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

S. Tumati, William R Roeske, T. M. Largent-Milnes, Todd W Vanderah, E. V. Varga

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)62-68
Number of pages7
JournalJournal of Neuroscience Methods
Volume199
Issue number1
DOIs
StatePublished - Jul 15 2011

Fingerprint

Calcitonin Gene-Related Peptide
Hyperalgesia
RNA Interference
Protein Kinases
Morphine
Opioid Analgesics
Pain
Cyclic AMP-Dependent Protein Kinases
Neurotransmitter Agents
Sensory Ganglia
Capsaicin
Spinal Ganglia
Therapeutics
Substance P
Adenylyl Cyclases
Cyclic AMP
Up-Regulation
Neurons

Keywords

  • Allodynia
  • Analgesic tolerance
  • Hyperalgesia
  • Opioid
  • PKA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Intrathecal PKA-selective siRNA treatment blocks sustained morphine-mediated pain sensitization and antinociceptive tolerance in rats. / Tumati, S.; Roeske, William R; Largent-Milnes, T. M.; Vanderah, Todd W; Varga, E. V.

In: Journal of Neuroscience Methods, Vol. 199, No. 1, 15.07.2011, p. 62-68.

Research output: Contribution to journalArticle

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