title: Sustained morphine treatment augments prostaglandin E2-evoked calcitonin gene-related peptide release from primary sensory neurons in a PKA-dependent manner.
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.
authors.affiliation: Department of Pharmacology, The University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Suneeta
authors.initials: S
authors.lastname: Tumati
authors.forename: William R
authors.initials: WR
authors.lastname: Roeske
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Eva V
authors.initials: EV
authors.lastname: Varga
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D010146:Pain / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018377:Neurotransmitter Agents; D047428:Protein Kinase Inhibitors; D018015:Receptors, Calcitonin Gene-Related Peptide; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D009020:Morphine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015740:Calcitonin Gene-Related Peptide; D015232:Dinoprostone
references.citation: J Neurosci. 1995 Apr;15(4):2768-76
references.pmid: 7722627
references.citation: Eur J Pharmacol. 1997 Dec 11;340(2-3):227-41
references.pmid: 9537820
references.citation: J Pharmacol Exp Ther. 1996 Sep;278(3):1083-9
references.pmid: 8819489
references.citation: J Pharmacol Exp Ther. 2009 Sep;330(3):810-7
references.pmid: 19491327
references.citation: Mol Pharmacol. 1993 Apr;43(4):556-63
references.pmid: 8386308
references.citation: Adv Prostaglandin Thromboxane Leukot Res. 1991;21B:739-41
references.pmid: 1705083
references.citation: Br J Pharmacol. 1999 Jun;127(3):631-44
references.pmid: 10401553
references.citation: J Pharmacol Exp Ther. 2007 Jul;322(1):360-8
references.pmid: 17468301
references.citation: Prog Neurobiol. 2001 Jul;64(4):327-63
references.pmid: 11275357
references.citation: Anesthesiology. 2005 Feb;102(2):421-8
references.pmid: 15681961
references.citation: Br J Pharmacol. 2002 May;136(1):37-48
references.pmid: 11976266
references.citation: Br J Pharmacol. 1993 Jan;108(1):185-90
references.pmid: 7679028
references.citation: J Biol Chem. 2001 May 11;276(19):16083-91
references.pmid: 11278900
references.citation: Proc Natl Acad Sci U S A. 1977 Aug;74(8):3365-9
references.pmid: 269396
references.citation: Anesthesiology. 2000 Aug;93(2):409-17
references.pmid: 10910490
references.citation: Pain. 1999 Jul;82(1):65-72
references.pmid: 10422661
references.citation: Anesthesiology. 2008 Mar;108(3):352-4
references.pmid: 18292670
references.citation: Anesth Analg. 2009 Aug;109(2):623-31
references.pmid: 19608840
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Eur J Pharmacol. 2008 Apr 28;584(2-3):272-7
references.pmid: 18328477
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19038-43
references.pmid: 18799742
references.citation: J Biol Chem. 1997 Feb 21;272(8):5040-7
references.pmid: 9030567
references.citation: J Neurosci. 1994 Aug;14(8):4987-97
references.pmid: 7519258
references.citation: Eur J Pharmacol. 2006 Jul 1;540(1-3):57-9
references.pmid: 16750187
references.citation: Biopolymers. 2005;80(2-3):319-24
references.pmid: 15795927
references.citation: Anesthesiology. 2002 Feb;96(2):381-91
references.pmid: 11818772
references.citation: Mol Pharmacol. 2001 Nov;60(5):1076-82
references.pmid: 11641436
references.citation: J Pharmacol Exp Ther. 2006 Dec;319(3):1096-103
references.pmid: 16966471
references.citation: Bone. 2004 Jan;34(1):157-62
references.pmid: 14751573
references.citation: Acta Biochim Biophys Sin (Shanghai). 2008 Jul;40(7):651-62
references.pmid: 18604457