Neuropathic pain due to
peripheral nerve injury may be associated with abnormal central nerve activity.
Glial cell-line-derived neurotrophic factor (
GDNF) can help attenuate
neuropathic pain in different animal models of nerve injury. However, whether
GDNF can ameliorate
neuropathic pain in the spinal cord dorsal horn (SCDH) in constriction-induced
peripheral nerve injury remains unknown. We investigated the
therapeutic effects of adenoviral-mediated
GDNF on
neuropathic pain behaviors, microglial activation, pro-inflammatory
cytokine expression and programmed cell death in a chronic constriction injury (CCI) nerve injury animal model. In this study,
neuropathic pain was produced by CCI on the ipsilateral SCDH.
Mechanical allodynia was examined with von Frey filaments and thermal sensitivity was tested using a plantar test apparatus post-operatively. Target
proteins GDNF-1, GDNFRa-1, MMP2, MMP9, p38, phospho-p38, ED1,
IL6, IL1β, AIF,
caspase-9, cleaved
caspase-9,
caspase-3, cleaved
caspase-3, PARP, cleaved PARP,
SPECTRIN, cleaved
SPECTRIN,
Beclin-1, PKCσ, PKCγ, iNOS, eNOS and nNOS were detected. Microglial activity was measured by observing changes in immunoreactivity with OX-42. NeuN and TUNEL staining were used to reveal whether apoptosis was attenuated by
GDNF. Results showed that administrating
GDNF began to attenuate both
allodynia and
thermal hyperalgesia at day 7. CCI-rats were found to have lower
GDNF and GDNFRa-1 expression compared to controls, and
GDNF re-activated their expression. Also,
GDNF significantly down-regulated CCI-induced
protein expression except for MMP2, eNOS and nNOS, indicating that the protective action of
GDNF might be associated with anti-
inflammation and prohibition of microglia activation. Immunocytochemistry staining showed that
GDNF reduced CCI-induced neuronal apoptosis. In sum,
GDNF enhanced the neurotrophic effect by inhibiting microglia activation and
cytokine production via p38 and PKC signaling.
GDNF could be a good therapeutic tool to attenuate programmed cell death, including apoptosis and autophagy, consequent to CCI-induced
peripheral nerve injury.