Reversal of thermal and mechanical allodynia with pregabalin in a mouse model of oxaliplatin-induced peripheral neuropathy

Reversal of thermal and mechanical allodynia with pregabalin in a mouse model of... Abstracts / Scandinavian Journal of Pain 12 (2016) 125–127Genetic variation in P2RX7 and painO. Kambur (Presenter) a,b,∗ , K. Cajanus b,e , M.Kaunisto c , Bendik Winsvold d , Audun Stubhaug a ,John A. Zwart d , Christopher S. Nielsen a , E.Kalso b,eaDepartment of Pain Research and Management,Oslo University Hospital, Oslo, Norwayb Pharmacology, University of Helsinki, Faculty ofMedicine, Helsinki, Finlandc Institute for Molecular Medicine Finland (FIMM),University of Helsinki, Helsinki, Finlandd Department of Neurology, Oslo University Hospitaland University of Oslo, Norwaye Pain Clinic, University of Helsinki and HelsinkiUniversity Hospital, Helsinki, FinlandE-mail address: oleg.kambur@gmail.com (O. Kambur).Background and aims: P2X7 is a purinoceptor and nonselective cation channel that is activated by extracellular ATP,especially in immune and glia cells. Activation of P2X7 triggersthe secretion of several pro-inflammatory substances, such as IL1␤, IL-18, TNF-␣, and nitric oxide. P2X7 activation contributes tothe pro-inflammatory response to injury or bacterial invasion andmediates apoptosis. It has been implicated in physiological andpathological conditions such as bone tissue remodelling, inflammation, oncogenesis, depression, and inflammatory, neuropathicand chronic pain. Here, we aim to characterize the effects of variation within the P2RX7 gene, which encodes the P2X7 receptor, onpain and opioid requirements in human patients.Methods: Pain was assessed in Norwegian and Finnish cohorts.The Norwegian cohort represents the 6th wave of the TromsøStudy, a longitudinal and cross-sectional population based study(N = 3700), whereas the Finnish cohort (BrePainGen) consists ofpatients who underwent breast cancer surgery (N = 1000). For bothcohorts, experimental pain data were analyzed. Pain intensity andtolerance were assessed with cold pressor test and after standardized noxious heat stimulation in both cohorts. In addition, dataon acute postoperative pain and opioid requirements were analyzed in the BrePainGen cohort. Postoperative pain and opioidresponses were followed during 20 h after surgery. In total, 29 single nucleotide polymorphisms (SNPs) in P2RX7 were genotyped andtheir association with outcome variables was assessed using linearregression and analysis of variances (ANOVA).Results: Several P2RX7 SNPs were associated with the painphenotypes. The strongest associations were seen with cold painintensity and tolerance. The results of this study will be presentedat the meeting.Conclusions: Our results suggest that P2X7 and genetic variation in the P2RX7-gene are involved in the modulation of humanpain responses.http://dx.doi.org/10.1016/j.sjpain.2016.05.030127Reversal of thermal and mechanical allodyniawith pregabalin in a mouse model ofoxaliplatin-induced peripheral neuropathyR. Magnúsdóttir a,∗ , A. Fisher b , C. Chenu a ,N. Upton baComparative Biomedical Sciences, The RoyalVeterinary College, London, UKb Transpharmation Ltd, The London BioscienceInnovation Centre, London, UKE-mail address: rmagnusdottir@rvc.ac.uk (R. Magnúsdóttir).Aims: Chemotherapy-induced peripheral neuropathy (CIPN) isa dose limiting side effect in the use of the platinum-based antineoplastic drug oxaliplatin as a treatment for colorectal cancer.Currently there is no treatment available to reverse the neurotoxicity which presents as pain, sensory loss and cold allodynia in up to80% of patients. The aim of this study is to investigate if pregabalincan reverse the allodynia caused by oxaliplatin in CIPN.Methods: CIPN was induced in 10 male C57BL/6 mice (6 weeksold) with a single intraperitoneal injection of oxaliplatin (15 mg/kgi.p.). Signs of thermal and mechanical allodynia were assessed frombaseline to 20 days after injection by Cold/Hot plate (Bioseb, France)at 20 ◦ C and hand-held von Frey (vF) hairs of gradually increasingweights. Pregabalin (3 mg/kg and 10 mg/kg p.o.) was administeredto treat CIPN.Results: Mechanical and thermal allodynia were established 3days post-oxaliplatin injection and remained stable for 14 days. Atday 15, pregabalin (3 mg/kg p.o.) reversed mechanical allodynia tobaseline scores at 2 h (H) post-dosing and thermal allodynia at 1 and2H post-dosing. Following a 2-day wash out where scores returnedto neuropathic baseline, pregabalin (10 mg/kg p.o.) reverted scoresfor mechanical and thermal allodynia to baseline scores at both 1and 2H. Thermal testing was performed either immediately after vFor alone and our results were similar, showing no iatrogenic effectsof vF on thermal sensitivity. Correlation analysis of the responsesto thermal and mechanical stimuli showed no significant trend,indicating that oxaliplatin- induced peripheral neuropathy affectsthe mechanical and thermal modalities in different ways.Conclusion: Oxaliplatin-induced peripheral neuropathy asmeasured by thermal and mechanical allodynia is reversible by asingle dose of pregabalin.This project has received funding from the European Union’sHorizon 2020 research and innovation programme under the MarieSklodowska-Curie grant agreement No. 642720. RM is funded by aMarie Sklodowska-Curie grant agreement No. 642720 doing a jointPhD with the Royal Veterinary Collage and Transpharmation Ltd.AF and NU are employees of Transpharmation Ltd.http://dx.doi.org/10.1016/j.sjpain.2016.05.031 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Scandinavian Journal of Pain de Gruyter

