Evidence for lack of direct causality between pain and affective disturbances in a rat peripheral neuropathy model

Abstract

[Epub ahead of print]Chronic pain is frequently accompanied by the manifestation of emotional disturbances and cognitive deficits. While a causality relation between pain and emotional/cognitive disturbances is generally assumed, several observations suggest a temporal dissociation and independent mechanisms. We therefore studied Sprague-Dawley rats that presented a natural resistance to pain manifestation in a neuropathy model (spared nerve injury [SNI]) and compared their performance in a battery of behavioral paradigms-anxiety, depression and fear memory-with animals that presented a pain phenotype. Afterward, we performed an extensive volumetric analysis across prefrontal, orbitofrontal and insular cortical areas. The majority of SNI animals manifested mechanical allodynia (low threshold [LT]), but 13% were similar to Sham controls (high threshold [HT]). Readouts of spontaneous hypersensivity (paw flinches) were also significantly reduced in HT and correlated with allodynia. To increase the specificity of our findings, we segregated the SNI animals in those with left (SNI-L) and right (SNI-R) lesions and the lack of association between pain and behavior still remains. Left-lesioned animals, independent of the LT or HT phenotype, presented increased anxiety-like behaviors and decreased well-being. In contrast, we found that the insular cortex (agranular division) was significantly smaller in HT than in LT. To conclude, pain and emotional disturbances observed following nerve injury are to some extent segregated phenomena. Also, HT and LT SNI presented differences in insular volumes, an area vastly implicated in pain perception, suggesting a supraspinal involvement in the manifestation of these phenotypes.This work has been funded by the European Regional Development Fund (FEDER), through the Competitiveness Factors Operational Programme (COMPETE) and the Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal 2020 Partnership Agreement (project NORTE-01-0145-FEDER-000023). It was also funded by National and International funds, through the Foundation for Science and Technology (FCT), under the scope of the projects POCI-01-0145- FEDER-007038 and PTDC/NEU-SCC/5301/2014 and by the IASP Early Career Research Grant 2015. Researchers were supported by FCT grant numbers PD/BD/114117/2015 (MRG via Inter-University Doctoral Programme in Ageing and Chronic Disease, PhDOC), SFRH/BD/109111/2015 (AMC via PhD Program in Health Sciences), SFRH/BD/52291/2013 (ME via PhDOC), SFRH/BD/89936/2012 (SB via PhD Program in Health Sciences (Applied)), PDE/BDE/113604/2015 (RM via PhD Program in Health Sciences (Applied)), PDE/BDE/113601/2015 (PSM via PhD Program in Health Sciences (Applied)) and SFRH/BPD/80118/2011 (HA). ARS integrated the Master Programme in Health Sciences of the School of Medicine, University of Minho.info:eu-repo/semantics/acceptedVersio