The effects of GABAB agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat

Abstract

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.

Effect of Intrahippocampal γ Aminobutyrate B Receptor on Pain Sensitivity during Estrous Cycle

“…This action of baclofen was more effective on EPSC than on Aδ fiber EPSC, while CGP35348 antagonized both actions (Ataka et al, 2000). There is evidence that the GABA B receptor antagonist CGP35024 reverses mechanical hyperalgesia in one model of neuropathic pain in the rat, with concomitant inhibitory activity on nociceptive transmission in the spinal cord (Patel et al, 2001).…”

“…This antinociceptive effect of baclofen was antagonized by pretreatment with GABA B receptor antagonist saclofen (Naderi et al, 2005). Patel et al (2001) reported that L-baclofen has marked antihyperalgesic activity in a model of neuropathic pain in the rat. The effect of baclofen was blocked by the selective GABA B receptor antagonist CGP56433A (Patel et al, 2001).…”

“…Patel et al (2001) reported that L-baclofen has marked antihyperalgesic activity in a model of neuropathic pain in the rat. The effect of baclofen was blocked by the selective GABA B receptor antagonist CGP56433A (Patel et al, 2001). Yang et al (2003) demonstrated that the activation of GABA B receptors by baclofen in the ventrolateral periaqueductal gray neurons has a threefold action: 1-hyperpolarization of periaqueductal gray neurons (postsynaptic inhibition), 2-decrease in the release of L-glutamate nerve terminals to periaqueductal gray neurons (presynaptic inhibition) and 3-decrease in the release of GABA from nerve terminals to periaqueductal gray neurons (presynaptic inhibition) (Yang et al, 2003).…”

Current and Future Issues in the development of spinal agents for the management of pain

“…Baclofen, the clinically approved GABA-B agonist, has potent stereospecific suppressive effects upon motor tone [253] and is widely used clinically to regulate motor tone in the case of spasticity [254][255][256]; but it has also been implicated in having suppressive effects upon nociceptive processing after intrathecal delivery in preclinical models of facilitated processing [217] and hyperpathia in mono and polyneuropathies and spinal injury [220][221][257][258][259] and in humans [260,261].…”

“…Other GABA-B agonists have been identified and include agents such asCGP35024 and the more potent CGP 44532, which were reported to induce antinociceptive responses at doses below those that cause sedation [257,269]. It has become clear that regulation of GABA-B activity is associated with a role for positive allosteric modulators to potentially reduce unwanted drug effects.…”