Abstract
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.
Highlights
Neuropathic pain is caused by lesions or diseases of the somatosensory system including peripheral nerve injury and central nerve injury
Glial cell-linederived neurotrophic factor (GDNF) attenuates constriction injury (CCI)-induced allodynia and hyperalgesia To measure the seriousness of neuropathic pain, the Von Frey filament and hot-plantar test were used to establish the animal model
adenovirus vectors encoding GDNF (Ad-GDNF) started to significantly alleviate both allodynia and thermal hyperalgesia associated with CCI at day 5 after surgery, but showed no effect at day 1 and 3 (Fig. 1A & 1B)
Summary
Neuropathic pain is caused by lesions or diseases of the somatosensory system including peripheral nerve injury and central nerve injury. Spontaneous pain, thermal-mediated hyperalgesia and tactile-evoked allodynia are common neuropathic pain symptoms following peripheral nerve injury, and significantly reduce quality of life and functional status. Previous data have shown that sprouting from lamina III into II in neuronal remodeling in the spinal cord might result in the development of persistent tactile allodynia [1,2]. Long-term administration of opiates has wellknown side effects including drug addiction and tolerance, immunosuppression, and decreased micturition reflex. New therapeutic approaches such as gene therapy with pain-killer genes may hold promise for treating such patients
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