Morphine ( serum/blood ) ELISA Kit

The roles of serotonin and noradrenaline in the modulation of chronic pruriceptive processing currently remain unclear. To clarify the contribution of serotonin and noradrenaline to chronic itch, the effects of the administration of antidepressants or noradrenaline reuptake inhibitors were evaluated in the present study. A pretreatment with milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine, a noradrenergic and specific serotonergic antidepressant, attenuated the induction of spontaneous scratching behavior in mice with chronic itch. The administration of a serotonin reuptake inhibitor, such as fluvoxamine and paroxetine, but not escitalopram, or a noradrenaline reuptake inhibitor, such as atomoxetine and nisoxetine, ameliorated the induction of spontaneous scratching behavior in mice with chronic itch. Furthermore, this attenuation was reversed by the administration of yohimbine, a selective alpha(2)-adrenoceptor antagonist, or methysergide, a nonselective serotonin receptor antagonist. These results suggest that elevated serotonin and noradrenaline levels are involved in the attenuation of scratching behavior induced by chronic itch, and serotonin receptors and an alpha(2)-adrenoceptor play a crucial role in chronic pruriceptive processing.

Based on studies using mutations of the mu-opioid receptor (MOR), phosphorylation of multiple sites on the C-terminus has been recognized as a critical step underlying acute desensitization and the development of cellular tolerance. The aim of this study is to explore which kinases mediate desensitization of MOR in brain slices from drug-naive and morphine-treated animals. Whole-cell recordings from locus coeruleus neurons were made, and the agonist-induced increase in potassium conductance was measured. In slices from naive animals, pharmacological inhibition of G-protein receptor kinase (GRK2/3) with compound 101 blocked acute desensitization. Following chronic treatment with morphine, compound 101 was less effective at blocking acute desensitization. Compound 101 blocked receptor internalization in tissue from both naive and morphine-treated animals, suggesting that GRK2/3 remained active. Kinase inhibitors aimed at blocking protein kinase C and c-Jun N-terminal kinase had no effect on desensitization in tissue taken from naive animals. However, in slices taken from morphine-treated animals, the combination of these blockers along with compound 101 was required to block acute desensitization. Acute desensitization of the potassium conductance induced by the somatostatin receptor was also blocked by compound 101 in slices from naive but not morphine-treated animals. As was observed with MOR, it was necessary to use the combination of kinase inhibitors to block desensitization of the somatostatin receptor in slices from morphine-treated animals. The results show that chronic treatment with morphine results in a surprising and heterologous adaptation in kinase-dependent desensitization. SIGNIFICANCE STATEMENT The results show that chronic treatment with morphine induced heterologous adaptations in kinase regulation of G protein coupled receptor (GPCR) desensitization. Although the canonical mechanism for acute desensitization through phosphorylation by G protein-coupled receptor kinase is supported in tissue taken from naive animals, following chronic treatment with morphine, the acute kinase-dependent desensitization of GPCRs is disrupted such that additional kinases, including protein kinase C and c-Jun N-terminal kinase, contribute to desensitization.