Reversal of thermal and mechanical allodynia with pregabalin in a mouse model of oxaliplatin-induced peripheral neuropathy

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© 2016 Scandinavian Association for the Study of Pain
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10.1016/j.sjpain.2016.05.031
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Abstract

Abstracts / Scandinavian Journal of Pain 12 (2016) 125–127Genetic variation in P2RX7 and painO. Kambur (Presenter) a,b,∗ , K. Cajanus b,e , M.Kaunisto c , Bendik Winsvold d , Audun Stubhaug a ,John A. Zwart d , Christopher S. Nielsen a , E.Kalso b,eaDepartment of Pain Research and Management,Oslo University Hospital, Oslo, Norwayb Pharmacology, University of Helsinki, Faculty ofMedicine, Helsinki, Finlandc Institute for Molecular Medicine Finland (FIMM),University of Helsinki, Helsinki, Finlandd Department of Neurology, Oslo University Hospitaland University of Oslo, Norwaye Pain Clinic, University of Helsinki and HelsinkiUniversity Hospital, Helsinki, FinlandE-mail address: oleg.kambur@gmail.com (O. Kambur).Background and aims: P2X7 is a purinoceptor and nonselective cation channel that is activated by extracellular ATP,especially in immune and glia cells. Activation of P2X7 triggersthe secretion of several pro-inflammatory substances, such as IL1␤, IL-18, TNF-␣, and nitric oxide. P2X7 activation contributes tothe pro-inflammatory response to injury or bacterial invasion andmediates apoptosis. It has been implicated in physiological andpathological conditions such as bone tissue remodelling, inflammation, oncogenesis, depression, and inflammatory, neuropathicand chronic pain. Here, we aim to characterize the effects of variation within the P2RX7 gene, which encodes the P2X7 receptor, onpain and opioid requirements in human patients.Methods: Pain was assessed in Norwegian and Finnish cohorts.The Norwegian cohort represents the 6th wave of the TromsøStudy, a longitudinal and cross-sectional population based study(N = 3700), whereas the Finnish cohort (BrePainGen) consists ofpatients who underwent breast cancer surgery (N = 1000). For bothcohorts, experimental pain data were analyzed. Pain intensity andtolerance were assessed with cold pressor test and after standardized noxious heat stimulation in both cohorts. In addition, dataon acute postoperative pain and opioid requirements were analyzed in the BrePainGen cohort. Postoperative pain and opioidresponses were followed during 20 h after surgery. In total, 29 single nucleotide polymorphisms (SNPs) in P2RX7 were genotyped andtheir association with outcome variables was assessed using linearregression and analysis of variances (ANOVA).Results: Several P2RX7 SNPs were associated with the painphenotypes. The strongest associations were seen with cold painintensity and tolerance. The results of this study will be presentedat the meeting.Conclusions: Our