Nerve-myeloid cell interactions in persistent human pain: a reappraisal using updated cell subset classifications.

ABSTRACT: The past 20 years have seen a dramatic shift in our understanding of the role of the immune system in initiating and maintaining pain. Myeloid cells, including macrophages, dendritic cells, Langerhans cells, and mast cells, are increasingly implicated in bidirectional interactions with nerve fibres in rodent pain models. However, our understanding of the human setting is still poor. High-dimensional functional analyses have substantially changed myeloid cell classifications, with recently described subsets such as epidermal dendritic cells and DC3s unveiling new insight into how myeloid cells interact with nerve fibres. However, it is unclear whether this new understanding has informed the study of human chronic pain. In this article, we perform a scoping review investigating neuroimmune interactions between myeloid cells and peripheral nerve fibres in human chronic pain conditions. We found 37 papers from multiple pain states addressing this aim in skin, cornea, peripheral nerve, endometrium, and tumour, with macrophages, Langerhans cells, and mast cells the most investigated. The directionality of results between studies was inconsistent, although the clearest pattern was an increase in macrophage frequency across conditions, phases, and tissues. Myeloid cell definitions were often outdated and lacked correspondence with the stated cell types of interest; overreliance on morphology and traditional structural markers gave limited insight into the functional characteristics of investigated cells. We therefore critically reappraise the existing literature considering contemporary myeloid cell biology and advocate for the application of established and emerging high-dimensional proteomic and transcriptomic single-cell technologies to clarify the role of specific neuroimmune interactions in chronic pain.

Ranking the risk factors for Alzheimer's disease; findings from the UK Biobank study.

Background: The cause of the most common form of dementia, sporadic Alzheimer's disease (AD), remains unknown. This may reflect insufficiently powered studies to date for this multi-factorial disorder. The UK Biobank dataset presents a unique opportunity to rank known risk factors and determine novel variables. Methods: A custom machine learning approach for high dimensionality data was applied to explore prospectively associations between AD in a sub-cohort of 156,209 UK Biobank participants aged 60-70 including more than 2,090 who were subsequently diagnosed with AD. Results: After the possession of the APOE4 allele, the next highest ranked risk factors were other genetic variants within the TOMM40-APOE-APOC1 locus. When stratified by their apolipoprotein epsilon 4 (APOE4) carrier status, the most prominent risk factors in carriers were AST:ALT ratio, the "number of treatments/ medications" taken as well as "time spent in hospital" while protection was conferred by "Sleeplessness/Insomnia". In non-APOE carriers, lower socioeconomic status and fewer years of education were highly ranked but effect sizes were small relative to APOE4 carriers. Conclusions: Possession of the APOE4 allele was confirmed as the most important risk factor in AD. Other TOMM40-APOE-APOC1 locus variants further moderate the risk of AD in APOE4 carriers. Liver pathology is a novel risk factor in APOE4 carriers while "Sleeplessness/Insomnia" is protective in AD irrespective of APOE4 status. Other factors such as "Number of treatments/ medications" suggest that multimorbidity is an important risk factor for AD. Future treatments aimed at co-morbidities, including liver disease, may concomitantly lower the risk of sporadic AD.

Machine learning analysis of the UK Biobank reveals prognostic and diagnostic immune biomarkers for polyneuropathy and neuropathic pain in diabetes.

AIMS: We assessed the health data of 11,047 people with diabetes in the UK Biobank to rank 329 risk factors for diabetic polyneuropathy (DPN) and DPN with chronic neuropathic pain without a priori assumption. METHODS: The Integrated Disease Explanation and Risk Scoring (IDEARS) platform applies machine learning algorithms to multimodal data to determine individual disease risk, and rank risk factor importance using mean SHapley Additive exPlanations (SHAP) score. RESULTS: IDEARS models showed discriminative performances with AUC > 0.64. Lower socioeconomic status, being overweight, poor overall health, cystatin C, HbA1C, and immune activation marker, C-reactive protein (CRP), predict DPN risk. Neutrophils and monocytes were higher in males and lymphocytes lower in females with diabetes that develop DPN. Neutrophil-to-Lymphocyte Ratio (NLR) was increased and IGF-1 levels decreased in people with type 2 diabetes that later develop DPN. CRP was significantly elevated in those with DPN and chronic neuropathic pain compared to DPN without pain. CONCLUSIONS: Lifestyle factors and blood biomarkers predict the later development of DPN and may relate to DPN pathomechanisms. Our results are consistent with DPN as a disease involving systemic inflammation. We advocate for the use of these biomarkers clinically to predict future DPN risk and improve early diagnosis.

