| Peripheral nerve or spinal nerve injury, even if the initial injury has healed, will lead to chronic persistent neuropathic pain. Bilateral effects of unilateral injury are very common phenomena, and there are many typical clinical bilateral symmetry of diseases, such as the mirror-image pain, mirror movements and symmetry of arthritis, et al. In addition, researches had found that rats developed mechanical and cold allodynia responses in the ipsilateral paw as well as in the contralateral paw in the L5and L6spinal nerve ligation model. Allodynia in the contralateral paw appeared later and contralateral pain was observed to be of lower intensity than that on the ipsilateral side. Schreiber et al. also reported the development of a temporarily delayed, robust and long-lasting contralateral allodynia in mice after hindpaw injection with4%carrageenan.The mouse cancer pain model showed significant contralateral ambulatory pain, mechanical allodynia, and reduction in weight bearing for the affected limb.These research show that mirror-image pain is an important pain behavior exists in clinical patients and animal pain models. Neural or immune activation theory have been speculated to elucidate the possible mechanisms responsible for mirror-image pain. Immune activation theory:on the one hand, when the peripheral tissue or nerves are injured, the injured site produced a large number of metabolites and large numbers of infiltrating immune cells at the same time. Metabolites produced by damage and inflammatory cytokines released by immune cells reach the contralateral area of injured sitevia blood circulation. While on the other hand, the injury can induce the release of stress-related hormones. These were likely to be involved in the process of mirror-image pain. But the immune theory does not explain the reasons that bilateral allodyniaare symmetricaland that unilateral damage can lead to similar changes in corresponding contralateral areaslike that of ipsilateral areas. Since the nervous system is anatomically symmetric, both peripherally and centrally at the spinal level, the neural pathways may be involved in the process of mirror-image pain. Schreiber’swork suggested that microglial activation may play a key role in contralateral sensitization, which may be responsible for possible mechanismsinvolved inmirror-image pain. The mechanism of spinal glia cellsunderlying mirror-image pain has been concerned more and more.Large amountof literature indicated that ectopic spontaneous activities of the axons of nerve injury site and the primary sensory neurons, or dorsal root ganglion neurons, are the origin of spontaneous pain, tactile allodynia and hyperalgesiaresulted from nerve injury and become the "pacemaker"of chronic pain signals.Zhang’s groupobserved mirror-image machanical hyperalgesia and allodynia in the chronic compression of single dorsal root ganglion model in2000.The hyperalgesiaof the contralateral hind limb may be related to central sensitization of the spinal cord. Professor Liu’s group also reported that there exited mirror-image mechanical allodynia and thermal hyperalgesia in lumbar5ventral root transection of the rat. The mechanism of mirror-image pain was speculated to be related to central sensitization in the spinal cord. Recently an obvious mirror-image mechincal allodynia could be observed in the chronic compression of multiple dorsal root ganglia of the rat in our work, an earlier phenomenon and higher degree could be observed after surgery compared to Zhang’s work, This is the same result as sciatic nerve chronic ligation, sciatic nerve partial injury and spinal nerve ligation model that bilateral hind limbs appear tactile mechanical hyperalgesia, and similar to some of the clinical burning pain bilateral mirror pain behavior. In addition, we further investigat the plastic changes of primary neurons concurrent with the mirror-image pain in the chronic compression of multiple dorsal root ganglia of rat model.1. The changes of one neuropeptide related to nociceptive information transmitted, calcitonin gene-related peptide(CGRP), and one nerve injury marker, activating transcription factor-3(ATF-3) were examined in chronic compression of multiple DRGs rats with tactile mirror-image allodynia.2. Whether peripheral mechanisms were involved in the change of behaviors of mirror-image mechincal allodynia in chronic compression of multiple DRG rats.Our work includestwo parts. The first part is to examine the behavioral changes of mirror-image mechanical allodynia and the corresponding time characteristics in the chronic compression of multipleDRGs inrats. Thesecond part is to further observe the changes of the expression of CGRP, the peripheral nerve damage information neurotransmitter, and ATF-3, the marker of nerve injury, in ipsilateral and contralateral DRG neurons in chronic compression of multiple DRGs model.In the first part, we made chronic compression of multiple DRGsmodel and tested the mechanical threshold between control group and CCD group on day1,3,5,7,10,14,21and35after surgery, and observed the behavior of mirror-image mechanical tactile allodynia of chronic compression of multiple DRGs.Results were as follows, the mechanical threshold began to decline on the first day after surgery, decreased obviously between the7-10th day and peaked on the14th day, and the changes could be observed within35days after surgery. There was a slight decrease of the mechanical threshold of the contralateral hind paw in1-5days after surgery, and significant decreases began from the5th day after operation, peaked on the10-14th day, the mechanical threshold began to restore on the35th day after surgery. This result indicated that the chronic compression of multiple DRGs in rats showed an obvious behavior of both ipsilateral and contralateral mechanical tactile allodynia.In the second part, the peripheral mechanisms of mirror-image mechanical tactile allodynia were further investigated in chronic compression of multiple DRGs in rats. The changes of the expression of CGRP,(the peripheral nerve damage information neurotransmitter) and ATF-3,(the marker of nerve injury) were examined in both ipsilateral and contralateral DRG neurons in chronic compression of multiple DRGs model with immunohistochemical methods.Results:1. Compared with the control group, the expression of CGRP in both ipsilateral and contralateral DRG neurons of multiple CCD rats showed an increase on the1st day after surgery, a significant increase on the7th day, it peaked on the10-14th day, then decreased gradually, a significant increment could still be observed on the21st day. The expression of CGRP in ipsilateral large and medium-sized DRG neurons in multiple CCD rats showed an obvious increase on the1st day after surgery and peaked on the10th day, the significant increment could still be observed on the21st day, but in small DRG neurons there were no obvious changes; in the contralateral large and medium-sized DRG meurons, the same results could be observerd as those of the ipsilateral side, there were no significant changes in small DRG neurons.2. Compared with the control group, the expression of ATF-3in ipsilateralDRG neurons showed significant increase after multiple CCDon the1st day after surgery, while there was no obvious change in the contralateral side, a high expression of ATF-3could be observed in bilateral sides on the7th day and peaked on the10th day, then decreased and there were no significant increment could be observed on the14th and21st day. A high expression of ATF-3could be observed in ipsilateral large and medium-sized DRG neurons on the1st day after surgery, it peaked on the7-10th day and then no significant increment could be observed on the14th and21st day, and the same phenomena could be observed in small DRG neuronsas those of the large and medium-sized DRG neurons;in the contralateral large and medium-sized DRG neurons there was no obvious change on the1st day, high expression of ATF-3could be observed on the7th day and peaked on the10th day, there were no significant increase on the14th and21st day, the same results could be ovserved as those of the large and medium-sized DRG neurons. The expression of ATF-3in ipsilateral DRG neurons was higher than that of the contralateral DRG neurons. Our results suggest that the plastic changes of bilateral primary sensory neurons may play a role in the mirror-image mechanical tactile in the chronic compression of multiple DRGs of rats, and the peripheral mechanism may be involved in the induction and the maintenance of mirror-image pain.Conclusions:1. The multiple CCD rats exhibited obvious mirror-image mechanical allodynia.2. The expression of CGRP was significantly increased in ipsilateral and contralateral DRGs in multiple CCD rats, and the increased change mainly occurred in large-and medium-sized DRG neurons.3. The expression of ATF-3was significantly increased in ipsilateral and contralateral DRGs in multiple CCD rats, and the increased change mainly occurred in large-and medium-sized,and small DRG neurons. |
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