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

Abstract

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.

The influence of rat strain on the development of neuropathic pain and comorbid anxio-depressive behaviour after nerve injury

“…Moreover, similarly to WKY rats, LEW rats have been suggested as a high-anxiety counterpart to the SHR strain when modeling high and low indices of basal anxiety 21,86,87 . Despite detecting very prominent differences in evoked pain-like behaviour between strains, we did not see any correlation between magnitude of neuropathic pain-like behaviour and affective changes indicative of the presence of anxiety-or depressive-like behaviour, confirming other recent findings 33,88 . Notably, the only strain showing anxiety-like behaviour in the EPM following nerve injury was the moderately pain-sensitive F344/DU.…”

How to study anxiety and depression in rodent models of chronic pain?

“…Thus, animals with or without anxiety‐ and/or depression‐like phenotype can show similar mechanical or thermal withdrawal thresholds in animal models of pain (Gui et al, 2016; Xie et al, 2017; Yang, Fang, et al, 2019). Conversely, a recent study showed that rats that do not develop mechanical allodynia after SNI can still develop anxiodepressive‐like behaviours similarly to painful rats (Guimaraes et al, 2019). There is thus no correlation in rodent models of chronic pain between the nociceptive response and the development of anxiodepressive disorders, which is similar to clinical reports (Bagnato et al, 2015; Dickens, Jayson, & Creed, 2002; Jensen et al, 2010; Keltner et al, 2012).…”

“…However, a causal link between pain and anxiodepressive consequences should not necessarily imply direct correlation between the intensity of nociceptive and anxiodepressive symptoms. Some observations suggest a temporal dissociation and partly independent mechanisms between these aspects of chronic pain (Gui et al, 2016; Guimaraes et al, 2019; Zhou et al, 2015). As example, in a model of sciatic nerve compression, mechanical hypersensitivity is no longer present 2–3 months after the surgery, while anxiodepressive‐like behaviours can persist after the recovery of hypersensitivity (Dimitrov et al, 2014; Sellmeijer et al, 2018).…”

“…As for the previously described tests, when LDB is performed in neuropathic pain models anxiety‐like behaviours can be observed 4 (Chen et al, 2013; Guimaraes et al, 2019; Matsuzawa‐Yanagida et al, 2008; Narita, Kaneko, et al, 2006; Narita, Kuzumaki, et al, 2006; Sieberg et al, 2018; Yalcin et al, 2011) to 8 weeks post‐surgery (Barthas et al, 2017; Lyons et al, 2015, 2018; Sellmeijer et al, 2018; Suzuki et al, 2007; Yalcin et al, 2011), except for the SCI model in which no decrease in time spent in light box was detected (Boadas‐Vaello et al, 2018; Table 1, Figures 2 and 3). Three studies also demonstrated a decrease in the time spent in the light box already detectable at 2 weeks after neuropathic pain induction (Chen et al, 2019; Gambeta et al, 2018; Mutso et al, 2012).…”

High trait impulsivity potentiates the effects of chronic pain on impulsive behavior

“…Mechanical allodynia was assessed as previously described (Guimarães et al, 2018) using the up-and-down method (Chaplan et al, 1994). Briefly, Von Frey monofilaments of different forces were used: 15.0 g, 8.0 g, 6.0 g, 4.0 g, 2.0 g, 1.0 g, 0.6 g and 0.4 g (North Coast Medical Inc., USA).…”