of L-
baclofen and CGP35024, but not
gabapentin, were blocked by the selective
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 tests. In the isolated hemisected spinal cord from the rat, CGP35024, L-
baclofen and
gabapentin all inhibited
capsaicin-evoked ventral root potentials (VRPs). CGP35024 and L-
baclofen, but not
gabapentin, also inhibited the polysynaptic and monosynaptic phases of electrically-evoked VRPs, as well as the 'wind-up' response to repetitive stimulation. These data indicate that CGP35024 and L-
baclofen modulate nociceptive transmission in the spinal cord to inhibit neuropathic
hyperalgesia, and that CGP35024 has a therapeutic window for antihyperalgesia over spasmolysis.