Analgesic properties of the novel amino acid, isovaline.
BACKGROUND
Isovaline, a nonproteinogenic alpha-amino acid rarely found in the biosphere, is structurally similar to the inhibitory neurotransmitters glycine and gamma-aminobutyric acid. Because glycine(A) and gamma-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 beta-alanine into the lumbar intrathecal space (5-microL volumes of 60, 125, 250, and 500 mM; n = 9/dose/group) on the response to formalin in the paw. The response to 20 microL intraplantar glutamate (750 mM) was compared with glutamate (750 mM) coadministered with isovaline. We also determined the response to intraplantar strychnine. Lumbar intrathecal (100 microM) or intracisternal (200 microM) 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 beta-alanine attenuated phase I and II responses (P < 0.01 for each drug). In contrast to beta-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.
MacLeod
Bernard A
BA
Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, BC, Canada V6T 1Z3. bmacleod@interchange.ubc.ca
Wang
Jimmy T C
JT
Chung
Cheryl C W
CC
Ries
Craig R
CR
Schwarz
Stephan K W
SK
Puil
Ernest
E
D000208:Acute Disease; D018712:Analgesics, Non-Narcotic; D000818:Animals; D002908:Chronic Disease; D002946:Cisterna Magna; D005260:Female; D005557:Formaldehyde; D018698:Glutamic Acid; D005998:Glycine / Q000737:chemistry / Q000494:pharmacology; D006993:Hypnotics and Sedatives; D007267:Injections; D007275:Injections, Intravenous; D007278:Injections, Spinal; D051379:Mice; D008958:Models, Molecular; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects*; D004856:Postural Balance / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects; D013331:Strychnine; D014633:Valine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015091:beta-Alanine / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D006993:Hypnotics and Sedatives; D017470:Receptors, Glutamate; D015091:beta-Alanine; D005557:Formaldehyde; D018698:Glutamic Acid; C032737:isovaline; D013331:Strychnine; D014633:Valine; D005998:Glycine