• DOI:10.1213/ANE.0b013e3181d27da2
• Corpus ID: 24383709

Analgesic Properties of the Novel Amino Acid, Isovaline

@article{MacLeod2010AnalgesicPO,
  title={Analgesic Properties of the Novel Amino Acid, Isovaline},
  author={Bernard A. MacLeod and Jimmy T. C. Wang and Cheryl C W Chung and Craig R. Ries and Stephan K. W. Schwarz and Ernest Puil},
  journal={Anesthesia \& Analgesia},
  year={2010},
  volume={110},
  pages={1206–1214}
}

• B. MacLeod, Jimmy T. C. Wang, +3 authors E. Puil
• Published 1 April 2010
• Medicine, Biology
• Anesthesia & Analgesia

BACKGROUND:Isovaline, a nonproteinogenic &agr;-amino acid rarely found in the biosphere, is structurally similar to the inhibitory neurotransmitters glycine and &ggr;-aminobutyric acid. Because glycineA and &ggr;-aminobutyric acid receptor agonists are antiallodynic, we hypothesized that isovaline produces antinociception in mice. METHODS:All experiments were performed on female CD-1 mice using a blinded, randomized, and controlled design. The effects of RS-isovaline were studied on nociceptive responses to (1) formalin injection into the hindpaw; (2) glutamate injection into the hindpaw; and (3) strychnine injection either into the lumbar intrathecal space or cisterna magna. We determined the effects of IV RS-isovaline (50, 150, or 500 mg/kg; n = 10/dose) or intrathecal RS-, R-, and S-isovaline, glycine, and &bgr;-alanine into the lumbar intrathecal space (5-&mgr;L volumes of 60, 125, 250, and 500 mM; n = 9/dose/group) on the response to formalin in the paw. The response to 20 &mgr;L intraplantar glutamate (750 mM) was compared with glutamate (750 mM) coadministered with isovaline. We also determined the response to intraplantar strychnine. Lumbar intrathecal (100 &mgr;M) or intracisternal (200 &mgr;M) injections of strychnine into the lumbar intrathecal space or the cisterna magna were used to induce allodynia as a measure of glycine inhibitory dysfunction. The effects of intrathecal or intracisternal strychnine were compared with isovaline coapplied with the strychnine (n = 8/group). RESULTS:In the formalin paw test, IV isovaline did not change phase I but decreased phase II responses in a dose-dependent manner (50% effective dose = 66 mg/kg, n = 10, P < 0.01). There was no effect on rotarod performance, appearance, or behavior of the mouse, and no respiratory depression. Intrathecal isovaline, glycine, and &bgr;-alanine attenuated phase I and II responses (P < 0.01 for each drug). In contrast to &bgr;-alanine and glycine, isovaline at maximally effective doses did not produce scratching, biting, or agitation. Intrathecal RS- and S-isovaline attenuated phase I (P < 0.05 for each group) and RS-, R-, and S-isovaline attenuated phase II responses (P < 0.05 for each group), with no significant difference between the efficacies of R- and S-enantiomers. Localized strychnine-induced glycine inhibitory dysfunction was greatly reduced by intracisternal (P < 0.01) and intrathecal (P < 0.01) isovaline. Although intraplantar strychnine did not induce peripheral allodynia, high doses of isovaline did not block the peripheral allodynia induced by glutamate. CONCLUSIONS:Isovaline reduced responses in mouse pain models without producing acute toxicity, possibly by enhancing receptor modulation of nociceptive information.