Neuropathic injury drives a generalized negative affective state in mice

Abstract

Neuropathic pain causes both sensory and emotional maladaptation. Preclinical animal studies of neuropathic pain-induced negative affect could result in novel insights into the mechanisms of chronic pain. Modeling pain-induced negative affect, however, is variable across research groups and conditions. The same injury may or may not produce robust negative affective behavioral responses across different species, strains, and laboratories. Here we sought to identify negative affective consequences of the spared nerve injury model on C57BL/6J male and female mice. We found no significant effect of spared nerve injury across a variety of approach-avoidance, hedonic choice, and coping strategy assays. We hypothesized these inconsistencies may stem in part from the short test duration of these assays. To test this hypothesis, we used the homecage-based Feeding Experimentation Device version 3 to conduct 12-hour, overnight progressive ratio testing to determine whether mice with chronic spared nerve injury had decreased motivation to earn palatable food rewards. Our data demonstrate that despite equivalent task learning, spared nerve injury mice are less motivated to work for a sugar pellet than sham controls. Further, when we normalized behavioral responses across all the behavioral assays we tested, we found that a combined normalized behavioral score is predictive of injury-state and significantly correlates with mechanical thresholds. Together these results suggest that homecage-based operant behaviors provide a useful platform for modeling nerve injury-induced negative affect and that valuable pain-related information can arise from agglomerative data analyses across behavioral assays - even when individual inferential statistics do not demonstrate significant mean differences.

Spared nerve injury causes motor phenotypes unrelated to pain in mice

“…The surgical procedure for the SNI-induced model of neuropathic pain was performed as described previously 4,10 . Mice were anesthetized with 3% isoflurane and right hind limb shaved and disinfected with 75% ethanol and betadine.…”

“…Mice were acclimated for 2 hours on an elevated wire mesh grid in 5-inch diameter plexiglass cylinders wrapped in black opaque plastic sheets. Mechanical hypersensitivity was determined by applying von Frey filaments (0.02 g to 3.5 g; Bioseb, Pinellas Park, FL,USA) to the lateral aspect of the hindpaw 14 using the up-down method and 50% withdrawal threshold was calculated as described previously 10,15 .…”

“…The SNI model of neuropathic pain has been shown to reliably induce ipsilateral mechanical hypersensitivity [2][3][4][5][6][7][8][9][10] . Here, we performed SNI or sham surgeries and used the von Frey assay to quantify mechanical withdrawal thresholds (Fig.…”

“…Considering this shortfall, it is critical that we deeply evaluate the validity of common neuropathic pain models to improve our interpretations of these studies and their implications. The spared nerve injury (SNI) model is widely used to model neuropathic pain in rodents due to its resulting robust and prolonged mechanical hypersensitivity [2][3][4][5][6][7][8][9][10] . Despite its common use, however, SNI has several limitations including gait changes that may not be pain-related and potential lack of direct clinical validity 8,11 .…”

Endogenous opioids gate the locus coeruleus pain generator

“…Catalog # Titer Source AAV1-hSyn1-SIO-stGtACR2-FusionRed 105669-AAV1 1x10 13 The surgical procedure for the SNI-induced model of neuropathic pain was performed as described previously (50,56,57). Mice were anesthetized with 3% isoflurane and right hind limb shaved and disinfected with 75% ethanol and betadine.…”