Research

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

Vijayan Gangadharan¹ , Nitin Agarwal¹ , Stefan Brugger^1,4 , Imgard Tegeder² , Bernhard Bettler³ , Rohini Kuner¹ and Martina Kurejova¹

¹  Pharmacology Institute, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany

²  pharmazentrum frankfurt/ZAFES, Goethe-University Clinic Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

³  Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland

⁴  Anesthesiology and Intensive Medicine, University Hospital of Basel, Switzerland

author email corresponding author email

Molecular Pain 2009, 5:68doi:10.1186/1744-8069-5-68

Published:	19 November 2009

Abstract

Background

γ-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_B(1) subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABA_B(1)^-/- mice). Lack of the GABA_B(1) subunit precludes the assembly of functional GABA_B receptor. We analyzed SNS-GABA_B(1)^-/- 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_B(1)^-/- 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-GABA_B(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_B(1) 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.