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The neural circuits underling sensory, affective, and cognitive dimensions of pain are well-defined, and there is strong evidence that these circuits are compromised by the activation of glial cells and the release of immune mediators in chronic pain states. Immune mediators can modulate glutamatergic and GABAergic signaling, synaptic plasticity, neurogenesis, and neurotrophic factors. Recent neural imaging studies highlight astrocyte and microglial activation within the sensory-discriminative circuits in chronic pain patients. There is also emerging pre-clinical evidence that individuals with neuropathic pain that are ‘susceptible’ to co-morbid affective disturbances have neuroinflammation in the interconnected prefrontal cortex-ventral hippocampal circuitry. The therapeutic potential of anti-inflammatory agents to mitigate these detrimental supraspinal neuroimmune interactions should be considered in chronic pain patients, particularly those with elevated peripheral immune biomarkers and co-morbid affective disturbances.

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.

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.

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.

In a large proportion of individuals nervous system damage may lead to a debilitating chronic neuropathic pain. Such pain may now be considered a neuro-immune disorder, since recent data indicate a critical involvement of innate and adaptive immune responses following nerve injury. Activation of immune and immune-like glial cells in the injured nerve, dorsal root ganglia and spinal cord results in the release of both pro- and anti-inflammatory cytokines, as well as algesic and analgesic mediators, the balance of which determines whether pain chronicity is established. This review will critically examine the role of the immune system in modulating chronic pain in animal models of nervous system injury, and highlight the possible therapeutic opportunities to intervene in the development and maintenance of neuropathic pain.

Following unilateral chronic constriction injury (CCI) of the sciatic nerve, histochemical and gene expression changes were examined in the rat nucleus accumbens (NAcc), a region critical to affective-motivational regulation. Rats were categorised as having Pain alone (45%) or Pain and Disability (30%), on the basis of either unaltered or decreased dominance behaviour in the resident-intruder paradigm, respectively. Tyrosine hydroxylase (TH) expression was significantly increased bilaterally, throughout the rostrocaudal extent of the NAcc in Pain alone animals. Increased TH likely reflects increased dopamine levels in the Pain alone group, which may modulate dopamine receptor subtype 2 (D2) receptor expression. Stereological analyses of D2 receptor immunoreactive (D2-IR) cells revealed lateralised changes which correlated significantly with dominance behaviour. In the contralateral NAcc, D2-IR negatively correlated with post-CCI dominance behaviour (i.e. Pain alone animals have decreased D2-IR), whereas ipsilaterally there was a positive correlation between D2-IR and post-CCI dominance behaviour (i.e. Pain and Disability animals have decreased D2-IR). Western blots for D2 protein expression confirmed these correlations. Additionally, D2 mRNA expression within the NAcc showed lateralised and group specific changes. In the ipsilateral NAcc D2 mRNA was increased in Pain alone animals. It is hypothesised that increased D2 mRNA in the ipsilateral NAcc of Pain alone animals may be a protective mechanism, maintaining D2-IR despite increased dopamine, which may otherwise induce receptor desensitisation. D2 mRNA is not altered in the ipsilateral NAcc of Pain and Disability animals, therefore loss of D2-IR is likely, albeit by an alternate mechanism. In summary, unilateral CCI in rats induces specific and lateralised adaptations in the dopaminergic circuitry of the NAcc. These distinct neural adaptations correlate with changes in social behaviour, and likely underlie some of the affective-motivational state changes associated with neuropathic pain in a subset of rats (i.e. Pain and Disability group).

Neuropathic pain conditions for which treatment is sought are characterized by complex behavioural disturbances, as well as "pain." Recent studies using chronic constriction injury of the sciatic nerve have shown that rats develop three distinct patterns of disability characterized by changes in social-interactions and sleep-wake cycle behaviours post-injury: (i) Persistent Disability, (ii) Transient Disability and (iii) No Disability. These patterns occur despite all rats showing identical levels of allodynia and hyperalgesia (i.e., pain). In rats, social-interactions and sleep-wake cycle behaviours are regulated in part, by neural networks, which converge on the periaqueductal grey (PAG). We sought therefore to identify neural adaptations in the PAG, 6 days following chronic constriction injury (CCI), the time at which rats in which disabilities persist are first distinguished from those without disabilities (i.e., No Disability and Transient Disability). GeneChips, RT-PCR and Western blotting revealed the select up-regulation in translation and transcription of glial fibrillary acidic protein (GFAP) and Vimentin in rats with Persistent Disability. Significant increases in GFAP immunoreactivity were localized histologically to the lateral and caudal ventrolateral columns of the PAG. This anatomically specific pattern of increased GFAP suggests activation of astrocytes by select neural pathways, which likely include afferents of both spinal and nucleus of the solitary tract (NTS) origin. The PAG columns in which astrocytes are activated play significant roles in modulating both social-interactions and the sleep-wake cycle. It is possible therefore that the persistent disabilities seen in a subgroup of CCI rats are in part a functional consequence of this specific pattern of astrocyte activation.