A dual role of microbiota type 17 immunity in tissue repair and pain.

In this commentary, we discuss the findings of Enamorado et al. who have, for the first time, demonstrated that immunity to the microbiota enhances repair of cutaneous sensory nerves and epithelial tissues following skin injury. Commensal-specific IL-17 producing CD4+ T helper cells have direct contact with injured sensory neurons, inducing multiple epithelial and neuronal repair genes. We speculate that an altered balance of T cell populations in the skin of people with chronic neuropathic pain may contribute to a reduction in neuronal repair and the consequent decease in intraepidermal nerve fibre density and persistent pain.

A systematic review of the effect of photobiomodulation on the neuroinflammatory response in animal models of neurodegenerative diseases.

This systematic review examines the effect of photobiomodulation (PBM), the application of red to near infrared light on body tissues, on the neuroinflammatory response and oxidative stress in animal models of neurodegenerative diseases. The research question and search protocol were prospectively registered on the PROSPERO database. Neurodegenerative diseases are becoming ever more prevalent in the ageing populations across the Western world, with no disease-modifying or neuroprotective treatment options being available. Hence there is a real need for the development of effective treatment options for patients. Inflammatory responses and oxidative stress within the central nervous system have a strong correlation with neuronal cell death. PBM is a non-invasive therapeutic option that has shown efficacy and promising effects in animal models of neurodegenerative disease; many studies have reported neuroprotection and improved behavioural outcomes. To the best of our knowledge, there has been no previous study that has reviewed the anti-inflammatory and the antioxidant effect of PBM in the context of neurodegeneration. This review has examined this relationship in animal models of a range of neurodegenerative diseases. We found that PBM can effectively reduce glial activation, pro-inflammatory cytokine expression and oxidative stress, whilst increasing anti-inflammatory glial responses and cytokines, and antioxidant capacity. These positive outcomes accompanied the neuroprotection evident after PBM treatment. Our review provides further indication that PBM can be developed into an effective non-pharmacological intervention for neurodegenerative diseases.

Altered basal ganglia infraslow oscillation and resting functional connectivity in complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a painful condition commonly accompanied by movement disturbances and often affects the upper limbs. The basal ganglia motor loop is central to movement, however, non-motor basal ganglia loops are involved in pain, sensory integration, visual processing, cognition, and emotion. Systematic evaluation of each basal ganglia functional loop and its relation to motor and non-motor disturbances in CRPS has not been investigated. We recruited 15 upper limb CRPS and 45 matched healthy control subjects. Using functional magnetic resonance imaging, infraslow oscillations (ISO) and resting-state functional connectivity in motor and non-motor basal ganglia loops were investigated using putamen and caudate seeds. Compared to controls, CRPS subjects displayed increased ISO power in the putamen contralateral to the CRPS affected limb, specifically, in contralateral putamen areas representing the supplementary motor area hand, motor hand, and motor tongue. Furthermore, compared to controls, CRPS subjects displayed increased resting connectivity between these putaminal areas as well as from the caudate body to cortical areas such as the primary motor cortex, supplementary and cingulate motor areas, parietal association areas, and the orbitofrontal cortex. These findings demonstrate changes in basal ganglia loop function in CRPS subjects and may underpin motor disturbances of CRPS.

T lymphocyte and monocyte subsets are dysregulated in type 1 diabetes patients with peripheral neuropathic pain.

