|Title||Intrathecal PKA-selective siRNA treatment blocks sustained morphine-mediated pain sensitization and antinociceptive tolerance in rats.|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Tumati S, Roeske WR, Largent-Milnes TM, Vanderah TW, Varga EV|
|Journal||J Neurosci Methods|
|Date Published||2011 Jul 15|
|Keywords||Animals, 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|
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.
|Alternate Journal||J. Neurosci. Methods|
|PubMed Central ID||PMC3120016|
|Grant List||P01 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
Intrathecal PKA-selective siRNA treatment blocks sustained morphine-mediated pain sensitization and antinociceptive tolerance in rats.
Faculty Member Reference:
Tally Largent-Milnes, PhD
Todd Vanderah, Ph.D.