Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner
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Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner. / Spahn, Viola; Fischer, Oliver; Endres-Becker, Jeannette; Schäfer, Michael; Stein, Christoph; Zöllner, Christian.
in: PAIN, Jahrgang 154, Nr. 4, 01.04.2013, S. 598-608.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner
AU - Spahn, Viola
AU - Fischer, Oliver
AU - Endres-Becker, Jeannette
AU - Schäfer, Michael
AU - Stein, Christoph
AU - Zöllner, Christian
N1 - Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
PY - 2013/4/1
Y1 - 2013/4/1
N2 - Hyperalgesia is a cardinal symptom of opioid withdrawal. The transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated ion channel expressed on sensory neurons responding to noxious heat, protons, and chemical stimuli such as capsaicin. TRPV1 can be inhibited via μ-opioid receptor (MOR)-mediated reduced activity of adenylyl cyclases (ACs) and decreased cyclic adenosine monophosphate (cAMP) levels. In contrast, opioid withdrawal following chronic activation of MOR uncovers AC superactivation and subsequent increases in cAMP and protein kinase A (PKA) activity. Here we investigated (1) whether an increase in cAMP during opioid withdrawal increases the activity of TRPV1 and (2) how opioid withdrawal modulates capsaicin-induced nocifensive behavior in rats. We applied whole-cell patch clamp, microfluorimetry, cAMP assays, radioligand binding, site-directed mutagenesis, and behavioral experiments. Opioid withdrawal significantly increased cAMP levels and capsaicin-induced TRPV1 activity in both transfected human embryonic kidney 293 cells and dissociated dorsal root ganglion (DRG) neurons. Inhibition of AC and PKA, as well as mutations of the PKA phosphorylation sites threonine 144 and serine 774, prevented the enhanced TRPV1 activity. Finally, capsaicin-induced nocifensive behavior was increased during opioid withdrawal in vivo. In summary, our results demonstrate an increased activity of TRPV1 in DRG neurons as a new mechanism contributing to opioid withdrawal-induced hyperalgesia.
AB - Hyperalgesia is a cardinal symptom of opioid withdrawal. The transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated ion channel expressed on sensory neurons responding to noxious heat, protons, and chemical stimuli such as capsaicin. TRPV1 can be inhibited via μ-opioid receptor (MOR)-mediated reduced activity of adenylyl cyclases (ACs) and decreased cyclic adenosine monophosphate (cAMP) levels. In contrast, opioid withdrawal following chronic activation of MOR uncovers AC superactivation and subsequent increases in cAMP and protein kinase A (PKA) activity. Here we investigated (1) whether an increase in cAMP during opioid withdrawal increases the activity of TRPV1 and (2) how opioid withdrawal modulates capsaicin-induced nocifensive behavior in rats. We applied whole-cell patch clamp, microfluorimetry, cAMP assays, radioligand binding, site-directed mutagenesis, and behavioral experiments. Opioid withdrawal significantly increased cAMP levels and capsaicin-induced TRPV1 activity in both transfected human embryonic kidney 293 cells and dissociated dorsal root ganglion (DRG) neurons. Inhibition of AC and PKA, as well as mutations of the PKA phosphorylation sites threonine 144 and serine 774, prevented the enhanced TRPV1 activity. Finally, capsaicin-induced nocifensive behavior was increased during opioid withdrawal in vivo. In summary, our results demonstrate an increased activity of TRPV1 in DRG neurons as a new mechanism contributing to opioid withdrawal-induced hyperalgesia.
KW - Analgesics, Opioid
KW - Animals
KW - Calcium
KW - Capsaicin
KW - Cells, Cultured
KW - Cyclic AMP
KW - Cyclic AMP-Dependent Protein Kinases
KW - Disease Models, Animal
KW - Diterpenes
KW - Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
KW - Enzyme Inhibitors
KW - Fentanyl
KW - Ganglia, Spinal
KW - Humans
KW - Hyperalgesia
KW - Male
KW - Membrane Potentials
KW - Morphine
KW - Mutagenesis, Site-Directed
KW - Protein Binding
KW - Rats
KW - Receptors, Opioid, mu
KW - Sensory Receptor Cells
KW - Substance Withdrawal Syndrome
KW - TRPV Cation Channels
KW - Tritium
U2 - 10.1016/j.pain.2012.12.026
DO - 10.1016/j.pain.2012.12.026
M3 - SCORING: Journal article
C2 - 23398938
VL - 154
SP - 598
EP - 608
JO - PAIN
JF - PAIN
SN - 0304-3959
IS - 4
ER -
