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Antiallodynia and surgical immobility produced by the non-proteinogenic brain impermeant amino acid, isovaline Whitehead, Ryan Arthur

Abstract

This thesis describes research stemming from investigation of the novel nonproteinogenic amino acid, isovaline. The first chapter is a background for the field of study. The second chapter investigates peripheral GABAB receptor-mediated mechanisms of action of isovaline, ɤ-aminobutyric acid (GABA), and baclofen. The third chapter details experimental evidence demonstrating that a combination of central hypnosis and peripheral analgesia produces general anesthesia. The fourth chapter describes the development and evaluation of a novel model of human trigeminal allodynia, a feature of intractable and severe pain in trigeminal neuralgia. The mechanism of action of isovaline, as for GABA and baclofen, was found involve peripheral GABAB receptors, revealed through attenuation of peripheral prostaglandin E₂ (PGE₂)-induced allodynia. This mechanism was tested by reversal of allodynia by the GABAB antagonist CGP52432 and potentiation of allodynia by the GABAB positive modulator CGP7930. Immunohistochemical staining showed confluence of GABAB₁ and GABAB₂ subunits on free nerve endings and keratinocytes. Peripherally administered isovaline and GABA produced analgesia but no CNS depression, whereas baclofen produced analgesia accompanied by pronounced sedation and hypothermia. In a forced exercise model of osteoarthritic dysfunction isovaline restored joint operability lost presumably due to knee pain. Next, we hypothesized that co-administration of a peripherally restricted analgesic with a central hypnotic (isovaline co-administered with propofol) would produce general anesthesia in mice. We first demonstrated that isovaline and fentanyl produced surgical analgesia without appreciable sedation. Propofol alone produced hypnosis without analgesia or surgical anesthesia. When administered with hypnotic doses of propofol, coadministration of isovaline resulted in general anesthesia. Under fixed ratio hypnotic and analgesic dose ratios, propofol-isovaline anesthesia had a markedly higher therapeutic index than propofol-fentanyl. When co-administered with a fixed hypnotic dose of propofol, isovaline in contrast to fentanyl did not have a maximum tolerated dose (MTD). Next we describe an intracisternal strychnine mouse model of human trigeminal neuropathic pain is described. The model reflects the efficacy of clinical drug treatments as morphine administered intraperitoneally was not effective, but intracisternally injected carbamazepine epoxide provided pain relief. Isovaline applied near the spinal trigeminal nucleus was effective in this model, validating its utility in detecting efficacy of novel analgesics.

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