Advertisement

Journal of Molecular Medicine

, Volume 87, Issue 5, pp 465–469 | Cite as

Subtype-selective GABAA receptor mimetics—novel antihyperalgesic agents?

  • Hanns Ulrich ZeilhoferEmail author
  • Robert Witschi
  • Katharina Hösl
Review

Abstract

Agonists at the benzodiazepine-binding site of ionotropic γ-aminobutyric acid (GABAA) receptors are in clinical use as hypnotics, anxiolytics, and anticonvulsants since the early 1960. Analgesic effects of classical benzodiazepines have occasionally been reported in certain subgroups of patients suffering from chronic pain or after spinal delivery through intrathecal catheters. However, these drugs are generally not considered as analgesics but should in fact be avoided in patients with chronic pain. Recent evidence from genetically modified mice now indicates that agents targeting only a subset of benzodiazepine (GABAA) receptors should provide pronounced antihyperalgesic activity against inflammatory and neuropathic pain. Several such compounds have been developed recently, which exhibit significant antihyperalgesia in mice and rats and appear to be devoid of the typical side-effects of classical benzodiazepines.

Keywords

Pain Analgesia GABA GABAA receptor Benzodiazepine Neuropathy 

References

  1. 1.
    Melzack R, Wall PD (1965) Pain mechanisms: a new theory. Science 150:971–979CrossRefPubMedGoogle Scholar
  2. 2.
    Beyer C, Roberts LA, Komisaruk BR (1985) Hyperalgesia induced by altered glycinergic activity at the spinal cord. Life Sci 37:875–882CrossRefPubMedGoogle Scholar
  3. 3.
    Yaksh TL (1989) Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists. Pain 37:111–123CrossRefPubMedGoogle Scholar
  4. 4.
    Zeilhofer HU (2008) Loss of glycinergic and GABAergic inhibition in chronic pain—contributions of inflammation and microglia. Int Immunopharmacol 8:182–187CrossRefPubMedGoogle Scholar
  5. 5.
    Jasmin L, Wu MV, Ohara PT (2004) GABA puts a stop to pain. Curr Drug Targets CNS Neurol Disord 3:487–505CrossRefPubMedGoogle Scholar
  6. 6.
    Bohlhalter S, Weinmann O, Mohler H, Fritschy JM (1996) Laminar compartmentalization of GABAA-receptor subtypes in the spinal cord: an immunohistochemical study. J Neurosci 16:283–297PubMedGoogle Scholar
  7. 7.
    Jourdan D, Ardid D, Bardin L, Bardin M, Neuzeret D, Lanphouthacoul L, Eschalier A (1997) A new automated method of pain scoring in the formalin test in rats. Pain 71:265–270CrossRefPubMedGoogle Scholar
  8. 8.
    Luger TJ, Hayashi T, Weiss CG, Hill HF (1995) The spinal potentiating effect and the supraspinal inhibitory effect of midazolam on opioid-induced analgesia in rats. Eur J Pharmacol 275:153–162CrossRefPubMedGoogle Scholar
  9. 9.
    Scholz J, Broom DC, Youn DH, Mills CD, Kohno T, Suter MR, Moore KA, Decosterd I, Coggeshall RE, Woolf CJ (2005) Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J Neurosci 25:7317–7323CrossRefPubMedGoogle Scholar
  10. 10.
    Tucker AP, Lai C, Nadeson R, Goodchild CS (2004) Intrathecal midazolam I: a cohort study investigating safety. Anesth Analg 98:1512–1520CrossRefPubMedGoogle Scholar
  11. 11.
    Tucker AP, Mezzatesta J, Nadeson R, Goodchild CS (2004) Intrathecal midazolam II: combination with intrathecal fentanyl for labor pain. Anesth Analg 98:1521–1527CrossRefPubMedGoogle Scholar
  12. 12.
    Thurauf N, Ditterich W, Kobal G (1994) Different sensitivity of pain-related chemosensory potentials evoked by stimulation with CO2, tooth pulp event-related potentials, and acoustic event-related potentials to the tranquilizer diazepam. Br J Clin Pharmacol 38:545–555PubMedGoogle Scholar
  13. 13.
    Knabl J, Witschi R, Hösl K, Reinold H, Zeilhofer UB, Ahmadi S, Brockhaus J, Sergejeva M, Hess A, Brune K, Fritschy J-M, Rudolph U, Möhler H, Zeilhofer HU (2008) Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature 451:330–334CrossRefPubMedGoogle Scholar
  14. 14.
    Barnard EA (2001) The Molecular Architecture of GABA-A Receptors. In: Möhler H (ed) Pharmacology of GABA and glycine neurotransmission. Springer, Berlin, pp 79–99Google Scholar
  15. 15.
    Wieland HA, Luddens H, Seeburg PH (1992) A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J Biol Chem 267:1426–1429PubMedGoogle Scholar
  16. 16.
    Rudolph U, Mohler H (2006) GABA-based therapeutic approaches: GABAA receptor subtype functions. Curr Opin Pharmacol 6:18–23CrossRefPubMedGoogle Scholar
  17. 17.
    Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Mohler H (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401:796–800CrossRefPubMedGoogle Scholar
  18. 18.
    Low K, Crestani F, Keist R, Benke D, Brunig I, Benson JA, Fritschy JM, Rulicke T, Bluethmann H, Mohler H, Rudolph U (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131–134CrossRefPubMedGoogle Scholar
  19. 19.
