Evidence for a distinct neuro-immune signature in rats that develop behavioural disability after nerve injury

Abstract

BackgroundChronic neuropathic pain is a neuro-immune disorder, characterised by allodynia, hyperalgesia and spontaneous pain, as well as debilitating affective-motivational disturbances (e.g., reduced social interactions, sleep-wake cycle disruption, anhedonia, and depression). The role of the immune system in altered sensation following nerve injury is well documented. However, its role in the development of affective-motivational disturbances remains largely unknown. Here, we aimed to characterise changes in the immune response at peripheral and spinal sites in a rat model of neuropathic pain and disability.MethodsSixty-two rats underwent sciatic nerve chronic constriction injury (CCI) and were characterised as either Pain and disability, Pain and transient disability or Pain alone on the basis of sensory threshold testing and changes in post-CCI dominance behaviour in resident-intruder interactions. Nerve ultrastructure was assessed and the number of T lymphocytes and macrophages were quantified at the site of injury on day six post-CCI. ATF3 expression was quantified in the dorsal root ganglia (DRG). Using a multiplex assay, eight cytokines were quantified in the sciatic nerve, DRG and spinal cord.ResultsAll CCI rats displayed equal levels of mechanical allodynia, structural nerve damage, and reorganisation. All CCI rats had significant infiltration of macrophages and T lymphocytes to both the injury site and the DRG. Pain and disability rats had significantly greater numbers of T lymphocytes. CCI increased IL-6 and MCP-1 in the sciatic nerve. Examination of disability subgroups revealed increases in IL-6 and MCP-1 were restricted to Pain and disability rats. Conversely, CCI led to a decrease in IL-17, which was restricted to Pain and transient disability and Pain alone rats. CCI significantly increased IL-6 and MCP-1 in the DRG, with IL-6 restricted to Pain and disability rats. CCI rats had increased IL-1β, IL-6 and MCP-1 in the spinal cord. Amongst subgroups, only Pain and disability rats had increased IL-1β.ConclusionsThis study has defined individual differences in the immune response at peripheral and spinal sites following CCI in rats. These changes correlated with the degree of disability. Our data suggest that individual immune signatures play a significant role in the different behavioural trajectories following nerve injury, and in some cases may lead to persistent affective-motivational disturbances.

Brain-derived neurotrophic factor-TrkB signaling in the medial prefrontal cortex plays a role in the anhedonia-like phenotype after spared nerve injury

“…The previous clinical studies demonstrated that the incidence of comorbid chronic pain and depression is around 30-50% [1,4,5], which is in line with the present study. In this study, we found that rats with or without anhedonia-like phenotypes showed similar mechanical withdrawal thresholds, suggesting that the alterations in mood-related behaviors were independent of the degree of nociceptive damage, consistent with the previous studies [8,31,[38][39][40].…”

“…In preclinical studies, rats with hyperalgesia were highly heterogeneous in depression-related behaviors. Keay and colleagues reported that chronic constriction injury (CCI) induced a subgroup (approximately 30%) of rats that had altered dominant behavior [8] and sleep-wake cycles [38] using resident-intruder social interaction and sleep-wake analyses. In this study, the hierarchical cluster analysis divided SNI rats into two clusters: one group (approximately 40%, 'anhedonia-like phenotype') with reduced sucrose preference in the SPT, the other group (approximately 60%, 'without anhedonia-like phenotype') with similar sucrose preference compared with sham-operated rats.…”

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

“…[10][11][12][13] However, substantial evidence has been accumulating, particularly in models of peripheral neuropathies, suggesting that hypersensitivity and the behavioral impairments can to a certain extent dissociate. [15][16][17][18][19][20][21][22][23] Also, previous studies from our group showed that left-and right-sided injuries are differentially associated with specific behavioral deficits, but no differences were observed in their algogenic quality. The proportion of affected animals was shown to be constant and associated with particular morphological, endocrine, inflammatory and genetic outcomes.…”

Developmental Changes in Pain and Spinal Immune Gene Expression after Radicular Trauma in the Rat

“…CCL2, CCL3, CCL5, IL-1β, and IL-6 are upregulated in damaged nerves, DRGs, and spinal cord dorsal horn (60–63) in variety of models and neuropathic pain is decreased by antagonists, neutralizing antibodies, microglia inhibitors, or in CCL2 deficient mice (62, 64–66). However, in the present study, CCL3 expression was elevated at all ages at PS1 in the root compression and at PS7 in the nerve compression injury, which is not consistent with the appearance of thermal or mechanical hyperalgesia.…”