Sustained morphine treatment was shown to increase the concentration of excitatory Gs protein-coupled neuromodulators (such as PGE2 and dynorphin) and augment pain neurotransmitter release in the spinal cord. In Project C we will investigate the role of cAMP-regulated signaling pathways in the regulation of pain neurotransmitter (CGRP) release from cultured neonatal rat primary sensory (DRG) neurons by PGE2 and a non-opioid fragment of spinal dynorphin, dyn2-13. In addition, since earlier we have shown that sustained morphine treatment leads to a Raf-1 -mediated sensitization of adenylyl cyclase(s) (AC superactivation) towards excitatory agents in recombinant cells, in Project C we also will investigate the physiological role of Raf-1-mediated AC superactivation in the sensitization of basal and/or capsaicin-evoked CGRP release from sensory neurons after sustained morphine-treatment. We hypothesize that Raf-1-mediated AC superactivation sensitizes primary sensory neurons to Gs protein-coupled neuromodulators leading to augmented basal and/or evoked CGRP release upon sustained morphine treatment. To evaluate this hypothesis we shall I. investigate the role of Raf-1 in the sensitization of cAMP formation in cultured neonatal rat DRG neurons toward the Gs protein-coupled excitatory neuromodulators, PGE2 and dyn2-13;II. test the role of cAMP, cAMP-dependent protein kinase (PKA) and Raf-1 in the regulation of basal and/or capsaicinevoked CGRP release by PGE2 and dyn2-13 in cultured neonatal rat DRG neurons before and after sustained morphine treatment;and III. study the effect of selected novel compounds - prepared in the Synthetic Core and Project A - on cAMP concentration and basal and capsaicin-evoked CGRP release in cultured neonatal rat DRG neurons, before and after sustained opioid agonist treatment.
Sustained morphine treatment leads to sensitization to painful and innocuous stimuli, contributing to the development of analgesic tolerance. Identification of the cellular mechanisms that sensitize primary sensory neurons toward excitatory stimuli upon sustained morphine treatment should enable us to eliminate sustaine morphine-induced paradoxical pain and thus, reduce antinociceptive tolerance.
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