Diminished inflammation and nociceptive pain with preservation of neuropathic pain in mice with a targeted mutation of the type I regulatory subunit of cAMP-dependent protein kinase.
To assess the contribution of PKA to injury-induced inflammation and pain, we evaluated nociceptive responses in mice that carry a null mutation in the gene that encodes the neuronal-specific isoform of the type I regulatory subunit (RIbeta) of PKA. Acute pain indices did not differ in the RIbeta PKA mutant mice compared with wild-type controls. However, tissue injury-evoked persistent pain behavior, inflammation of the hindpaw, and ipsilateral dorsal horn Fos immunoreactivity was significantly reduced in the mutant mice, as was plasma extravasation induced by intradermal injection of capsaicin into the paw. The enhanced thermal sensitivity observed in wild-type mice after intraplantar or intrathecal (spinal) administration of prostaglandin E2 was also reduced in mutant mice. In contrast, indices of pain behavior produced by nerve injury were not altered in the mutant mice. Thus, RIbeta PKA is necessary for the full expression of tissue injury-evoked (nociceptive) pain but is not required for nerve injury-evoked (neuropathic) pain. Because the RIbeta subunit is only present in the nervous system, including small diameter trkA receptor-positive dorsal root ganglion cells, we suggest that in inflammatory conditions, RIbeta PKA is specifically required for nociceptive processing in the terminals of small-diameter primary afferent fibers.
Malmberg
A B
AB
Department of Anatomy, University of California, San Francisco, San Francisco, California 94143, USA.
Brandon
E P
EP
Idzerda
R L
RL
Liu
H
H
McKnight
G S
GS
Basbaum
A I
AI
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D004056:Differential Threshold; D015232:Dinoprostone / Q000494:pharmacology; D015870:Gene Expression; D018390:Gene Targeting; D006358:Hot Temperature; D007527:Isoenzymes / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009443:Neuritis / Q000209:etiology / Q000503:physiopathology; D009619:Nociceptors / Q000502:physiology*; D010146:Pain; D012584:Sciatic Nerve / Q000293:injuries*; D012684:Sensory Thresholds / Q000187:drug effects; D019076:Transgenes / Q000235:genetics; D014949:Wounds, Nonpenetrating / Q000473:pathology* / Q000503:physiopathology
D054753:Cyclic AMP-Dependent Protein Kinase RIbeta Subunit; D007527:Isoenzymes; C517768:Prkar1b protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D002211:Capsaicin