Stress and IL-1β contribute to the development of depressive-like behavior following peripheral nerve injury

Abstract

The physiological link between neuropathic pain and depression remains unknown despite a high comorbidity between these two disorders. A mouse model of spared nerve injury (SNI) was used to test the hypothesis that nerve injury precipitates depression through the induction of inflammation in the brain, and that prior exposure to stress exacerbates the behavioral and neuroinflammatory consequences of nerve injury. As compared with sham surgery, SNI induced mechanical allodynia, and significantly increased depressive-like behavior. Moreover, SNI animals displayed increased interleukin-1β (IL-1β) gene expression within the frontal cortex and concurrent increases in the expression of glial fibrillary acidic protein (GFAP) within the periaqueductal grey (PAG). Additionally, exposure to chronic restraint stress for 2 weeks before SNI exacerbated mechanical allodynia and depressive-like behavior, and resulted in an increase in IL-1β gene expression in the frontal cortex and brain-derived neurotrophic factor (BDNF) gene expression in PAG. Treatment with metyrapone (MET), a corticosteroid synthesis inhibitor, before stress eliminated deleterious effects of chronic stress on SNI. Finally, this study showed that interference with IL-1β signaling, through administration of IL-1 receptor antagonist (IL-1ra), ameliorated the effects of neuropathic pain on depressive-like behavior. Taken together, these data suggest that peripheral nerve injury leads to increased cytokine expression in the brain, which in turn, contributes to the development of depressive-like behavior. Furthermore, stress can facilitate the development of depressive-like behavior after nerve injury by promoting IL-1β expression.

Maternal Deprivation Is Associated With Sex-Dependent Alterations in Nociceptive Behavior and Neuroinflammatory Mediators in the Rat Following Peripheral Nerve Injury

“…Although the neurobiological mechanisms underlying the effects of MD on nociceptive responding in adulthood remain unknown, it has been shown that MD induces a range of sex-dependent developmental and psychoneuroimmunendocrine alterations 54 . It has been proposed that Alterations in affective responding such as anxiety-and depressive-like behaviours have been shown to be induced in a number of models of peripheral nerve injury 45,47,51,57 , although in the present study SNL failed to modulate affective behaviour. The short period following surgery over which these behaviours were examined (Day16), may account for the lack of effects as previous studies have indicated that alterations in affective behaviour only manifest after at least a month post-surgery 45,51,57 .…”

“…Moreover, MD females also exhibited enhanced mechanical (ipsilateral) and cold (bilateral) allodynia 14 days following SNL compared with control females. Mechanical allodynia following peripheral-nerve injury has been shown to be enhanced following chronic restraint stress and in a genetic model of depression (Wistar-Kyoto rat) 47,58 , however, to our knowledge, this is the first study to examine the effect of early-life stress on neuropathic pain behaviour in rodents. Although the neurobiological mechanisms underlying the effects of MD on nociceptive responding in adulthood remain unknown, it has been shown that MD induces a range of sex-dependent developmental and psychoneuroimmunendocrine alterations 54 .…”

“…Specifically, chronic constriction injury is associated with increased hippocampal TNFα levels 23 while spared nerve injury is associated with increased IL-1β expression in the frontal cortex and GFAP expression in the periaquaductal grey 2,11,47 . Chronic stress prior to peripheral nerve injury has been shown to exacerbate mechanical allodynia, depressive behaviour and augment injury-induced IL-1β expression in the frontal cortex 47 , thus indicating a possible functional interaction between stress, neuroinflammation and pain. Thus, we hypothesised that early life stress-induced changes in affective and nociceptive behaviour may be accompanied by alterations in supraspinal neuroinflammatory processing.…”

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…In a further study, chronic restraint stress-induced hyperalgesia was associated with reduced expression of the glial fibrillary acidic protein (GFAP), an astrocyte biomarker, and the excitatory amino acid transporter 2 (EAAT-2) in the PAG (Imbe et al, 2012)). Furthermore, hyperalgesia observed in a mouse model of spared nerve injury following exposure to restraint stress, was associated with increased the mRNA expression of GFAP, BDNF and interleukin (IL)-1 in the PAG (Norman et al, 2010).…”

Minocycline modulates neuropathic pain behaviour and cortical M1–M2 microglial gene expression in a rat model of depression

“…Pre-clinical studies have demonstrated peripheral nerve injury-induced neuroimmune activation in brain regions responsible for the modulation of nociception and/or affect, including the prefrontal cortex (Apkarian et al, 2006, Al-Amin et al, 2011. Furthermore, the expression of genes coding for the pro-inflammatory cytokines IL-1β, IL-6 and/or TNFα, is enhanced in brain regions responsible for processing emotion and pain in animal models of depression with concomitant inflammatory (Kim et al, 2012, Arora et al, 2011 and neuropathic (Norman et al, 2010, Apkarian et al, 2006, Burke et al, 2013a, Burke et al, 2013b pain-related responding. Thus, modulating neuroimmune responses has been proposed as a novel target for the treatment of CNS disorders with an inflammatory component, including depression and associated chronic pain.…”