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Contribution of neuroplasticity in the insular cortex induced by nerve injury to neuropathic pain

Other Titles
 신경손상에 의해 유발된 insular cortex의 신경가소성이 신경병증성 통증에 미치는 영향 
Authors
 한정수 
Issue Date
2017
Abstract
The insular cortex (IC) has been conventionally known to be involved in taste sensation. According to recent evidence, IC may play a role in diverse functions related to pain, emotion, and the regulation of the homeostasis. The IC is a pain-related brain region that receives various types of sensory input and processes the emotional aspects of pain. Peripheral nerve injury can induce neural plasticity of pain pathways including the IC that may contribute to chronic pain. However, there is no systematic report which studied the relationship between neuroplasticity and pain modulation after nerve injury in the IC. Therefore, this study was conducted to observe plastic changes in the IC after nerve injury and alleviation of pain by modulating these changes. Firstly, the optical imaging study was conducted to investigate spatiotemporal patterns related to neuroplastic changes in the IC after nerve injury using voltage-sensitive dye imaging. The tibial and sural nerves of rats were injured under pentobarbital anesthesia. To observe optical signals in the IC, rats were re-anesthetized with urethane on post-operative day (POD) 7, and a craniectomy was performed for optical imaging. Optical signals of the IC were elicited by peripheral electrical stimulation. Neuropathic rats showed a significantly higher optical intensity following 5.0 mA electrical stimulation compared to sham-injured rats. A larger area of activation was observed by 1.25 and 2.5 mA electrical stimulation compared to sham-injured rats. The activated areas tended to be larger, and the peak amplitudes of optical signals were increased with increasing stimulation intensity in both groups. These results suggest that the elevated responsiveness of the IC to peripheral stimulation is related to neuropathic pain, and that neuroplastic changes are likely to be involved in the IC after nerve injury. Secondly, the immunohistochemistry (IHC) and western blotting studies were conducted to observe protein kinase M ζ (PKMζ)-related plasticity of the IC after nerve injury. Continuous active kinase, PKMζ, has been known to maintain the late phase of long-term potentiation (L-LTP). Mechanical allodynia test and zif268 immunohistochemistry were performed after nerve injury. Zif268 have been to known as neuronal marker of plasticity and LTP. IHC was performed to test whether plasticity occur in the IC and the IC processes pain information. Zif268 expression level was significantly increased in the IC by nerve injury. Western blotting was conducted after nerve injury to assess expression of PKMζ phosphorylated-PKMζ (p-PKMζ) which is responsible in late-LTP. The results indicated that the expressions of PKMζ and p-PKMζ in the nerve-injured group on POD 3 tended to be increased than those of sham group, but showed no significant differences. The expression levels of PKMζ and p-PKMζ in the nerve-injured group on POD 7 were significantly increased than those of sham group. The third study was conducted to determine the functional role of PKMζ which may be involved in the modulation of neuropathic pain IC. After ζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical withdrawal threshold and expression level of PKMζ, p-PKMζ, GluR1 and GluR2 were observed. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hrs. Moreover, the levels of GluR1, GluR2, and p-PKMζ were decreased after ZIP microinjection. These results suggest that nerve injury induces plasticity related to PKMζ in the IC, and that the IC has a pain modulation function. Taken together, these results suggest that the elevated responsiveness of the IC to peripheral stimulation is related to neuropathic pain, and that neuroplastic changes are involved in the IC after nerve injury. Furthermore, peripheral nerve injury induces neural plasticity related to PKMζ, and ZIP has potential applications for relieving chronic pain.
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Appears in Collections:
1. College of Medicine (의과대학) > Others (기타) > 5. Others
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175124
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