| Cervical radicularpathy pain(CRP) is a high risky disorder among the modern people’s career, which become one of the mostthreat for the people affected. The symptom of CRP patient always deteriorates with the time. Compared with low back pain, 97% CRP patients express severe pain behavior, including persistent spontaneous pain, phatom pain, and sudden trigger pain after the movement of the vertebra. While the pain behavior is secondary to the loss of weight-bearingand walking function in those with low back pain patients. Concening with the complexity of anatomy in the cervical back of experimental animals and the difficulty of the exprosure of cercical vertebra in the surgery. So, there is few researches of the cervical pain model. Besides animal pain behaviors, pharmacological study israrely studied in animal researches.We previously estanblished a stable chronic compression of lumbar DRG by the stainless steel rod in the rat. In the model of the chronic compression of DRG(CCD) plenty of spontaneous discharges were observed from the peripheraldorsal roots and somata of injured DRG neurons. Under physiological condition, the spontaneous activities(SA) raely appears in DRG neurons, whilethe SA is widely generated in DRG neurons in chronic pain state.Our previous work showed that the SA originated mainly from A type of DRG neurons, but not from C type in CCD rats. The SA originated from injured DRG neurons may be generated on the basis of the subthreshold membrane potential oscillation(STMO) of DRG neurons. Membrane intrinsic properties undergo changes due to the activation and inactivation of ion channels in DRG neurons with STMO. Thus, DRG neurons usually exhibit abnormal membrane properties in pathological pain models. And the activation of nociceptivesensory neurons and increased inputs to spinal superficial laminae in the dorsal horn coexist with gene and molecular changes, which indicate neuron plasticity change after the chronic compression. However, the mechanismof CRP after choric injury of cervical DRG is not well ducumented.Recently, mechanical sensitive channels are considerd to be involved in the estabilishment of allodynia in the chronic pain model. But sensory neurons in the DRG have different mechanical properties. The DRG neuron with mechanical sensitive proterty exhibits more transmembrane currents andactivitiy-depended change, comparedwith sensory neurons which are not responsive to mechanicalstimulation. But the classification of sensory neurons regarding of the mechanical sensitivity is poor described in the chronic pain condition, and the possible role of mechanical sensitive channel blocker in the analgesic effectis not known.The first part of the present work,(1) we established an animal model which mimic the clinic feature of CRP, and pain behavioral tests showed pain hypersensitivity;(2) charicterized the classification of DRG small neurons in CRP rats, and the cell and molecular target for the analgesia.Firstly, we preformed a small surgery to insert L-shape stainless steel pillars into C7 and C8 intervertebral foraminato result in persistent compressions of cervical DRGs, which mimic the pathology of intervertebral disc herniation orcervical stenosis. We tested pain behaviors inthe CRP rat. Cervical radiculopathy represented aberrant mechanical hypersensitivity andspontaneouspain, as well as moderate heat hypersensititvty. The pain hypersensitivity was induced one day after the CRP surgery, which became more serious in the following days and reached the peak in four days after the surgery. The mechanical allodynia was kept persistently in the continous four weeks. The heat hypersensitivity of the CRP rat was found 3 days after CRP surgery, which lasted four weeks to the end of the behavioral test. The spontaneous pain was character as the rate of duration of the licking and biting as well weight shifting in the one minute. The obvious spontaneous pain behavior was found in 1 day after the CRP surgery, which reach to the peak in the first week.The c-Fos staining results showed the c-Fos expression were increased in the small sensory neurons in DRG and the spincal neurons in superficial laminea of dorsal horn. The c-Fos expression reached the peak afte 24 hours after CRP surgery. The time course of c-Fos expressions between DRG and spinal slice were similar, indicating the peripheral pain pathway were activated step by step. To confirm that, we also tested the extracellular signal-related kinase(p ERK) expression in CRP rats. The results showed the p ERK 1/2 expression were increasd in the neurons in the DRG and dorsal horn of CRP rats compared with the sham rat. It was indicated that DRG neurons were acitivated due to the mechanical compression of the DRG in the CRP rat. The peripheral noceciptive input to the CNS was increased obviously.Among nociceptive DRG neurons, isolectin B4 negative Aδ-type(IB4~- Aδ) DRG neuron or one type of mechanically sensitive neurons, showeda more dramtic increase in the membrane property, compared with IB4~- or IB4~+and C type DRG neurons. Besides only IB4~- Aδ displayed SAs on the third day? after CRP surgery. The SArecorded from DRG neuronshad lasted for two hours.Primary sensory neuron’s ability to sense mechanical force forms mechanotransduction. In the second part of our work, we found that(1) IB4~- Aδ sensory neuronsdisplayed mechanical hypersensitivity in the choronic pain;(2) HCN channelswere related with the mechinal hypersensitiviry of IB4~- Aδ neurons;(3) the possible pharmacologic target of the analgesia for the neuropathic pain treatment.In the present study, focal mechanical stimulation(MS) on somata of IB4~- Aδ neuron induced abnormal hypersensitivity, while the intensity of MS would not do any harm to the health of DRG neuron in the CRP rat. And high-fequency action potentialswere generated in the soma of IB4~- Aδ DRGneurons andwas kept even long time after the MS was released. And all evoked ectopic discharges due to mechical stimuli were recovered to the normal in all the neuron recorded.Upregulated hyperpolarization-activated cyclic nucleotide-gated(HCN) HCN1 and HCN3 channels and increased Ih currents on IB4~- Aδ type DRG sensory neuron underlied the spontaneous activity together with neuronal mechanical hypersensitivity, which further contributed to the behavioral mechanical hypersensitivity associated with CRP. The intrathecal injection of the HCN antagonist, ZD7288, totally reversed the mechanical allodia and spontaneous pain behaviors in CRP rats in 12 hours after the injection, while had no effect on the sham control group. Moreover, ZD7288 did not alleviate the heat hypersensitivity of CRP rats.This study sheds new light on the functional plasticity of a specific subset of nociceptive DRG neurons to mechanical stimulation and reveals a novel mechanism that could underlie the mechanical hypersensitivity associated with cervical radiculopathy. |
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