Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo

BACKGROUND gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABA(A)) and metabotropic (GABA(B)) receptors. GABA(B) receptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABA(B) receptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABA(B) receptors is unclear. RESULTS In order to elucidate the functional relevance of GABA(B) receptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABA(B1) subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABA(B1)-/- mice). Lack of the GABA(B1) subunit precludes the assembly of functional GABA(B) receptor. We analyzed SNS-GABA(B1)-/- mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABA(B1)-/- mice compared to corresponding control littermates. However no differences were seen in basal nociceptive sensitivity between these groups. The development of neuropathic and chronic inflammatory pain was similar across the two genotypes. The duration of nocifensive responses evoked by intraplantar formalin injection was prolonged in the SNS-GABAB(1)-/- animals as compared to their control littermates. Pharmacological experiments revealed that systemic baclofen-induced inhibition of formalin-induced nociceptive behaviors was not dependent upon GABA(B1) expression in nociceptors. CONCLUSION This study addressed contribution of GABA(B) receptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABA(B) agonist was significantly changed upon a specific deletion of GABA(B) receptors from peripheral nociceptive neurons in vivo. This lets us conclude that GABA(B) receptors in the peripheral nervous system play a less important role than those in the central nervous system in the regulation of pain.