GABAB receptors on central terminals of C-afferents mediate intersegmental Aδ-afferent evoked hypoalgesia

The current study tested the hypothesis that repetitive activation of sciatic Aδ-afferents evokes a saphenous C-afferent hypoalgesia mediated by pre-synaptic GABAB receptors. Tonic activation of sciatic Aδ-afferents was produced by cutaneous application of dimethyl sulfoxide (DMSO) followed by repetitive thermal activation of Aδ-afferents on the dorsolateral hind paw. The tonic activation of sciatic Aδ-afferents produced hypoalgesia in saphenous C-afferents. Intrathecal administration of the GABAB receptor antagonist, saclofen, attenuated saphenous hypoalgesia demonstrating at least partial mediation by central GABAB receptors. To determine if this central GABAB receptor activation occurs at pre-synaptic primary afferent terminals or postsynaptic spinal cord neurons, the dorsal hind paws of mice were infected with a recombinant herpes simplex virus type 1 (HSV-1) designed to selectively knock down expression of the GABAB1a receptor subunit (PAGB1a) in primary afferents or a control virus encoding the E. coli lacZ gene (PZ). Four weeks after infection, GABAB receptor immunoreactivity in the superficial dorsal horns ipsilateral to PAGB1a application was reduced and hypoalgesia in saphenous C-afferents was attenuated when compared to PZ-infected mice. These findings indicate an intersegmental, sciatic Aδ-afferent-evoked hypoalgesic effect on saphenous C-afferent responses that is mediated by pre-synaptic GABAB receptors on the terminals of those C-afferents.