title: 4-bromopropofol decreases action potential generation in spinal neurons by inducing a glycine receptor-mediated tonic conductance.
abstract: OBJECTIVE
  Impaired function of spinal strychnine-sensitive glycine receptors gives rise to chronic pain states and movement disorders. Therefore, increased activity of glycine receptors should help to treat such disorders. Although compounds targeting glycine receptors with a high selectivity are lacking, halogenated analogues of propofol have recently been considered as potential candidates. Therefore we asked whether 4-bromopropofol attenuated the excitability of spinal neurons by promoting glycine receptor-dependent inhibition.
  
  
  METHODS
  The actions of sub-anaesthetic concentrations of propofol and 4-bromopropofol were investigated in spinal tissue cultures prepared from mice. Drug-induced alterations in action potential firing were monitored by extracellular multi-unit recordings. The effects on GABAA and glycine receptor-mediated inhibition were quantified by whole-cell voltage-clamp recordings.
  
  
  RESULTS
  Low concentrations of 4-bromopropofol (50 nM) reduced action potential activity of ventral horn neurons by about 30%, compared with sham-treated slices. This effect was completely abolished by strychnine (1 μM). In voltage-clamped neurons, 4-bromopropofol activated glycine receptors, generating a tonic current of 65 ± 10 pA, while GABAA - and glycine receptor-mediated synaptic transmission remained unaffected.
  
  
  CONCLUSIONS
  The highest glycine levels in the CNS are found in the ventral horn of the spinal cord, a region mediating pain-induced motor reflexes and participating in the control of muscle tone. 4-Bromopropofol may serve as a starting point for the development of non-sedative, non-addictive, muscle relaxants and analgesics to be used to treat low back pain.
authors.affiliation: Experimental Anaesthesiology Section, Department of Anaesthesiology and Intensive Care, Eberhard-Karls-University, Tübingen, Germany.
authors.forename: V S
authors.initials: VS
authors.lastname: Eckle
authors.forename: C
authors.initials: C
authors.lastname: Grasshoff
authors.forename: V
authors.initials: V
authors.lastname: Mirakaj
authors.forename: P M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: N G
authors.initials: NG
authors.lastname: Berry
authors.forename: M
authors.initials: M
authors.lastname: Leuwer
authors.forename: B
authors.initials: B
authors.lastname: Antkowiak
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects*; D001966:Bromine; D018684:Glycine Agents / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015742:Propofol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018009:Receptors, Glycine / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects; D013331:Strychnine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D046509:Tissue Culture Techniques
chemical_list: C000599735:4-bromopropofol; D018686:Anesthetics, Intravenous; D018684:Glycine Agents; D018009:Receptors, Glycine; C027822:strychnine receptor; D013331:Strychnine; D001966:Bromine; D015742:Propofol