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.
Highlights
Chronic neuropathic pain is a neuro-immune disorder, characterised by allodynia, hyperalgesia and spontaneous pain, as well as debilitating affective-motivational disturbances
There is a growing number of studies in rodent models of neuropathic pain where peripheral nerve injury alone leads to increases in pro-inflammatory cytokines (e.g., interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor (TNF)) in pain-related brain regions: namely the periaqueductal gray (PAG) [23, 24], hypothalamus [24], hippocampus [25,26,27,28,29], prefrontal cortex [23, 27, 30, 31], nucleus accumbens (NAcc) [32] and rostral ventromedial medulla [33]
We found that Pain and disability rats had a distinct immune response at both peripheral and spinal cord sites compared to rats without disabilities, despite equal levels of damage to the sciatic nerve and degree of allodynia
Summary
Chronic 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). There is a growing number of studies in rodent models of neuropathic pain where peripheral nerve injury alone leads to increases in pro-inflammatory cytokines (e.g., interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor (TNF)) in pain-related brain regions: namely the periaqueductal gray (PAG) [23, 24], hypothalamus [24], hippocampus [25,26,27,28,29], prefrontal cortex [23, 27, 30, 31], nucleus accumbens (NAcc) [32] and rostral ventromedial medulla [33] Some of these studies have demonstrated that nerve injury-induced pro-inflammatory cytokine release in the brain is responsible for behavioural changes, including memory deficits [29, 34], reduced conditioned place-preference to morphine [32], and depressive-like behaviour [23]
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