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Volume 17, Number 19,
Issue of October 1, 1997
pp. 7462-7470
Copyright ©1997 Society for Neuroscience
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
Received May 5, 1997; revised July 16, 1997; accepted July 18, 1997.
Annika B. Malmberg1,
Eugene P. Brandon2,
Rejean
L. Idzerda2,
Hantao Liu1,
G. Stanley McKnight2, and
Allan I. Basbaum1
1 Departments of Anatomy and Physiology and W. M. Keck Center for Integrative Neuroscience, University of California, San
Francisco, San Francisco, California 94143, and
2 Department of Pharmacology, University of Washington
School of Medicine, Seattle, Washington 98195
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 (RI ) of PKA. Acute pain indices did not
differ in the RI 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, RI 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 RI subunit is only
present in the nervous system, including small diameter trkA
receptor-positive dorsal root ganglion cells, we suggest that in
inflammatory conditions, RI PKA is specifically required for
nociceptive processing in the terminals of small-diameter primary
afferent fibers.
Key words:
peripheral and central sensitization;
inflammatory pain;
plasma extravasation;
prostaglandins;
spinal cord plasticity;
PKA RI
expression
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