Choice of rat strain in pre-clinical pain-research – Does it make a difference for translation from animal model to human condition?

Choice of rat strain in pre-clinical pain-research – Does it make a difference for translation... Scientific presentations at the 2017 Annual Meeting / Scandinavian Journal of Pain 16 (2017) 165–188KNa and h) which were implemented across a detailed and realisticaxon morphology.Results: The model predicts that the small diameter of the axoncan accumulate intracellular sodium when it is repeatedly activatedin a similar fashion as during single fiber microneurography. Thisincrease of intracellular sodium concentration can shift the balance between ion channel currents, shift the membrane potentialand membrane input resistance, and thereby generate activitydependent changes of velocity, such as ADS as well as recoverycycle supernormality.Conclusions: Our results thus provide insight into how activitydependent excitability changes can be generated in C-fibers.By identifying which ion channels are contributing to activitydependent changes of velocity this could provide insight into ionchannel alterations in neuropathic pain patients.187injection, and were less sensitive to morphine in both pain-tests(MED = 6.0 mg/kg). LEW rats were completely insensitive to morphine in the hot plate, in contrast to reversal of CFA-inducedhyperalgesia (MED = 3.0 mg/kg). Additionally, neuropathic sensitivity developed with a later onset and less robustly in this strainafter SNI. All strains tested in LMA exhibited sedative effects at3.0 mg/kg.Conclusions: Sensory phenotyping in response to acute, inflammatory and neuropathic pain, and sensitivity to morphine in thesestrains indicates that different pathophysiological mechanisms areengaged after injury. This could have profound implications fortranslating preclinical drug discovery efforts into pain-patients.http://dx.doi.org/10.1016/j.sjpain.2017.04.063http://dx.doi.org/10.1016/j.sjpain.2017.04.062Omics as a potential tool to identify biomarkersand to clarify the mechanism of chronic paindevelopmentChoice of rat strain in pre-clinical pain-research– Does it make a difference for translation fromanimal model to human condition?M.C. Gerra ∗ , C. Dagostino, S. D’Agnelli, L. Boggiani,V. Rizza, M. Marchesini, M. Allegri, G. FanelliS. Hestehave a,b,∗ , G. Munro a,c , T.Brønnum-Pedersen d , A.M. Heegaard e , K.S.P.Abelson bAnesthesia Intensive Care and Pain Unit, SurgicalSciences Division, Department of Medicine andSurgery, University of Parma, ItalyE-mail address: mariacarla.gerra@studenti.unipr.it (M.C. Gerra).Aims: The present study aims to identify the underlying mechanisms in the acute to chronic pain transition. Acute pain is aphysiological response to an experience of noxious stimuli thatcan progress to chronic, becoming a disease. The negative consequences as personal suffering, reduction in physical function,maladaptive behaviours, reduction of productivity, make this condition a central and common problem affecting individuals andthe society. After an acute damage, pain in some cases persists,being the process attributed to different causes, in particular persistent tissue and neuronal damages, central neuroplastic changes,psychosocial factors.Methods: The techniques actually used to investigate acuteand chronic pain offer only a partial explanation of the processand in addition, the obtained results are often far away from thepossibility to lead some benefits in the clinical practice. Omics technologies could be the right way to detect biomarkers explainingthese mechanisms. Our previous study examined epigenetic andpharmacogenetic aspects of acute and chronic pain in a large groupof patients. Other omic approaches, such as metabolomics and glycomics, could help to (1) better identify metabolites that can serveas chronic pain development or side effects therapy biomarkersand to (2) better understand new insights involved into the pathophysiological mechanism that drives from acute to chronic pain.SNPs, DNA methylation, miRNA analyses, expression and proteinassays on the identified pathway would than clarify the causativemolecular mechanisms. In addition, linking these results to clinicalevaluation of the central sensitization processes through algometry in nociceptive and neuropathic pain patients may reveal crucialclinical and pharmacological implications.Conclusions: Our project will be implemented by omic technologies in different chronic pain patient cohorts (acute low backpain vs chronic low back pain patients and chronic postsurgicalpain patients) in order to evaluate new possible pathophysiologicalmechanism with special focus in central sensitization.aDepartment of In Vivo Neurodegeneration, H.Lundbeck A/S, Valby, Denmarkb Department of Experimental Medicine, Faculty ofHealth and Medical Sciences, University ofCopenhagen, Denmarkc Department of Neurology, Danish Headache Center,Glostrup Research Institute, Glostrup, Denmarkd Department of Non-Clinical Safety Research, H.Lundbeck A/S, Valby, Denmarke Department Drug Design and Pharmacology,Faculty of Health and Medical Sciences, Copenhagen,DenmarkE-mail address: sara.kristensen@sund.ku.dk (S. Hestehave).Aims: Translating preclinical drug-efficacy of analgesics fromanimal models to humans has proven challenging with manyfailures. Reasons are likely multifaceted, but lack of sufficiently rigorous study design, and phenotypical relevant animal models maybe part of the explanation. Chronic pain is often associated withsubstantial comorbid burden, consisting of changes in affectivestate and cognitive impairment amongst other behavioral disturbances. Accordingly, many preclinical pain research activities havestarted to include assessment of comorbidity as a possible experimental outcome measure, but surprisingly, little consideration hasbeen paid to the influence of animal-related factors to pain models.To address this essential issue, we have embarked on several comparative experiments in different pain-models, comparing SpragueDawley’s (SD) from two different vendors with different inbredrat strains (Lewis (LEW), Fisher (F344) and Wistar Kyoto (WKY))selected based on reported stress, depression, inflammatory andpain phenotypes.Methods: Male rats were characterized in acute (hot-plate),inflammatory (Complete Freund’s Adjuvant (CFA)) and neuropathic(Spared Nerve Injury (SNI)) pain models, with dose-response tomorphine (0.3–6.0 mg/kg) in hot-plate, CFA-induced hyperalgesia,and a locomotor motility-assay (LMA).Results: F344 and SD’s were sensitive to morphine in hotplate and CFA (Minimum Effective Dose (MED) = 3.0 mg/kg). WKYrats developed a less robust mechanical hypersensitivity after CFAhttp://dx.doi.org/10.1016/j.sjpain.2017.04.064 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Scandinavian Journal of Pain de Gruyter

