British journal of pharmacology
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In a hamster model (genetic symbol dt(sz)) of primary paroxysmal non-kinesiogenic dystonic choreoathetosis, recent studies have shown beneficial effects of glutamate and dopamine receptor antagonists. Nitric oxide (NO), synthesized from L-arginine by NO synthase in response to glutamate receptor activation, elicits cyclic GMP and modulates glutamate-mediated processes and striatal dopamine release. Therefore, the effects of NO synthase inhibitors and of L-arginine on severity of dystonia were investigated in dt(sz) hamsters in which dystonic attacks, characterized by twisting movements and postures, can be induced by stress. ⋯ L-NAME significantly decreased the cerebellar cyclic GMP levels in both dt(sz) and control hamsters. Although an overproduction of NO is probably not critically involved in the pathogenesis of paroxysmal dystonia, it may contribute to the manifestation of dystonic attacks, as indicated by the antidystonic effects of NO synthase inhibitors. Peripheral side effects may limit the clinical use of NO synthase inhibitors, but more selective inhibitors of the neuronal NO synthase should be considered as interesting candidates for the treatment of paroxysmal dystonia.
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This study examined the effects of the peptide CGRP receptor antagonist CGRP(8-37) and the newly-developed non-peptide CGRP receptor antagonist BIBN4096BS for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. Repeated administration of intrathecal morphine (15 microg), once daily, produced a progressive decline of antinociceptive effect and an increase in the ED(50) value in the tailflick and paw pressure tests. Co-administration of CGRP(8-37) (4 microg) or BIBN4096BS (0.05, 0.1 microg) with morphine (15 microg) prevented the decline of antinociceptive effect and increase in ED(50) value in the tailflick test. ⋯ In animals already tolerant to morphine, the increase in CGRP but not substance P-like immunostaining was partially reversed by CGRP(8-37) (4 microg). These data suggest that activation of spinal CGRP receptors contributes to both the development and expression of spinal opioid tolerance. CGRP receptor antagonists may represent a useful therapeutic approach for preventing as well as reversing opioid tolerance.