Phosphodiesterase 4 (PDE4) is an
adenosine cyclic 3,5-monophosphate-specific degradative
enzyme, which is closely associated with the inflammatory response. Among its four subtypes (A-D), it remains unclear which one exerts suppressive effects on
inflammation and reduces
neuropathic pain. The present study aimed to examine the modulation of
neuroinflammation by PDE4 subtypes in the spinal cord of a rat model of L5 spinal nerve
ligation (SNL)-induced
neuropathic pain. The expression levels of PDE4A-D were measured in the lumbar spinal cords of naïve rats. The rats were then divided into seven groups: The
sham group (
sham surgery + saline), the saline group (SNL + saline), the vehicle group (SNL + Lipofectamine® RNAiMAX), the mismatch small interfering (si)
RNA group (SNL + mismatch
siRNA), the PDE4A-siRNA group (SNL + PDE4A-
siRNA), the PDE4B-siRNA group (SNL + PDE4B-
siRNA) and the PDE4D-siRNA group (SNL + PDE4D-
siRNA). In order to determine behavioral changes, mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded. The
mRNA and
protein expression levels of PDE4s were also detected. Furthermore, the association between behavioral changes and individual subtypes of PDE4 were studied following intrathecal administration of PDE4A, B and D-specific
siRNA. The expression levels of
protein kinases, including phosphorylated-
extracellular signal-regulated kinases (p-ERK), and inflammatory
cytokines were measured, in order to explore the underlying mechanisms. Subtypes A, B and D, but not C, were detected in the naïve rats. After SNL, both MWT and TWL were reduced. The
mRNA and
protein expression levels of PDE4A, B and D were significantly upregulated after 2, 4, 6 and 8 days of SNL. Subtype-specific
siRNA significantly suppressed the elevated expression levels; however, only rats treated with PDE4B
siRNA exhibited improved MWT and TWL. Further analysis of the PDE4B
siRNA-treated rats demonstrated that 8 days after SNL, the intensity of p-ERK was reduced, the expression levels of CD11b and
glial fibrillary acidic protein GFAP were reduced, as well as the expression levels of proinflammatory
cytokines such as
tumor necrosis factor-α,
interleukin (IL)-1β and
IL-6. These results suggested that selective inhibition of PDE4B may relieve
neuropathic pain, potentially via the suppression of glial activation and the release of
cytokines in the spinal cord.