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 Adelta-afferents evokes a saphenous C-afferent hypoalgesia mediated by pre-synaptic GABA(B) receptors. Tonic activation of sciatic Adelta-afferents was produced by cutaneous application of dimethyl sulfoxide (DMSO) followed by repetitive thermal activation of Adelta-afferents on the dorsolateral hind paw. The tonic activation of sciatic Adelta-afferents produced hypoalgesia in saphenous C-afferents. Intrathecal administration of the GABA(B) receptor antagonist, saclofen, attenuated saphenous hypoalgesia demonstrating at least partial mediation by central GABA(B) receptors. To determine if this central GABA(B) 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 GABA(B1a) receptor subunit (PAGB1a) in primary afferents or a control virus encoding the E. coli lacZ gene (PZ). Four weeks after infection, GABA(B) 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 Adelta-afferent-evoked hypoalgesic effect on saphenous C-afferent responses that is mediated by pre-synaptic GABA(B) receptors on the terminals of those C-afferents.