期刊
PAIN
卷 141, 期 3, 页码 233-238出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.pain.2008.10.015
关键词
Pain; Diazepam; Benzodiazepine; Spinal cord; Hyperalgesia; GABA(A) receptor; Point mutation
资金
- Schweizerischer Nationalfonds (SNF)
- Deutsche Forschungsgemeinschaft (DFG)
Ionotropic gamma-aminobutyric add (GABA(A)) receptors control the relay of nociceptive signals at several levels of the neuraxis. Experiments with systemically applied benzodiazepines, which enhance the action of GABA at these receptors, have Suggested both anti- and pronociceptive effects. The interpretation of such experiments has been notoriously difficult because of confounding sedation, Here, we have used genetically engineered mice, which carry specific benzodiazepine-insensitive GABA(A) receptor subunits, to test whether diazeparn, a frequently used classical benzodiazepine, exerts antihyperalgesia after systemic administration in the formalin test, a model of tonic nociception. In wild-type mice, systemic diazeparn (3-30 mg/kg, p.o.) dose-dependently reduced the number of formalin-induced flinches during both phases of the test by about 40-70%. This antinociception was reversed by the benzodiazepine site antagonist flumazenil (10 mg/kg, i.p.), but fully retained in GABAA receptor alpha 1 point-mutated mice, which were resistant against the sedative action of diazeparn. Experiments carried out in mice with two diazepam-insensitive subunits (alpha 1/alpha 2, alpha 1/alpha 3 and alpha 1/alpha 5 double point-mutated mice) allowed addressing the contribution of alpha 2, alpha 3 and alpha 5 subunits to systemic diazepam-induced antihyperalgesia in the absence of sedation. The relative contributions of these subunits were alpha 2 approximate to alpha 3 > alpha 5, and thus very similar to those found for intrathecal diazepam (0.09 mg/kg). Accordingly, SL-651498 (10 mg/kg, p.o.), an anxioselective benzodiazepine site agonist with preferential activity at alpha 2/alpha 3 subunits, significantly reduced formalin-induced flinching in wild-type mice. We conclude that systemic diazeparn exerts a genuine antihyperalgesic effect, which depends on spinal GABA(A) receptors containing alpha 2 and/or alpha 3 subunits. (C) 2008 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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