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. 1997 Oct 1;17(19):7462-70.
doi: 10.1523/JNEUROSCI.17-19-07462.1997.

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

A B Malmberg  1 , E P Brandon, R L Idzerda, H Liu, G S McKnight, A I Basbaum
Affiliations

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

A B Malmberg et al. J Neurosci. .

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Formalin-evoked paw-licking behavior and paw swelling in wild-type and mutant mice. A, Time course of licking behavior of the formalin-injected paw presented as the mean licking time ± SEM per 2 min; n = 5 per group. B, The formalin-evoked paw licking behavior was divided into two phases: phase 1, 0–9 min; andphase 2, 10–60 min. Data are presented as the mean total licking time ± SEM of the first and second phases after formalin injection into the paw. **p < 0.01,t test, comparing wild-type and mutant mice.C, Data are presented as the mean paw diameter ± SEM in millimeters of the formalin-injected and noninjected paws. **p < 0.01, t test, comparing wild-type and mutant mice. ipsi, Ipsilateral;contra, contralateral.
Fig. 2.
Fig. 2.
Photomicrographs illustrating formalin-evoked Fos immunoreactivity at the L4 spinal segment of wild-type (A, B) and mutant (C, D) mice contralateral (A, C) and ipsilateral (B, D) to the paw that received formalin. Scale bar, 150 μm.
Fig. 3.
Fig. 3.
Formalin-evoked Fos immunoreactivity. Data are presented as mean number of Fos-immunoreactive neurons ± SEM on the formalin-injected side at the L4–L5 level; n = 5 mice per group. *p < 0.05; **p < 0.01, Fisher’s PLSD test, comparing the two groups.
Fig. 4.
Fig. 4.
Capsaicin-evoked plasma extravasation. Mutant mice displayed significantly reduced capsaicin-evoked plasma extravasation. Data are presented as mean micrograms per sample extravasated Evans blue ± SEM; n = 5 per group.Asterisks indicate significant differences between wild-type and mutant mice (**p < 0.01,t test).
Fig. 5.
Fig. 5.
Paw withdrawal latencies before and after intraplantar (A) or intrathecal (B) injection of 0.1 μg of PGE2 in wild-type and mutant mice. Mutant mice showed significantly less thermal allodynia compared with wild-type mice after both intraplantar (p < 0.01, repeated measures ANOVA) or intrathecal (p < 0.05) administration of PGE2. Data are presented as the mean latency in seconds ± SEM; n = 5 per group.Asterisks indicate significant differences between the groups (*p < 0.05; **p < 0.01, Fisher’s PLSD test).
Fig. 6.
Fig. 6.
Effect of nerve injury on withdrawal responses to thermal and mechanical stimulation in wild-type and mutant mice.A, Paw withdrawal latencies to thermal stimulation. Data are presented as the mean time in seconds ± SEM to paw withdrawal of the injured (ipsilateral) and the noninjured (contralateral) sides;n = 3 per group. Both groups developed thermal allodynia of comparable magnitude on the injured side.B, Paw withdrawal thresholds to mechanical stimulation. Data are presented as the mean von Frey hair threshold in grams ± SEM of the injured (ipsilateral) and the noninjured (contralateral) sides. There was no difference between the groups in the response to acute thermal or mechanical stimulation (day 0), and the threshold did not change in the nerve-injured animals.
Fig. 7.
Fig. 7.
Photomicrographs illustrating the density of SP (A, B) and SPR (C, D) immunoreactivity at the L4 spinal segment of wild-type mice contralateral (A, C) and ipsilateral (B, D) to the partial injury of the sciatic nerve. Scale bar, 150 μm.
Fig. 8.
Fig. 8.
Nerve injury-induced decreases of SP immunoreactivity (A) and increases of SPR immunoreactivity (B) in the L4–L6 spinal segments in wild-type and mutant mice. The magnitude of nerve injury-induced changes in SP or SPR immunoreactivity was similar for the two groups (ANOVA, p > 0.05). The density of labeling was quantified after digitizing images of the immunostaining. Data are presented as mean percent of the density ± SEM on the injured versus the control side; n = 3 per group.
Fig. 9.
Fig. 9.
RIβlacZ expression in DRG cells revealed by β-gal staining. A, β-Gal activity (blue dots) was observed in all laminae of the spinal cord but not in the white matter (arrowhead). The arrowpoints to heavily labeled motoneurons. The sections were counterstained with neutral red. Scale bar, 320 μm. B, In the DRG, β-gal activity was found in both small (arrows) and large cells. Some DRG cells did not stain for β-gal (arrowheads). Scale bar, 100 μm. C, β-Gal activity was observed in both trkA-positive (arrows) and trkA-negative (arrowheads) DRG neurons. Other DRG cells showed neither trkA immunoreactivity nor β-gal activity. Scale bar, 100 μm.
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