Sustained morphine treatment augments prostaglandin E2-evoked calcitonin gene-related peptide release from primary sensory neurons in a PKA-dependent manner

Suneeta Tumati, William R Roeske, Todd W Vanderah, Eva V. Varga

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Tissue damage leads to pain sensitization due to peripheral and central release of excitatory mediators such as prostaglandin E2 (PGE2). PGE2 sensitizes spinal pain neurotransmitter such as calcitonin gene-related peptide (CGRP) release via activation of cyclic AMP (cAMP)/protein kinase A (PKA)-dependent signaling mechanisms. Our previous data demonstrate that sustained morphine pretreatment sensitizes adenylyl cyclase(s) (AC) toward the direct stimulator, forskolin, in cultured primary sensory neurons (AC superactivation). In the present work we investigated the hypothesis that morphine pretreatment also sensitizes ACs toward Gs-protein-coupled excitatory modulators (such as PGE2), leading to augmented PKA-dependent CGRP release from PGE2-stimulated primary sensory dorsal root ganglion (DRG) neurons. Our results show that sustained morphine treatment potentiated PGE2-mediated cAMP formation and augmented PGE2-evoked CGRP release from cultured primary sensory neurons in a PKA-dependent manner. Our data suggest that attenuation of AC superactivation in primary sensory neurons may prevent the development of opioid-induced hyperalgesia.

Original languageEnglish (US)
Pages (from-to)95-101
Number of pages7
JournalEuropean Journal of Pharmacology
Volume648
Issue number1-3
DOIs
StatePublished - Dec 1 2010

Fingerprint

Calcitonin Gene-Related Peptide
Sensory Receptor Cells
Cyclic AMP-Dependent Protein Kinases
Dinoprostone
Morphine
Cyclic AMP
Therapeutics
Sensory Ganglia
Pain
Adenylate Kinase
Hyperalgesia
Spinal Ganglia
Colforsin
Adenylyl Cyclases
Opioid Analgesics
Neurotransmitter Agents
Neurons
Proteins

Keywords

  • CGRP release
  • DRG neurons
  • Gs protein signaling
  • Morphine
  • Opioid-induced hyperalgesia
  • PGE
  • PKA

ASJC Scopus subject areas

  • Pharmacology

Cite this

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abstract = "Tissue damage leads to pain sensitization due to peripheral and central release of excitatory mediators such as prostaglandin E2 (PGE2). PGE2 sensitizes spinal pain neurotransmitter such as calcitonin gene-related peptide (CGRP) release via activation of cyclic AMP (cAMP)/protein kinase A (PKA)-dependent signaling mechanisms. Our previous data demonstrate that sustained morphine pretreatment sensitizes adenylyl cyclase(s) (AC) toward the direct stimulator, forskolin, in cultured primary sensory neurons (AC superactivation). In the present work we investigated the hypothesis that morphine pretreatment also sensitizes ACs toward Gs-protein-coupled excitatory modulators (such as PGE2), leading to augmented PKA-dependent CGRP release from PGE2-stimulated primary sensory dorsal root ganglion (DRG) neurons. Our results show that sustained morphine treatment potentiated PGE2-mediated cAMP formation and augmented PGE2-evoked CGRP release from cultured primary sensory neurons in a PKA-dependent manner. Our data suggest that attenuation of AC superactivation in primary sensory neurons may prevent the development of opioid-induced hyperalgesia.",
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AU - Varga, Eva V.

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AB - Tissue damage leads to pain sensitization due to peripheral and central release of excitatory mediators such as prostaglandin E2 (PGE2). PGE2 sensitizes spinal pain neurotransmitter such as calcitonin gene-related peptide (CGRP) release via activation of cyclic AMP (cAMP)/protein kinase A (PKA)-dependent signaling mechanisms. Our previous data demonstrate that sustained morphine pretreatment sensitizes adenylyl cyclase(s) (AC) toward the direct stimulator, forskolin, in cultured primary sensory neurons (AC superactivation). In the present work we investigated the hypothesis that morphine pretreatment also sensitizes ACs toward Gs-protein-coupled excitatory modulators (such as PGE2), leading to augmented PKA-dependent CGRP release from PGE2-stimulated primary sensory dorsal root ganglion (DRG) neurons. Our results show that sustained morphine treatment potentiated PGE2-mediated cAMP formation and augmented PGE2-evoked CGRP release from cultured primary sensory neurons in a PKA-dependent manner. Our data suggest that attenuation of AC superactivation in primary sensory neurons may prevent the development of opioid-induced hyperalgesia.

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