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Reversal of pathological pain through specific spinal GABAA receptor subtypes

Abstract

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment1,2. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology3,4,5,6,7. Facilitation of spinal γ-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABAA receptors should be able to compensate for this loss8,9. With the use of GABAA-receptor point-mutated knock-in mice in which specific GABAA receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands10,11,12, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABAA receptors containing the α2 and/or α3 subunits. We show that their selective activation by the non-sedative (‘α1-sparing’) benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.

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Figure 1: Antinociceptive effects of spinal diazepam in different mouse pain models.
Figure 2: GABA A receptor α subunits in capsaicin-sensitive primary afferent DRG neurons and in intrinsic dorsal horn neurons.
Figure 3: Anti-hyperalgesic effects of the non-sedative benzodiazepine site ligand L-838,417 in rats.
Figure 4: Effects of L-838,417 (1 mg kg -1 i.p.) on the supraspinal representation of pain.

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Acknowledgements

We thank M. Rudin for critical reading of the manuscript, and R. Keist, I. Camenisch, B. Layh, S. Gabriel, C. Sidler and S. John for technical assistance. This work was supported by grants from the Deutsche Forschungsgemeinschaft to H.U.Z. and A.H., by the Bundesministerium für Bildung und Forschung (migraine and BCCN) to A.H., by grants from the Schweizerischer Nationalfonds to J.M.F., H.M., U.R. and H.U.Z., the NCCR Neural Plasticity and Repair, and by the Doerenkamp Foundation for Innovations in Animal and Consumer Protection to K.B.

Author Contributions J.K., R.W., K.H., H.R. and U.B.Z. conducted the behavioural experiments. S.A. and J.B. made the electrophysiological recordings and analyses. M.S., A.H. and K.B. performed the fMRI study. J.M.F. made the morphological analyses. U.R. and H.M. provided the four lines of genetically modified mice. H.M. suggested experiments with L-838,417. H.U.Z. initiated the research, analysed behavioural and electrophysiological data and wrote the manuscript. All authors made comments on the manuscript.

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Correspondence to Hanns Ulrich Zeilhofer.

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The file contains Supplementary Methods with additional references, Supplementary Figures 1-3 with Legends and Supplementary Tables 1-2. (PDF 1058 kb)

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Knabl, J., Witschi, R., Hösl, K. et al. Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature 451, 330–334 (2008). https://doi.org/10.1038/nature06493

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