    Knabl J, Zeilhofer U, Crestani F, Rudolph U, Zeilhofer HU (2009) Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABAA receptor point-mutated mice. Pain 141:233–238CrossRefPubMedGoogle Scholar
  20. 20.
    McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nat Neurosci 3:587–592CrossRefPubMedGoogle Scholar
  21. 21.
    Griebel G, Perrault G, Simiand J, Cohen C, Granger P, Decobert M, Francon D, Avenet P, Depoortere H, Tan S, Oblin A, Schoemaker H, Evanno Y, Sevrin M, George P, Scatton B (2001) SL651498: an anxioselective compound with functional selectivity for α2- and α3-containing gamma-aminobutyric acidA (GABAA) receptors. J Pharmacol Exp Ther 298:753–768PubMedGoogle Scholar
  22. 22.
    Mirza NR, Larsen JS, Mathiasen C, Jacobsen TA, Munro G, Erichsen HK, Nielsen AN, Troelsen KB, Nielsen EO, Ahring PK (2008) NS11394 [3′-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a unique subtype-selective GABAA receptor positive allosteric modulator: in vitro actions, pharmacokinetic properties and in vivo anxiolytic efficacy. J Pharmacol Exp Ther 327:954–968CrossRefPubMedGoogle Scholar
  23. 23.
    Munro G, Lopez-Garcia JA, Rivera-Arconada I, Erichsen HK, Nielsen EO, Larsen JS, Ahring PK, Mirza NR (2008) Comparison of the novel subtype-selective GABAA receptor-positive allosteric modulator NS11394 [3′-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] with diazepam, zolpidem, bretazenil, and gaboxadol in rat models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 327:969–981CrossRefPubMedGoogle Scholar
  24. 24.
    Rogawski MA (2006) Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 69:273–294CrossRefPubMedGoogle Scholar
  25. 25.
    de Haas SL, de Visser SJ, van der Post JP, de Smet M, Schoemaker RC, Rijnbeek B, Cohen AF, Vega JM, Agrawal NG, Goel TV, Simpson RC, Pearson LK, Li S, Hesney M, Murphy MG, van Gerven JM (2007) Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. J Psychopharmacol 21:374–383CrossRefPubMedGoogle Scholar
  26. 26.
    de Haas SL, Franson KL, Schmitt JA, Cohen AF, Fau JB, Dubruc C, van Gerven JM (2008) The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A α2,3 selective agonist, in comparison with lorazepam in healthy volunteers. J Psychopharmacol, epub ahead of print doi: 10.1177/0269881108092595
  27. 27.
    Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal B, Pike A, Sur C, Melillo D, Bristow L, Bromidge F, Ragan I, Kerby J, Street L, Carling R, Castro JL, Whiting P, Dawson GR, McKernan RM (2006) TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluor ophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for α2- and α3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates. J Pharmacol Exp Ther 316:410–422CrossRefPubMedGoogle Scholar
  28. 28.
    Crestani F, Keist R, Fritschy JM, Benke D, Vogt K, Prut L, Bluthmann H, Mohler H, Rudolph U (2002) Trace fear conditioning involves hippocampal α5 GABAA receptors. Proc Natl Acad Sci U S A 99:8980–8985CrossRefPubMedGoogle Scholar
  29. 29.
    Dawson GR, Maubach KA, Collinson N, Cobain M, Everitt BJ, MacLeod AM, Choudhury HI, McDonald LM, Pillai G, Rycroft W, Smith AJ, Sternfeld F, Tattersall FD, Wafford KA, Reynolds DS, Seabrook GR, Atack JR (2006) An inverse agonist selective for α5 subunit-containing GABAA receptors enhances cognition. J Pharmacol Exp Ther 316:1335–1345CrossRefPubMedGoogle Scholar
  30. 30.
    Mirza NR, Nielsen EO (2006) Do subtype-selective gamma-aminobutyric acid A receptor modulators have a reduced propensity to induce physical dependence in mice. J Pharmacol Exp Ther 316:1378–1385CrossRefPubMedGoogle Scholar
  31. 31.
    Licata SC, Rowlett JK (2008) Abuse and dependence liability of benzodiazepine-type drugs: GABAA receptor modulation and beyond. Pharmacol Biochem Behav 90:74–89CrossRefPubMedGoogle Scholar
  32. 32.
    Samaha AN, Robinson TE (2005) Why does the rapid delivery of drugs to the brain promote addiction. Trends Pharmacol Sci 26:82–87CrossRefPubMedGoogle Scholar
  33. 33.
    Griebel G, Perrault G, Simiand J, Cohen C, Granger P, Depoortere H, Françon D, Avenet P, Schoemaker H, Evanno Y, Sevrin M, George P, Scatton B (2003) SL651498, a GABAA receptor agonist with subtype-seletive efficacy, as a potential treatment for generalized anxiety disorder and muscle spasm. CNS Drug Reviews 9:3–20PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Hanns Ulrich Zeilhofer
    • 1
    • 2
    Email author
  • Robert Witschi
    • 1
    • 2
  • Katharina Hösl
    • 3
    • 4
  1. 1.Institute of Pharmacology and ToxicologyUniversity of ZurichZurichSwitzerland
  2. 2.Institute of Pharmaceutical SciencesSwiss Federal Institute of Technology (ETH)ZurichSwitzerland
  3. 3.Institute for Experimental and Clinical Pharmacology and ToxicologyUniversity of Erlangen-NürnbergErlangenGermany
  4. 4.Department of NeurologyUniversity of Erlangen-NürnbergErlangenGermany

Personalised recommendations