Reversal of pathological pain through specific spinal GABAA receptor subtypes.

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Bibliographic Details
Title:	Reversal of pathological pain through specific spinal GABAA receptor subtypes.
Authors:	Knabl, Julia, Witschi, Robert, Hösl, Katharina, Reinold, Heiko, Zeilhofer, Ulrike B., Ahmadi, Seifollah, Brockhaus, Johannes, Sergejeva, Marina, Hess, Andreas, Brune, Kay, Fritschy, Jean-Marc, Rudolph, Uwe, Möhler, Hanns, Zeilhofer, Hanns Ulrich
Source:	Nature. 1/17/2008, Vol. 451 Issue 7176, p330-334. 5p. 1 Diagram, 1 Chart, 3 Graphs.
Subjects:	Medical research, Inflammation, Pain, GABA, Amino acids, Diagnostic imaging, Magnetic resonance imaging, Pathology, Preventive medicine
Abstract:	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 γ-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 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. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
Abstract:	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 γ-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 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. [ABSTRACT FROM AUTHOR]
ISSN:	00280836
DOI:	10.1038/nature06493