Choice of rat strain in pre-clinical pain-research – Does it make a difference for translation from animal model to human condition?

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De Gruyter
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© 2017 Scandinavian Association for the Study of Pain
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1877-8860
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10.1016/j.sjpain.2017.04.063
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Abstract

Scientific presentations at the 2017 Annual Meeting / Scandinavian Journal of Pain 16 (2017) 165–188KNa and h) which were implemented across a detailed and realisticaxon morphology.Results: The model predicts that the small diameter of the axoncan accumulate intracellular sodium when it is repeatedly activatedin a similar fashion as during single fiber microneurography. Thisincrease of intracellular sodium concentration can shift the balance between ion channel currents, shift the membrane potentialand membrane input resistance, and thereby generate activitydependent changes of velocity, such as ADS as well as recoverycycle supernormality.Conclusions: Our results thus provide insight into how activitydependent excitability changes can be generated in C-fibers.By identifying which ion channels are contributing to activitydependent changes of velocity this could provide insight into ionchannel alterations in neuropathic pain patients.187injection, and were less sensitive to morphine in both pain-tests(MED = 6.0 mg/kg). LEW rats were completely insensitive to morphine in the hot plate, in contrast to reversal of CFA-inducedhyperalgesia (MED = 3.0 mg/kg). Additionally, neuropathic sensitivity developed with a later onset and less robustly in this strainafter SNI. All strains tested in LMA exhibited sedative effects at3.0 mg/kg.Conclusions: Sensory phenotyping in response to acute, inflammatory and neuropathic pain, and sensitivity to morphine in thesestrains indicates that different pathophysiological mechanisms areengaged after injury. This could have profound implications fortranslating preclinical drug discovery efforts into pain-patients.http://dx.doi.org/10.1016/j.sjpain.2017.04.063http://dx.doi.org/10.1016/j.sjpain.2017.04.062Omics as a potential tool to identify biomarkersand to clarify the mechanism of chronic paindevelopmentChoice of rat strain in pre-clinical pain-research– Does it make a difference for translation fromanimal model to human condition?M.C. Gerra ∗ , C. Dagostino, S. D’Agnelli, L. Boggiani,V. Rizza, M. Marchesini, M. Allegri, G. FanelliS. Hestehave a,b,∗ , G. Munro a,c , T.Brønnum-Pedersen d , A.M. Heegaard e , K.S.P.Abelson bAnesthesia Intensive Care and Pain Unit, SurgicalSciences Division, Department of Medicine andSurgery, University of Parma, ItalyE-mail address: mariacarla.gerra@studenti.unipr.it (M.C. Gerra).Aims: The present study aims to identify the underlying mechanisms in the acute to chronic pain transition. Acute pain is aphysiological response to an experience of noxious stimuli thatcan progress to chronic, becoming a disease. The negative consequences as personal suffering, reduction in physical function,maladaptive behaviours, reduction of productivity, make this condition a central and common problem affecting individuals andthe society. After an acute damage, pain in some cases persists,being the process attributed to different causes, in particular persistent tissue and neuronal damages, central neuroplastic changes,psychosocial factors.Methods: The techniques actually used to