1. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany
2. Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland
3. Institute of Pharmaceutical Sciences, ETH Zurich, CH-8093 Zurich, Switzerland
4. Laboratory of Genetic Neuropharmacology, McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts 02478, USA
5. Collegium Helveticum, CH-8092 Zurich, Switzerland
6. Present addresses: Department of Physiology, University of Bonn, D-53111 Bonn, Germany (S.A.); Department of Physiology, University of Münster, D-48149 Münster, Germany (J.B.).

Correspondence to: Hanns Ulrich Zeilhofer^1,2,3 Correspondence and requests for materials should be addressed to H.U.Z. (Email: zeilhofer@pharma.uzh.ch).

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment^{1, 2}. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology^{3, 4, 5, 6, 7}. Facilitation of spinal -aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA_A receptors should be able to compensate for this loss^{8, 9}. With the use of GABA_A-receptor point-mutated knock-in mice in which specific GABA_A receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands^{10, 11, 12}, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA_A 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.

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