Diabetic neuropathic pain is a common and devastating complication of type 1 diabetes, but the mechanism by which it develops and persists is yet to be fully elucidated. This study utilised high-dimensional suspension mass cytometry in a pilot cohort to investigate differences in peripheral blood immunophenotypes between type 1 diabetes patients with (n â€‹= â€‹9) and without (n â€‹= â€‹9) peripheral neuropathic pain. The abundance and activation of several leukocyte subsets were investigated with unsupervised clustering approaches FlowSOM and SPADE, as well as by manual gating. Major findings included a proportional increase in CD4+ central memory T cells and an absolute increase in classical monocytes, non-classical monocytes, and mature natural killer cells in type 1 diabetes patients with pain compared to those without pain. The expression of CD27, CD127, and CD39 was upregulated on select T cell populations, and the phosphorylated form of pro-inflammatory transcription factor MK2 was upregulated across most populations. These results provide evidence that distinct immunological signatures are associated with painful neuropathy in type 1 diabetes patients. Further research may link these changes to mechanisms by which pain in type 1 diabetes is initiated and maintained, paving the way for much needed targeted treatments.

Kynurenine, Tetrahydrobiopterin, and Cytokine Inflammatory Biomarkers in Individuals Affected by Diabetic Neuropathic Pain.

Neuropathic pain is a common complication of diabetes with high morbidity and poor treatment outcomes. Accumulating evidence suggests the immune system is involved in the development of diabetic neuropathy, whilst neuro-immune interactions involving the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways have been linked to neuropathic pain pre-clinically and in several chronic pain conditions. Here, using a multiplex assay, we quantified serum levels of 14 cytokines in 21 participants with type 1 diabetes mellitus, 13 of which were classified as having neuropathic pain. In addition, using high performance liquid chromatography and gas chromatography-mass spectrometry, all major KYN and BH4 pathway metabolites were quantified in serum from the same cohort. Our results show increases in GM-CSF and IL-8, suggesting immune cell involvement. We demonstrated increases in two inflammatory biomarkers: neopterin and the KYN/TRP ratio, a marker of indoleamine 2,3-dioxygenase activity. Moreover, the KYN/TRP ratio positively correlated with pain intensity. Total kynurenine aminotransferase activity was also higher in the diabetic neuropathic pain group, indicating there may be increased production of the KYN metabolite, xanthurenic acid. Overall, this study supports the idea that inflammatory activation of the KYN and BH4 pathways occurs due to elevated inflammatory cytokines, which might be involved in the pathogenesis of neuropathic pain in type 1 diabetes mellitus. Further studies should be carried out to investigate the role of KYN and BH4 pathways, which could strengthen the case for therapeutically targeting them in neuropathic pain conditions.

Novel immune biomarkers in complex regional pain syndrome.

We investigated serum levels of 29 cytokines and immune-activated kynurenine and tetrahydrobiopterin pathway metabolites in 15 complex regional pain syndrome (CRPS) subjects and 14 healthy controls. Significant reductions in interleukin-37 and tryptophan were found in CRPS subjects, along with positive correlations between kynurenine/tryptophan ratio and TNF-α levels with kinesiophobia, tetrahydrobiopterin levels with McGill pain score, sRAGE, and xanthurenic acid and neopterin levels with depression, anxiety and stress scores. Using machine learning, we identified a set of binary variables, including IL-37 and GM-CSF, capable of distinguishing controls from established CRPS subjects. These results suggest possible involvement of various inflammatory markers in CRPS pathogenesis.

Effect of Photobiomodulation in Rescuing Lipopolysaccharide-Induced Dopaminergic Cell Loss in the Male Sprague-Dawley Rat.

Photobiomodulation (PBM) provides neuroprotection against dopaminergic cell death and associated motor deficits in rodent and primate models of Parkinson's disease (PD). However, it has not yet been tested in the lipopolysaccharide (LPS) model of PD, which leads to dopaminergic cell death through microglia-evoked neuroinflammation. We investigated whether transcranial PBM could protect against dopaminergic cell death within the substantia nigra in male Sprague-Dawley rats following supranigral LPS injection. PBM fully protected rats from 10 µg LPS which would have otherwise caused 15% cell loss, but there was no significant neuroprotection at a 20 µg dose that led to a 50% lesion. Cell loss at this dose varied according to the precise site of injection and correlated with increased local numbers of highly inflammatory amoeboid microglia. Twenty microgram LPS caused motor deficits in the cylinder, adjusted stepping and rotarod tests that correlated with dopaminergic cell loss. While PBM caused no significant improvement at the group level, motor performance on all three tests no longer correlated with the lesion size caused by 20 µg LPS in PBM-treated rats, suggesting extranigral motor improvements in some animals. These results provide support for PBM as a successful neuroprotective therapy against the inflammatory component of early PD, provided inflammation has not reached a devastating level, as well as potential benefits in other motor circuitries.

