Mechanisms Involved In The Efficacy Of Nerve Decompression For Mechanical Allodynia In Painful Diabetic Peripheral Neuropathy

Objective:The outcome of pharmacological treatment for painful diabetic peripheral neuropathy(PDPN)is far from satisfactory while the effect of surgical treatment has been challenged and remains controversial.By combining the peripheral and central mechanisms of PDPN and taking previous clinical experience into consideration,this study was conducted to investigate the pathogenesis of PDPN as well as the mechanisms underlying the efficacy of nerve decompression for mechanical allodynia(MA)in PDPNMaterials and Methods:The Streptozotocin(STZ)-injected diabetic rats and the modified diabetic rat model with chronic nerve compression by latex tube were used in this study.PDPN rats were selected by detecting MA and thermal hyperalgia with the measurement of paw withdrawal threshold(PWT)and paw withdrawal latency(PWL)respectively.1)Comparison of pain behavior was made between different rat models.The effect of surgical decompression on pain behavior was also observed and evaluated.2)Diabetic rats from different groups were further divided into MA positive diabetic peripheral neuropathy(DPN)and MA negative DPN according to the presence of MA.The expression of c-fos protein in dorsal root ganglion(DRG)and spinal dorsal horn(SDH)was examined in all the subgroups.The expression of both NF-200 and CGRP in DRG were combined with the above results to compare the activation of the related neurons in DRG and secondary neurons in SDH of different primary afferents.3)The impairment of nerve fibers as well as the expression of GABAB receptor in SDH were examined in different PDPN groups of different stages.The changes of GABAB receptor in central terminals of different primary afferent fibers were quantified and localized by labeling different primary afferent nerve fibers.4)In clinical research,patients with PDPN were divided into different groups according to the presence of MA.Nerve conduction velocity and high-frequency ultrasound were used to respectively evaluate the functional and morphological changes of peripheral nerves.Pain intensity was assessed with the use of visual analogue scales while the psychological condition was evaluated with the use of hospital anxiety and depression scalesResults:1)Chronic nerve compression by latex tube had increased the incidence of MA in diabetic rats and in turn,nerve decompression could decrease PWT,and thus ameliorate MA.2)When compared to MA negative DPN rats,severer demyelination of peripheral nerve could be noted in MA positive DPN rats.The related neurons in DRG and SDH were activated,resulting in increasing impulse of primary afferents and hyperactivation of neurons in SDH.3)Decreased GABAB receptor in SDH,majorly located in the central terminals areas of large myelinated primary afferent fibers,was noted in PDPN rats.4)Better pain reduction and more improvements in nerve function were achieved in patients with signs of MA than those withoutConclusion:MA in PDPN was proved to be caused originally by the compression of large myelinated fibers,which would activate the corresponding neurons in DRG and SDH and thus result in increasing impulse of primary afferents and hyperactivation of neurons in SDH.The hyperactivation of neurons in SDH could be related closely to the down regulation of GAB AB receptor in SDH.MA is a reliable predictor of better surgical outcome for PDPN.