Reversal of pathological pain through specific spinal GABA A receptor subtypes

• Published in: Nature (London) 2008-01, Vol.451 (7176), p.330-334
• Main Authors: Ahmadi, Seifollah, Zeilhofer, Hanns Ulrich, Fritschy, Jean-Marc, Sergejeva, Marina, Reinold, Heiko, Brockhaus, Johannes, Möhler, Hanns, Knabl, Julia, Brune, Kay, Rudolph, Uwe, Witschi, Robert, Hösl, Katharina, Zeilhofer, Ulrike B, Hess, Andreas
• Format: Article
• Language: English
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature06493

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal -aminobutyric acid (GABA)ergic neurotransmission through modulation of GABAA receptors should be able to compensate for this loss. 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 ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABAA receptors containing the 2 and/or 3 subunits. We show that their selective activation by the non-sedative (' 1-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.