Peripheral Nerve Injury Triggers Neuroinflammation in the Medial Prefrontal Cortex and Ventral Hippocampus in a Subgroup of Rats with Coincident Affective Behavioural Changes.

Nerve damage leads to the development of disabling neuropathic pain in susceptible individuals, where patients present with pain as well as co-morbid affective behavioural disturbances, such as anhedonia, decreased motivation and depression. In this study we aimed to characterise changes in neuroinflammation in the medial prefrontal cortex (mPFC) and hippocampus (HP) in a rat model of neuropathic pain (NP) and behavioural changes. 53 rats underwent sciatic nerve chronic constriction injury (CCI) and were characterised as either, No effect, Acute effect or Lasting effect on the basis of changes in exploration behaviour in a radial-arm maze. Microglial and astrocyte morphology, as well as IL-1ß, IL-6, IL-10, MCP-1, p38 MAPK and BDNF expression was quantified throughout the mPFC and HP using protein multiplex assays and immunofluorescence. All behavioural groups of CCI rats displayed equal levels of mechanical allodynia; however, the characteristic withdrawal from pellet-seeking observed in Lasting effect rats was accompanied by neuroimmune activation within the contralateral ventral HP and mPFC. This includes increased expression of IL-1ß, IL-6 and MCP-1, increased phospho-p38 MAPK expression in neurons and microglia, and a shift to a reactive microglial morphology in the caudal PL and IL, ventral CA1 and DG. Therefore, neuroinflammation in the mPFC and ventral HP may influence individual differences in radial-arm maze behaviour following CCI. Our data provide further evidence that individual differences in neuroimmune activation in the interconnected ventral HP-mPFC circuitry may play a role in the divergent behavioural trajectories following nerve injury, with neuroinflammation being coincident with affective behavioural changes in susceptible individuals.

Correction to: Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome.

Following publication of the original article [1], the authors reported an error in Figure 4 as the wrong figure was used.

Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is a debilitating condition where trauma to a limb results in devastating persistent pain that is disproportionate to the initial injury. The pathophysiology of CRPS remains unknown; however, accumulating evidence suggests it is an immunoneurological disorder, especially in light of evidence of auto-antibodies in ~ 30% of patients. Despite this, a systematic assessment of all circulating leukocyte populations in CRPS has never been performed. METHODS: We characterised 14 participants as meeting the Budapest clinical criteria for CRPS and assessed their pain ratings and psychological state using a series of questionnaires. Next, we performed immunophenotyping on blood samples from the 14 CRPS participants as well as 14 healthy pain-free controls using mass cytometry. Using a panel of 38 phenotypic and activation markers, we characterised the numbers and intracellular activation status of all major leukocyte populations using manual gating strategies and unsupervised cluster analysis. RESULTS: We have shown expansion and activation of several distinct populations of central memory T lymphocytes in CRPS. The number of central memory CD8+ T cells was increased 2.15-fold; furthermore, this cell group had increased phosphorylation of NFkB and STAT1 compared to controls. Regarding central memory CD4+ T lymphocytes, the number of Th1 and Treg cells was increased 4.98-fold and 2.18-fold respectively, with increased phosphorylation of NFkB in both populations. We also found decreased numbers of CD1c+ myeloid dendritic cells, although with increased p38 phosphorylation. These changes could indicate dendritic cell tissue trafficking, as well as their involvement in lymphocyte activation. CONCLUSIONS: These findings represent the first mass cytometry immunophenotyping study in any chronic pain state and provide preliminary evidence of an antigen-mediated T lymphocyte response in CRPS. In particular, the presence of increased numbers of long-lived central memory CD4+ and CD8+ T lymphocytes with increased activation of pro-inflammatory signalling pathways may indicate ongoing inflammation and cellular damage in CRPS.

Glial-cytokine-neuronal Adaptations in the Ventral Hippocampus of Rats with Affective Behavioral Changes Following Peripheral Nerve Injury.

