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: J E Cooke, D A Mathers, E Puil
• Journal: Neuroscience (Neuroscience) Vol. 164 Issue 3 Pg. 1235-43 (Dec 15 2009) ISSN: 1873-7544 [Electronic] United States
• PMID: 19720114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Potassium Channels
• Receptors, Glycine
• isovaline
• Valine
• Glycine

Topics

• Action Potentials (drug effects, physiology)
• Analgesics (pharmacology, therapeutic use)
• Animals
• Animals, Newborn
• Calcium Signaling (drug effects, physiology)
• Dose-Response Relationship, Drug
• Glycine (agonists)
• Neural Inhibition (drug effects, physiology)
• Neurons (drug effects, metabolism)
• Organ Culture Techniques
• Pain (drug therapy, metabolism, physiopathology)
• Patch-Clamp Techniques
• Potassium Channels (drug effects, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Glycine (drug effects, metabolism)
• Valine (pharmacology, therapeutic use)
• Ventral Thalamic Nuclei (drug effects, metabolism)