| Summary: | Chronic pain is a prevalent problem in society and is inadequately managed using current analgesics. Central disinhibition, produced by dysregulation of excitatory or inhibitory signaling, is responsible for most, if not all, chronic pain states. In particular, an impairment of glycinergic and GABAergic pathways is associated with hypersensitivity and allodynia. Selectively restoration of such inhibitory signaling will likely be of therapeutic value. We explored this hypothesis by characterizing in vivo effects of novel analgesics isovaline and 1-amino-cyclobutane carboxylic acid (ACBC), using a broad spectrum of acute, tonic and chronic pain models.
At all doses tested, neither isovaline nor ACBC have appreciable effects on heart rate, breathing rate or behaviour in rodents. They decreased both formalin-induced phase I and II paw licking response. The effect of isovaline and ACBC on monosodium iodoacetate- (MIA-) induced osteoarthritis in rats could not be evaluated due to large interanimal variability. However, behavioural assays for mouse osteoarthritis were examined; of these, the inverted wire mesh was the most promising. A substantial decrease of hind paw grip duration was observed in MIA-treated animals which lasted for over 21 days. The grip impairment was reversed by morphine, but not diclofenac, on day 14 only.
Isovaline and ACBC are effective in heat-induced acute nociceptive models in mice. Both compounds increased tail flick latency in the hot water tail immersion assay with a non-sigmoidal dose-response relationship, in which middle, but not higher doses were efficacious. A similar pattern of dose-response was observed in the hotplate model for ACBC. High dose isovaline did not change latency to paw licking on the hotplate.
The effects of intraplantar administration of glutamate in mice have also been examined. Peripheral glutamate elicited paw licking and allodynia in a dose-dependent fashion. Paw licking response was blocked by co-administration of ACBC, while isovaline was not effective.
These results indicate both compounds have antinociceptive properties without obvious side effects. They likely have mixed effects on different receptor systems. Further exploration is required to elucidate their mechanisms of action. However restoration of central inhibition appears to be a route for the discovery of new analgesics.
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