Nerve damage leads to the development of disabling neuropathic pain in susceptible individuals, where patients present with pain as well as co-morbid behavioral changes, such as anhedonia, decreased motivation and depression. In this study we evaluated whether radial maze behavioral disruptions and glia-cytokine-neuronal adaptations in the hippocampus occurred in individual rats after nerve injury. Exploration behavior and spatial memory were quantified using a radial maze task, while mechanical allodynia was assessed using von Frey testing. Sciatic nerve chronic constriction injury (CCI) reduced withdrawal thresholds in all rats, while pellet-seeking behaviors were altered in some but not all rats. One group, termed 'No effect', had no behavioral changes compared to sham rats. Another group, termed 'Acute effect', had a temporary alteration to their exploration pattern, displaying more risk-assessment behavior in the early phase post-injury. In a third group, termed 'Lasting effect', exploratory behaviors were remarkably different for the entire post-injury period, showing a withdrawal from pellet-seeking. The withdrawal from pellet-seeking was found to be concomitant with distinct glial-cytokine-neuronal adaptations within the contralateral ventral hippocampus, including; increased expression of IL-1ß and MCP-1; astrocyte atrophy and decreased area in the dentate gyrus; reactive microglia and increased FosB/ΔFosB expression in the cornu ammonis subfield. Therefore, glial-cytokine-neuronal adaptations in the ventral hippocampus may mediate individual differences in radial maze behavior following CCI. Our data suggest that individual neuroimmune signatures play a significant role in divergent behavioral trajectories following nerve injury, toward functional recovery and coping, or the emergence of ongoing affective state disturbances.

Peripheral nerve injury impairs the ability to maintain behavioural flexibility following acute stress in the rat.

Chronic neuropathic pain often leads to impaired cognition and reduced behavioural flexibility. This study used a rat model to investigate if a peripheral nerve injury, with or without an additional acute psychological stress, alters behavioural flexibility and goal directed behaviour as measured by sensitivity to devaluation. Neuropathic pain was induced by a chronic constriction injury (CCI) of the sciatic nerve. CCI, sham-injury and naïve rats were trained to press two levers for two rewards. In outcome devaluation tests, one of the rewards was devalued by pre-feeding it to satiety, immediately prior to an extinction test measuring responding on the two levers. The ability to preferentially direct responding toward the action earning the currently-valued reward was taken as evidence of goal-directed behaviour. To test the impact of acute stress, rats were subjected to 15min restraint following pre-feeding and prior to the devaluation test. Neither CCI surgery nor acute stress alone altered sensitivity to devaluation, but in combination CCI and acute stress significantly reduced sensitivity to devaluation. This Study demonstrates that relatively mild stressors that are without effect in uninjured populations can markedly impair cognition under conditions of chronic pain. It further suggests that overlapping neural substrates regulated by nerve injury and/or acute stress are having a cumulative effect on behavioural flexibility.

Are the emergence of affective disturbances in neuropathic pain states contingent on supraspinal neuroinflammation?

Neuro-immune interactions contribute to the pathogenesis of neuropathic pain due to peripheral nerve injury. A large body of preclinical evidence supports the idea that the immune system acts to modulate the sensory symptoms of neuropathy at both peripheral and central nervous system sites. The potential involvement of neuro-immune interactions in the highly debilitating affective disturbances of neuropathic pain, such as depression, anhedonia, impaired cognition and reduced motivation has received little attention. This is surprising given the widely accepted view that sickness behaviour, depression, cognitive impairment and other neuropsychiatric conditions can arise from inflammatory mechanisms. Moreover, there is a set of well-described immune-to-brain transmission mechanisms that explain how peripheral inflammation can lead to supraspinal neuroinflammation. In the last 5years increasing evidence has emerged that peripheral nerve injury induces supraspinal changes in cytokine or chemokine expression and alters glial cell activity. In this systematic review, based on strong preclinical evidence, we advance the argument that the emergence of affective disturbances in neuropathic pain states are contingent on pro-inflammatory mediators in the interconnected hippocampal-medial prefrontal circuitry that subserve affective behaviours. We explore how dysregulation of inflammatory mediators in these networks may result in affective disturbances through a wide variety of neuromodulatory mechanisms. There are also promising results from clinical trials showing that anti-inflammatory agents have efficacy in the treatment of a variety of neuropsychiatric conditions including depression and appear suited to sub-groups of patients with elevated pro-inflammatory profiles. Thus, although further research is required, aggressively targeting supraspinal pro-inflammatory mediators at critical time-points in appropriate clinical populations is likely to be a novel avenue to treat debilitating affective disturbances in neuropathic conditions.

