| Summary: | 碩士 === 國立臺灣大學 === 藥理學研究所 === 90 === 1.Injury to peripheral nerves may result in severe and intractable neuropathic pain. In recent years much effort has been put into elucidating the mechanisms of the neuropathic pain, including the central and peripheral effects. Central nerve sensitization, reorganization of the spinal cords, and changes in the sensory pathway are suggested to be included in the induction of hyperalgesia. In addition, the sprouting of sympathetic nerves and primary afferent neurons, alteration of ion channel expressions, and ectopic or spontaneous discharge may be involved in the induction of neuropathic pain. Here, we investigated the role of integrin in the induction of neuropathic pain and possible application of disintegrin in the treatment of neuropathic pain.
2.The animal model used is the modified Chung model performed by tightly ligating the L5 spinal nerve and cut just distal to the ligature on one side. Mechanical and thermal stimuli were applied in the L4 middle dermatome of the hind paw. Triflavin (TFV), which is a RGD-dependent disintegrin, was administered via three different routes: including epidural, intrathecal, and intraplantar injection. The epidural injection of TFV (1.35 nmole) is the most efficient route for inhibiting hyperalgesia derived from mechanical and thermal stimulations. Intrathecal injection of TFV inhibited mechanical but not thermal hyperalgesia. Intraplantar injection of TFV did not affect neuropathic pain.
3.Immunohistomchemistry was used to investigate the sprouting of sympathetic nerves and CGRP-IR fibers in the dorsal horn of spinal cord. The sprouting of sympathetic nerves into the DRGs by neuropathic surgery was markedly inhibited by the epidural injection but not intrathecal and intraplantar injection of TFV. The invagination of CGRP-IR fiber into deeper laminae by neuropathic surgery was inhibited by epidural and intrathecal injection but not by intraplantar injection of TFV.
4.CGRP-IR fibers in the lateral dermatome of hind paw decrease d significantly 7 days after the neuropathic surgery. Injection of TFV via three different routes did not obviously affect CGRP-IR fibers in the middle site belonging to L4 dermatome.
5.CGRP immunoreactivity decreased in L5 DRG and increased in L4 DRG 7 days following tight ligation and cut of L5 spinal nerve. Daily injection of TFV inhibited the increase of CGRP immunoreactivity in L4 DRG in rats received neuropathic surgery.
6.Beta1 integrin mRNA of single DRG was measured by real time PCR.Beta1 integrin mRNA of L5 DRG increased on both day-1 and day-3 after tight ligation and cut of L5 spinal nerve. However, the increase of 1 integrin mRNA in L4 DRG appeared later on day-3 after surgery.
7.Alpha-CGRP precursor mRNA of single DRG was measured also by real time PCR. -CGRP precursor mRNA decreased in L5 DRG but increased in L4 DRG on day-1 and day-3 after neuropathic surgery.
8.Cortex neurons were cultured from E19 embryos of rats. TFV (1μg/mL) was bath applied to 6 hr’s cultures and neuronal growth was observed 12 hr later. TFV inhibited neurites outgrowth in neurons grown on either poly-d-lysine- or fibronectin-coated glasses.
9.Daily epidural administration of propranolol inhibited mechanical hyperalgesia in rats received neuropathic surgery. Propranolol inhibited sprouting of CGRP-IR fibers into deeper laminae of dorsal horn of L4 lumbar spinal cord.
10.In conclusion, the induction of neuropathic pain is related to neuronal sprouting in various regions. Disintegrin is able to inhibit neuronal sprouting and the induction of hyperalgesia induced by neuropathy. Disintegrin may be developed to be a new category of drugs to treat neuropathic pain.
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