Analgesic Effects And Mechanisms Of Lacosamide On Mechanical Hypersensitivity In A Rat Model Of Chronic Compression Of Dorsal Root Ganglia

BackgroundSpinal injury,disc herniation,foraminal stenosis and so on usually lead to chroniccompression of relevant dorsal root ganglion and its adjacent nerve root,which are theimportant reasons of low back pain and sciatica. As a common kind of neuropathic pain,itaffects the patient’s life and work severely. Due to the limitations of surgical indications,non-steroidal anti-inflammatory drugs are usually used for conservative treatment, but theresults were not satisfactory. Consequently,to find effective analgesic drugs is the goal ofdoctors’. Epilepsy and neuropathic pain have the common features of abnormal activity ofneuronal circuits and ectopic discharges, antiepileptic drugs have played important role inthe treatment of neuropathic pain. Antiepileptic drugs,such as carbamazepine, phenytoin,lamotrigine, Oxcarbazepine and so on, usually take effect on the fast active sodium channelby reducing Na+influx to reduce excitability. Lacosamide, one kind of new antiepilepticdrugs, has been approved by European Union and the United States for several years.It ismainly used in the treatment of adult complex partial seizures by means of strengtheningthe slow inactivation of voltage-gated sodium channels.For this reason,the voltage-gatedsodium channel activation is a necessary condition for the action potential and it is also thebasis of the pathological neural abnormal discharge.This raises research interests of theLacosamide for neuropathic pain. Several studies have indicated that Lacosamide is effectivein many kinds of animal models of muscle pain, spinal cord injury, trigeminal neuralgiaand clinical cases of diabetic polyneuropathy pain. But so far, analgesic effects ofLacosamide on an animal model of chronic compression of dorsal root ganglion neuronswhich simulates clinical low back pain has not been reported.Therefore, in this study weobserved that the analgesic effects of the Lacosamide and discussed its potentialmechanism.ObjectiveIn this study, rat models of chronic dorsal root ganglion compression were successfullyprepared for neuropathic pain,then the analgesic effect of Lacosamide was observed andDRGNav1.8of the injury site of the rat model was investigated.This would be helpful forfurther clinical study in the future. MethodsPreparation of animal models:72Specific pathogen Free (SPF) female SD rats withweight between120gram and130gram were randomly divided into five groups: shamoperation group (SⅠ group, n=18), model group (MⅠ group, n=18),sham operationgroup (SⅡ group, n=12), model2(MⅡ group, n=12) and Lacosamide group (L, n=12).To prepare CCD model,a stainless steel column with the length of4.0mm and thediameter of0.63mm was inserted into the L5intervertebral foramen of the rats in order tothe dorsal root ganglion neurons and the adjacent nerve root were chronically stablelycompressed while group S were only exposed to the intervertebral foramen.Behavioral experiments:All rats in the preoperative2d, the postoperative2,4,6,7,8,9,10d (T0-7) were measured the mechanical pain threshold using Von-Freymethod. Group SⅡ and group L received intraperitoneal injection of Lacosamide at7thday after operation while group MⅡ were given equivalent saline at the same time for4days with twice per day. One hour after administration,behavioral tests were observedevery day.Real-time PCR and immunohistochemistry chemical experiments: to observe theexpression changes of Nav1.8mRNA of L5DRG in the rat models with dorsal rootganglion chronically compressed and MⅡ、L group L5DRG on Nav1.8expression at T7using real-time PCR and immunohistochemical staining fluorescence technique.ResultsBehavioral experiments (1) Rat models of chronic compression of dorsal rootganglion were successfully established.The diference of mechanical pain thresholdbetween MI and SⅠ group at T0was not statistically significant (P>0.05). Compared withthe SⅠ, MⅠ group limped, raised leg spontaneously and licked the operative side of thefoot at T1.From T1to T7, the mechanical pain threshold at each time point of group MⅠwere lower than group SⅠ (P <0.05).(2) Lacosamide intervention in the experimental.After that Lacosamide (20mg/kg,2t/d) was administered for4days, mechanical painthreshold of group L were higher than group MⅡ at T4-7(P <0.05). Unlikely, mechanicalpain threshold of group SⅡ did not change at T4-7(P>0.05).Real-time fluorescent quantitative PCR assay and immunohistochemistry Comparedwith group SⅠ, Nav1.8mRNA of group MⅠ upregulated significantly at T3and T7(P<0.05).After the intervention of Lacosamide, compared with group MⅡ, Nav1.8mRNAand protein of group L down regulated significantly at T7(P <0.05). ConclusionThis study found that Lacosamide could reduce mechanical hyperalgesia of theoperative side foot in rats with chronic compression of the dorsal root ganglion.But it hadno effect in rats of sham operation. The mechanism may be related to the downregulationof the Nav1.8expression of DRG of the injury site.