title: Isovaline causes inhibition by increasing potassium conductance in thalamic neurons.
abstract: The rare amino acid isovaline has analgesic properties in pain models and is a structural analogue of the inhibitory neurotransmitter glycine. Glycinergic inhibition is prevalent in pain pathways. In this paper, we examined the possibility that isovaline inhibits neurons by activating strychnine (Str)-sensitive glycine(A) receptors in ventrobasal thalamus. Sagittal brain sections containing ventrobasal nuclei were prepared from P10-P15 rats. Whole-cell recordings were made in current-clamp and voltage-clamp modes. R-isovaline (R-Iva) increased input conductance and hyperpolarized the membrane. The conductance increase shunted action potentials and low-threshold Ca(2+) spikes evoked by current pulse injection. Unlike the Cl(-)-mediated responses to glycine, isovaline responses were insensitive to Str antagonism and usually not reversible. The concentration-response curve was non-sigmoidal, rising to a maximum at approximately 100 microM, and thereafter declining in amplitude. Current-voltage relationships showed that isovaline increased inward and outward rectification. The isovaline current reversed polarity close to the K(+) equilibrium potential. The relationships were negligibly affected by tetrodotoxin (TTX), chelation of intracellular Ca(2+) or blockade of the hyperpolarization-activated current, I(h). Internal Cs(+) and external Ba(2+) or Cs(+) prevented isovaline responses. In conclusion, isovaline inhibited firing mainly by activating rectifying and possibly leak K(+) currents. Isovaline-induced changes shunted action potentials and suppressed rebound excitation in ventrobasal neurons, as expected for analgesic actions.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, V6T 1Z3 Canada.
authors.forename: J E
authors.initials: JE
authors.lastname: Cooke
authors.forename: D A
authors.initials: DA
authors.lastname: Mathers
authors.forename: E
authors.initials: E
authors.lastname: Puil
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000819:agonists; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000187:drug effects / Q000378:metabolism; D014633:Valine / Q000494:pharmacology* / Q000627:therapeutic use; D020651:Ventral Thalamic Nuclei / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000700:Analgesics; D015221:Potassium Channels; D018009:Receptors, Glycine; C032737:isovaline; D014633:Valine; D005998:Glycine