The first evidence that metabotropic GABA-B receptors play important role in the modulation of nociception comes from early 80's. Many preclinical studies reported that the GABA-B agonist baclofen is antinociceptive in models of acute and chronic pain (Malcangio et al. Br J Pharmacol 1991; Potes et al., Brain Res 2006). Although the involvement of GABA-B receptors at both spinal and supraspinal nociceptive sites might be ascribed to the inhibition of the release of glutamate and neuropeptides (e.g. Substance P, CGRP) from primary afferent fibers, the mechanism of action is still not clear. The nociceptive phenotype of GABA-B1 knock-out mice has been evaluated for central pain. The hotplate, tail flick and plantar tests revealed that the latency to a painful stimulus was reduced in knock-out mice. These mice also showed a reduced paw withdrawal threshold to mechanical hyperalgesic test (Schuler et al., Neuron 2001). Surprisingly, the Von Frey test revealed that these mice have a higher withdrawal threshold to mechanical allodynic stimuli. Therefore the GABA-B1 knock-out mice are hyperalgesic, suggesting a GABA-B-mediated tonic control over the central pain, whereas they are not allodynic. In order to explain the different pain behaviour we have investigated whether the GABA-B-mediated antinociception relates preferably to central or peripheral pain. Our experiments indicate that the peripheral nervous system of GABA-B1 knock-out mice shows a higher number of small myelinated fibers (likely Ad or C primary afferents) and small neurons of the lumbar dorsal root ganglia. The intraepidermal nerve fiber density and the immunolabeling of peripheral nerves for specific neuropeptides suggest that primarily the Ad-sensory fibers are increased in these mice. In conclusion, our findings are in accordance with a GABA-B receptor involvement in the central pain pathways, raising the possibility that the peripheral GABA-B receptors contribute to the nociceptive phenotypes of GABA-B1 knock-out mice.