Recruitment of dorsal midbrain catecholaminergic pathways in the recovery from nerve injury evoked disabilities.

BACKGROUND: The periaqueductal gray region (PAG) is one of several brain areas identified to be vulnerable to structural and functional change following peripheral nerve injury. Sciatic nerve constriction injury (CCI) triggers neuropathic pain and three distinct profiles of changes in complex behaviours, which include altered social and sleep-wake behaviours as well as changes in endocrine function. The PAG encompasses subgroups of the A10 dopaminergic and A6 noradrenergic cell groups; the origins of significant ascending projections to hypothalamic and forebrain regions, which regulate sleep, complex behaviours and endocrine function. We used RT-PCR, western blots and immunohistochemistry for tyrosine hydroxylase to determine whether (1) tyrosine hydroxylase increased in the A10/A6 cells and/or; (2) de novo synthesis of tyrosine hydroxylase, in a 'TH-naïve' population of ventral PAG neurons characterized rats with distinct patterns of behavioural and endocrine change co-morbid with CCI evoked-pain. RESULTS: Evidence for increased tyrosine hydroxylase transcription and translation in the constitutive A10/A6 cells was found in the midbrain of rats that showed an initial 2-3 day post-CCI, behavioural and endocrine change, which recovered by days 5-6 post-CCI. Furthermore these rats showed significant increases in the density of TH-IR fibres in the vPAG. CONCLUSIONS: Our data provide evidence for: (1) potential increases in dopamine and noradrenaline synthesis in vPAG cells; and (2) increased catecholaminergic drive on vPAG neurons in rats in which transient changes in social behavior are seen following CCI. The data suggests a role for dopaminergic and noradrenergic outputs, and catecholaminergic inputs of the vPAG in the expression of one of the profiles of behavioural and endocrine change triggered by nerve injury.

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

BACKGROUND: 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). 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. METHODS: Sixty-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. RESULTS: All 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-1ß, IL-6 and MCP-1 in the spinal cord. Amongst subgroups, only Pain and disability rats had increased IL-1ß. CONCLUSIONS: This 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.

Injury-Dependent and Disability-Specific Lumbar Spinal Gene Regulation following Sciatic Nerve Injury in the Rat.

Allodynia, hyperalgesia and spontaneous pain are cardinal sensory signs of neuropathic pain. Clinically, many neuropathic pain patients experience affective-motivational state changes, including reduced familial and social interactions, decreased motivation, anhedonia and depression which are severely debilitating. In earlier studies we have shown that sciatic nerve chronic constriction injury (CCI) disrupts social interactions, sleep-wake-cycle and endocrine function in one third of rats, a subgroup reliably identified six days after injury. CCI consistently produces allodynia and hyperalgesia, the intensity of which was unrelated either to the altered social interactions, sleep-wake-cycle or endocrine changes. This decoupling of the sensory consequences of nerve injury from the affective-motivational changes is reported in both animal experiments and human clinical data. The sensory changes triggered by CCI are mediated primarily by functional changes in the lumbar dorsal horn, however, whether lumbar spinal changes may drive different affective-motivational states has never been considered. In these studies, we used microarrays to identify the unique transcriptomes of rats with altered social behaviours following sciatic CCI to determine whether specific patterns of lumbar spinal adaptations characterised this subgroup. Rats underwent CCI and on the basis of reductions in dominance behaviour in resident-intruder social interactions were categorised as having Pain & Disability, Pain & Transient Disability or Pain alone. We examined the lumbar spinal transcriptomes two and six days after CCI. Fifty-four 'disability-specific' genes were identified. Sixty-five percent were unique to Pain & Disability rats, two-thirds of which were associated with neurotransmission, inflammation and/or cellular stress. In contrast, 40% of genes differentially regulated in rats without disabilities were involved with more general homeostatic processes (cellular structure, transcription or translation). We suggest that these patterns of gene expression lead to either the expression of disability, or to resilience and recovery, by modifying local spinal circuitry at the origin of ascending supraspinal pathways.