Isovaline causes inhibition by increasing potassium conductance in thalamic neurons

• Published in: Neuroscience 2009-12, Vol.164 (3), p.1235-1243
• Main Authors: Cooke, J.E, Mathers, D.A, Puil, E
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; analgesic; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Animals, Newborn; Biological and medical sciences; Calcium Signaling - drug effects; Calcium Signaling - physiology; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Glycine - agonists; glycine receptor; Neural Inhibition - drug effects; Neural Inhibition - physiology; Neurology; Neurons - drug effects; Neurons - metabolism; nociception; Organ Culture Techniques; Pain - drug therapy; Pain - metabolism; Pain - physiopathology; Patch-Clamp Techniques; Potassium Channels - drug effects; Potassium Channels - metabolism; potassium conductance; R-isovaline; Rats; Rats, Sprague-Dawley; Receptors, Glycine - drug effects; Receptors, Glycine - metabolism; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; thalamus; Valine - pharmacology; Valine - therapeutic use; Ventral Thalamic Nuclei - drug effects; Ventral Thalamic Nuclei - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2009.08.045

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 glycineA 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 Ca2+ 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 ∼100 μM, 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 Ca2+ or blockade of the hyperpolarization-activated current, Ih . Internal Cs+ and external Ba2+ 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.