Arizona Health Sciences

Intrathecal PKA-selective siRNA treatment blocks sustained morphine-mediated pain sensitization and antinociceptive tolerance in rats.

TitleIntrathecal PKA-selective siRNA treatment blocks sustained morphine-mediated pain sensitization and antinociceptive tolerance in rats.
Publication TypeJournal Article
Year of Publication2011
AuthorsTumati S, Roeske WR, Largent-Milnes TM, Vanderah TW, Varga EV
JournalJ Neurosci Methods
Volume199
Issue1
Pagination62-8
Date Published2011 Jul 15
ISSN1872-678X
KeywordsAnimals, Calcitonin Gene-Related Peptide, Capsaicin, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Genetic Therapy, Hot Temperature, Hyperalgesia, Injections, Spinal, Male, Morphine, Narcotics, Posterior Horn Cells, Presynaptic Terminals, Rats, Rats, Sprague-Dawley, RNA Interference, RNA, Small Interfering, Second Messenger Systems, Spinal Cord, Stress, Mechanical
Abstract

Sustained morphine treatment has been shown to produce paradoxical pain sensitization (opioid-induced hyperalgesia) and also causes increase in spinal pain neurotransmitter, such as calcitonin gene related peptide (CGRP), concentration in experimental animals. Studies have also shown that cyclic adenosine-monophosphate (cAMP)-dependent protein kinase (PKA) plays a major role in the regulation of presynaptic neurotransmitter (such as CGRP and substance P) synthesis and release. We have previously shown that in cultured primary sensory dorsal root ganglion (DRG) neurons sustained in vitro opioid agonist treatment upregulates cAMP levels (adenylyl cyclase (AC) superactivation) and augments basal and capsaicin evoked CGRP release in a PKA dependent manner. In the present study, we investigated the in vivo role of PKA in sustained morphine-mediated pain sensitization. Our data indicate that selective knock-down of spinal PKA activity by intrathecal (i.th.) pretreatment of rats with a PKA-selective small interference RNA (siRNA) mixture significantly attenuates sustained morphine-mediated augmentation of spinal CGRP immunoreactivity, thermal hyperalgesia, mechanical allodynia and antinociceptive tolerance. The present findings indicate that sustained morphine-mediated activation of spinal cAMP/PKA-dependent signaling may play an important role in opioid induced hyperalgesia.

DOI10.1016/j.jneumeth.2011.04.036
Alternate JournalJ. Neurosci. Methods
PubMed ID21571003
PubMed Central IDPMC3120016
Grant ListP01 DA006284-04 / DA / NIDA NIH HHS / United States
GM 065465 / GM / NIGMS NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
P01 DA006284 / DA / NIDA NIH HHS / United States
DA06284 / DA / NIDA NIH HHS / United States
R01 GM065465 / GM / NIGMS NIH HHS / United States
P01 DA006284-04S1 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, Ph.D.
Todd Vanderah, PhD