investigate acuteand chronic pain offer only a partial explanation of the processand in addition, the obtained results are often far away from thepossibility to lead some benefits in the clinical practice. Omics technologies could be the right way to detect biomarkers explainingthese mechanisms. Our previous study examined epigenetic andpharmacogenetic aspects of acute and chronic pain in a large groupof patients. Other omic approaches, such as metabolomics and glycomics, could help to (1) better identify metabolites that can serveas chronic pain development or side effects therapy biomarkersand to (2) better understand new insights involved into the pathophysiological mechanism that drives from acute to chronic pain.SNPs, DNA methylation, miRNA analyses, expression and proteinassays on the identified pathway would than clarify the causativemolecular mechanisms. In addition, linking these results to clinicalevaluation of the central sensitization processes through algometry in nociceptive and neuropathic pain patients may reveal crucialclinical and pharmacological implications.Conclusions: Our project will be implemented by omic technologies in different chronic pain patient cohorts (acute low backpain vs chronic low back pain patients and chronic postsurgicalpain patients) in order to evaluate new possible pathophysiologicalmechanism with special focus in central sensitization.aDepartment of In Vivo Neurodegeneration, H.Lundbeck A/S, Valby, Denmarkb Department of Experimental Medicine, Faculty ofHealth and Medical Sciences, University ofCopenhagen, Denmarkc Department of Neurology, Danish Headache Center,Glostrup Research Institute, Glostrup, Denmarkd Department of Non-Clinical Safety Research, H.Lundbeck A/S, Valby, Denmarke Department Drug Design and Pharmacology,Faculty of Health and Medical Sciences, Copenhagen,DenmarkE-mail address: sara.kristensen@sund.ku.dk (S. Hestehave).Aims: Translating preclinical drug-efficacy of analgesics fromanimal models to humans has proven challenging with manyfailures. Reasons are likely multifaceted, but lack of sufficiently rigorous study design, and phenotypical relevant animal models maybe part of the explanation. Chronic pain is often associated withsubstantial comorbid burden, consisting of changes in affectivestate and cognitive impairment amongst other behavioral disturbances. Accordingly, many preclinical pain research activities havestarted to include assessment of comorbidity as a possible experimental outcome measure, but surprisingly, little consideration hasbeen paid to the influence of animal-related factors to pain models.To address this essential issue, we have embarked on several comparative experiments in different pain-models, comparing SpragueDawley’s (SD) from two different vendors with different inbredrat strains (Lewis (LEW), Fisher (F344) and Wistar Kyoto (WKY))selected based on reported stress, depression, inflammatory andpain phenotypes.Methods: Male rats were characterized in acute (hot-plate),inflammatory (Complete Freund’s Adjuvant (CFA)) and neuropathic(Spared Nerve Injury (SNI)) pain models, with dose-response tomorphine (0.3–6.0 mg/kg) in hot-plate, CFA-induced hyperalgesia,and a locomotor motility-assay (LMA).Results: F344 and SD’s were sensitive to morphine in hotplate and CFA (Minimum Effective Dose (MED) = 3.0 mg/kg). WKYrats developed a less robust mechanical hypersensitivity after CFAhttp://dx.doi.org/10.1016/j.sjpain.2017.04.064

Journal

Scandinavian Journal of Painde Gruyter

Published: Jul 1, 2017

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