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

Abstract

Maternal deprivation is associated with sex dependant alterations in nociceptive behaviour and neuroinflammatory mediators in the rat following peripheral nerve injury. AbstractEarly-life stress is associated with an increased risk of developing affective disorders and chronic pain conditions. This study examined the effect of maternal deprivation (MD) on nociceptive responding prior to and following peripheral nerve injury (L5-L6 spinal nerve ligation (SNL)). As neuroimmune signalling plays an important role in pain and affective disorders, associated alterations in glial and cytokine expression were assessed in key brain regions associated with emotional and nociceptive responding, the hippocampus and prefrontal cortex (PFC). MD female, but not male, rats exhibited thermal hypoalgesia and mechanical allodynia when compared to control (non-MD) counterparts. SNL resulted in mechanical and cold allodynia in MD and control rats of both sexes. However, MD females exhibited enhanced SNL-induced allodynic responding when compared to non-MD counterparts. IL-6 expression was reduced in the PFC of MD-SNL males when compared with non-SNL counterparts. GFAP and IL-1β expression in the hippocampus of MD-SNL males was increased compared with non-MD controls. MD-SNL females exhibited reduced TNFα in the PFC with a concomitant increase in IL-6 and TNFα expression in the hippocampus, compared with either MD or SNL alone. In conclusion, MD female, but not male, rats exhibit enhanced nociceptive responding following peripheral nerve injury, effects which may relate to the distinct neuroinflammatory profile observed in female versus male rats.Perspective: This study demonstrates that females rats exposed to early-life stress exhibit enhanced neuropathic pain responding, effects associated with alterations in neuroinflammatory mediators. Increased understanding of the interactions between early-life stress, gender and pain may lead to the identification o novel therapeutic targets for the treatment of chronic pain disorders.

Neuroinflammatory Mechanisms Linking Pain and Depression

“…We have recently shown that following peripheral nerve injury (SNL), females, but not males, exposed to early life stress exhibited exacerbated nerve-injury induced mechanical and cold allodynia compared with non-stressed counterparts [62]. This behavioural change was accompanied by reduced TNFα in the PFC with a concomitant increase in IL-6 and TNFα expression in the hippocampus, compared with either MD or SNL alone.…”

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

“…TaqMan gene expression assays (Applied Biosystems, UK) were used to quantify the genes of interest: cluster of differentiation molecule 11b (CD11b; Rn00709342_m1), CD68 (Rn01495634_g1), MRC2 (mannose receptor, Rn01456616_m1), Interleukin-1β (IL-1β; Rn00580432_m1), tumour necrosis factor-α (TNFα, Rn99999017_m1), IL-6 (Rn00561420_m1), IL-10 (Rn00563409_m1), SOCS3 (Rn00585674_s1) and IL-1 receptor antagonist (IL-1ra, Rn00573488_m1). RT-PCR was performed using an ABI Prism 7500 instrument (Applied Biosystems, UK), as previously described (Burke et al, 2013a, Kerr et al, 2013, Kerr et al, 2012, Burke et al, 2013b. β-actin (Rn00667869_m1) was used as an endogenous control and to normalise gene expression data.…”

“…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.…”

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

“…Unpredictable Chronic stress for 6 weeks; Thermal hypoalgesia, mechanical allodynia in females (Burke et al, 2013) SpragueDawley rats…”