Effects And Underlying Mechanisms Of Mirtazapine And Pregabalin On The Oxaliplatin-induced Neuropathic Pain In Rats

Oxaliplatin has widely been used as a key drug in the treatment of metastaticcolorectal cancer. However, it causes severe acute and chronic peripheral neuropathies.Acute neuropathy includes acral paresthesias and dysesthesia triggered or enhanced byexposure to cold, and it appears soon after administration. After multiple cycles oftreatment, the patients develop chronic neuropathy characterized by sensory and motordysfunction. This chronic neuropathy is a dose-limiting toxicity and a major clinicalproblem in oxaliplatin chemotherapy.Antidepressant drugs have been recommended to be used as first-line drugs for thetreatment of neuropathic pain. Mirtazapine, which was used in our study, is used for majordepression. As a noradrenergic and specific serotonergic antidepressant (NaSSA),mirtazapine is an antidepressant with a unique pharmacological profile. Mirtazapineenhances both noradrenergic and serotonergic transmission by antagonizingalpha-2-adrenergic autoreceptors and heteroreceptors. The enhanced serotonergictransmission is mainly mediated by5-HT1Aserotonin receptors because mirtazapine blocks5-HT2A,5-HT2Cand5-HT3receptors. This pharmacological profile accounts for theclinical characteristics of mirtazapine, a faster onset of action than selective serotoninreuptake inhibitors (SSRIs) and a low incidence of SSRI-related adverse effects, such asagitation, sexual dysfunction, nausea and vomiting. In particular, mirtazapine isdemonstrated to possess an analgesic activity for neuropathic pain in many randomizedcontrolled trials.Neuropathic pain is often resistant to treatment with conventional analgesics such asopioids, therefore other classes of drugs such as anticonvulsants and antidepressants arefrequently used in ameliorating neuropathic pain. The anticonvulsants pregabalin and itsclose analogue gabapentin have recently appeared as alternative treatments for neuropathicpain from postherpetic neuralgia and diabetic peripheral neuropathy. The usefulness ofpregabalin for fibromyalgia also has been reported. Several in vivo behavioural studies have demonstrated pregabalin suppress mechanical allodynia as well as cold allodynia inrodents. It is generally accepted that pregabalin binds α2δ-1subunits of voltage-dependentcalcium ion channels and blocks the development of hyperalgesia and central sensitization.Part1Effects of different doses and schedules of oxaliplatin treatmenton the onset of neuropathic pain in ratsObjective: Chemotherapeutics with oxaliplatin produce chronic, bilaterally symmetrical,sensory, peripheral neuropathies that are often accompanied by neuropathic pain. The aimof this study was to determine the influence of different doses and schedules of oxaliplatinon the onset of neuropathic pain in a rat model.Methods: Sprague-Dawley rats were treated with four different doses of oxaliplatin (1,2,4, and8mg/kg), which was given intraperitoneally (i.p.) every other day (a total of eighti.p. injections). Subsequently, the dose of4mg/kg oxaliplatin was applied to rats usingthree different schedules:(1)4mg/kg for8condecutive days;(2)4mg/kg twice a week for4weeks;(3)4mg/kg every other day (8i.p. injection). The general condition was recorded,as well as the behavioral tests, including cold/thermal hyperalgesia and mechanicalallodynia were performed.Results: The results revealed that intraperitoneal injection of32and64mg/kg oxaliplatinsuccessfully induced both cold hyperalgesia and mechanical allodynia in rat. But the latterhad a higher mortality. The shorter the interval between the injections, the shorter theduration and the higher the severity of the neuropathic pain.Conclusion: Our findings indicate that rat with4mg/kg oxaliplatin intraperitonealinjection twice a week for4weeks, may be a suitable animal model for imitating clinicalsituation. Part2Effects of mirtazapine on the oxaliplatin-induced neuropathicpainObjective: Oxaliplatin treatment may elicit acute and chronic peripheral neuropathies.Mirtazapine, as an antidepressant, is also used for the treatment of neuropathic pain. Thecurrent study aimed to investigate the effect of mirtazapine on the oxaliplatin-inducedneuropathy in rats as well as the underlying mechanism.Methods: A neuropathy model was established in Sprague-Dawley rats by intraperitoneal(i.p.) injection of oxaliplatin4mg/kg twice a week for4weeks. The therapeutic potentialof mirtazapine10,20, and30mg/kg/day per-orally for28consecutive days was evaluated.Subsequently, a dose of1mg/kg of WAY100635i.p., a selective antagonist of5-HT1Areceptor, was preadministrated before mirtazapine20mg/kg/day per-orally inoxaliplatin-induced neuropathy. The behavioral tests and the expression of NMDAreceptor subunit NR2B in lumbar segment of spinal cord were determined.Results: The results displayed that repeated administration of mirtazapine20or30mg/kg/day for28consecutive days significantly attenuated the mechanical allodynia andthe up-regulation of spinal cord NR2B but not the cold hyperalgesia in rats withoxaliplatin-induced neuropathy, which was reversed by WAY100635preadministration.Conclusion: Our findings suggest that oxaliplatin-induced mechanical allodynia isassociated with spinal NR2B up-regulation, which may be attenuated by mirtazapineadministration.Part3Effects of pregabalin on the oxaliplatin-induced neuropathicpainObjective: Oxaliplatin is a third-generation platinum compound with significant activitymainly against metastatic colorectal cancer, but it causes acute and chronic neuropathies in patients. Pregabalin, as an anticonvulsant, is also used for the treatment of neuropathic pain.The current study aimed to investigate the effect of pregabalin on the oxaliplatin-inducedneuropathy in rats as well as the underlying mechanism.Methods: A neuropathy model was established in Sprague-Dawley rats by intraperitoneal(i.p.) injection of oxaliplatin4mg/kg twice a week for4weeks. The therapeutic potentialof pregabalin5,10,20, and40mg/kg/12h per-orally for28consecutive days wasevaluated. The behavioral tests were performed. The expression of NMDA receptorsubunit NR2B in the lumbar segment of spinal cord and transient receptor potentialmelastatin8(TRPM8) in the dorsal root ganglia (DRG) were determined.Results: The results displayed that repeated administration of pregabalin significantly anddose-dependent attenuated the cold hyperalgesia and the up-regulation of DRG TRPM8but not the mechanical allodynia and NR2B in rats.Conclusion: Our findings suggest that oxaliplatin-induced cold hyperalgesia is associatedwith DRG TRPM8up-regulation, which may be attenuated by pregabalin administration.ConclusionThe current study established neuropathic pain model in rats by using repeatedintraperitoneal injection of oxaliplatin. We investigated the effects of different doses andschedules of oxaliplatin administration on the onset and development of neuropathic pain.Several particular types of pain related protein and receptors were tested in the lumbarsegment dorsal root ganglion and spinal cord, as well as the potential mechanisms werediscussed. Our findings suggest that repeated administration of antidepressant drugmirtazapine20and30mg/kg/day could significantly reduce the oxaliplatin-inducedmechanical allodynia and the up-regulation of spinal cord NR2B but not the coldhyperalgesia, and the5-HT1Areceptors activation plays a crucial role in the therapeuticprocess. Anticonvulsant pregabalin significantly and dose-dependent attenuated the cold hyperalgesia but not mechanical allodynia, and this therapeutic activity maybe resultedfrom the reduction of TRPM8expression in the dorsal root ganglion.