results suggest that P2X7 and genetic variation in the P2RX7-gene are involved in the modulation of humanpain responses.http://dx.doi.org/10.1016/j.sjpain.2016.05.030127Reversal of thermal and mechanical allodyniawith pregabalin in a mouse model ofoxaliplatin-induced peripheral neuropathyR. Magnúsdóttir a,∗ , A. Fisher b , C. Chenu a ,N. Upton baComparative Biomedical Sciences, The RoyalVeterinary College, London, UKb Transpharmation Ltd, The London BioscienceInnovation Centre, London, UKE-mail address: rmagnusdottir@rvc.ac.uk (R. Magnúsdóttir).Aims: Chemotherapy-induced peripheral neuropathy (CIPN) isa dose limiting side effect in the use of the platinum-based antineoplastic drug oxaliplatin as a treatment for colorectal cancer.Currently there is no treatment available to reverse the neurotoxicity which presents as pain, sensory loss and cold allodynia in up to80% of patients. The aim of this study is to investigate if pregabalincan reverse the allodynia caused by oxaliplatin in CIPN.Methods: CIPN was induced in 10 male C57BL/6 mice (6 weeksold) with a single intraperitoneal injection of oxaliplatin (15 mg/kgi.p.). Signs of thermal and mechanical allodynia were assessed frombaseline to 20 days after injection by Cold/Hot plate (Bioseb, France)at 20 ◦ C and hand-held von Frey (vF) hairs of gradually increasingweights. Pregabalin (3 mg/kg and 10 mg/kg p.o.) was administeredto treat CIPN.Results: Mechanical and thermal allodynia were established 3days post-oxaliplatin injection and remained stable for 14 days. Atday 15, pregabalin (3 mg/kg p.o.) reversed mechanical allodynia tobaseline scores at 2 h (H) post-dosing and thermal allodynia at 1 and2H post-dosing. Following a 2-day wash out where scores returnedto neuropathic baseline, pregabalin (10 mg/kg p.o.) reverted scoresfor mechanical and thermal allodynia to baseline scores at both 1and 2H. Thermal testing was performed either immediately after vFor alone and our results were similar, showing no iatrogenic effectsof vF on thermal sensitivity. Correlation analysis of the responsesto thermal and mechanical stimuli showed no significant trend,indicating that oxaliplatin- induced peripheral neuropathy affectsthe mechanical and thermal modalities in different ways.Conclusion: Oxaliplatin-induced peripheral neuropathy asmeasured by thermal and mechanical allodynia is reversible by asingle dose of pregabalin.This project has received funding from the European Union’sHorizon 2020 research and innovation programme under the MarieSklodowska-Curie grant agreement No. 642720. RM is funded by aMarie Sklodowska-Curie grant agreement No. 642720 doing a jointPhD with the Royal Veterinary Collage and Transpharmation Ltd.AF and NU are employees of Transpharmation Ltd.http://dx.doi.org/10.1016/j.sjpain.2016.05.031

Journal

Scandinavian Journal of Painde Gruyter

Published: Dec 29, 2017

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