A wealth of research over the past 2 decades has expanded our understanding of the impact of early-life adversity on physiological function and, consequently, health and wellbeing in later life. Early-life adversity increases the risk of developing a number of disorders, such as chronic pain, fibromyalgia, and irritable bowel syndrome. Although much of the research has examined the impact of physical maltreatment, an increasing number of studies have been published over the past few years examining the effect of childhood psychological stress and trauma on the development of various types of chronic pain conditions. We review the clinical and preclinical data examining the link among early-life psychological stress, altered nociceptive behavior, and chronic pain in later life. Evidence supporting a role for certain key neurobiological substrates, including the hypothalamic-pituitary-adrenal axis; monoaminergic, opioidergic, endocannabinoid and immune systems; and epigenetic mechanisms in the association between early-life psychological stress and chronic pain, is provided. Greater understanding of the impact of early-life stress may inform the development of personalized treatments for chronic pain in later life and strategies to prevent its onset in susceptible individuals. © 2016 Wiley Periodicals, Inc.

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The association between chronic pain and depression is widely recognized, the comorbidity of which leads to a heavier disease burden, increased disability and poor treatment response. This study examined nociceptive responding to mechanical and thermal stimuli prior to and following L5-L6 spinal nerve ligation (SNL), a model of neuropathic pain, in the olfactory bulbectomized (OB) rat model of depression. Associated changes in the expression of genes encoding for markers of glial activation and cytokines were subsequently examined in the amygdala, a key brain region for the modulation of emotion and pain. The OB rats exhibited mechanical and cold allodynia, but not heat hyperalgesia, when compared with sham-operated counterparts. Spinal nerve ligation induced characteristic mechanical and cold allodynia in the ipsilateral hindpaw of both sham and OB rats. The OB rats exhibited a reduced latency and number of responses to an innocuous cold stimulus following SNL, an effect positively correlated with interleukin (IL)-6 and IL-10 mRNA expression in the amygdala, respectively. Spinal nerve ligation reduced IL-6 and increased IL-10 expression in the amygdala of sham rats. The expression of CD11b (cluster of differentiation molecule 11b) and GFAP (glial fibrillary acidic protein), indicative of microglial and astrocyte activation, and IL-1β in the amygdala was enhanced in OB animals when compared with sham counterparts, an effect not observed following SNL. This study shows that neuropathic pain-related responding to an innocuous cold stimulus is altered in an animal model of depression, effects accompanied by changes in the expression of neuroinflammatory genes in the amygdala.

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.

(2010). Enhanced nociceptive responding in two rat models of depression is associated with alterations in monoamine levels in discrete brain regions. Neuroscience, 171: 1300-1313. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Abbreviations: 5-HT serotonin; 5-HIAA 5-hydroxyindoleacetic acid; NA Noradrenaline; OB Olfactory Bulbectomy; PFC prefrontal cortex; SD Sprague Dawley; WKY Wistar-Kyoto rat 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 AbstractAltered pain responding in depression is a widely recognized but poorly understood phenomenon. The present study investigated nociceptive responding to acute (thermal and mechanical) and persistent (inflammatory) noxious stimuli in two animal models of depression, the olfactory bulbectomised (OB) and the Wistar-Kyoto (WKY) rat. In addition, this study examined if altered nociceptive behaviour was associated with changes in monoamine levels in discrete brain regions. OB rats exhibited mechanical allodynia (von Frey test) but not thermal hyperalgesia (hot plate and tail-flick tests) when compared to shamoperated counterparts. Formalin-induced nociceptive behaviour was both heightened and prolonged in OB versus sham-operated controls. An inverse correlation was observed between 5-hydroxyindoleacetic acid (5-HIAA) concentration in the hippocampus and amygdaloid cortex and nociceptive behaviour in the formalin test. In comparison, WKY rats exhibited thermal hyperalgesia in the hot plate test, while behaviour in the tail-flick and vonFrey tests did not differ between WKY and Sprague-Dawley rats. Furthermore, WKY rats exhibited enhanced formalin-evoked nociceptive responding up to 40 minutes post administration, an effect inversely correlated with serotonin and 5-HIAA levels in the hypothalamus. In conclusion, these findings demonstrate that altered pain responding observed in clinically depressed patients can be modelled pre-clinically, providing a means of investigating the neurochemical basis of, and possible treatments for, this phenomenon.Keyword: olfactory bulbectomy, Wistar-Kayto rat, hot plate, formalin test, mechanical allodynia, serotonin 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4 The clinical connection between pain and depression has long been recognised.Epidemiological studies indicate that up to 66% of major depressed patients report co-morbid chronic pain (Bair et al., 2003;Bair et al., 2004;Arnow et al., 2006) and chronic pain patients are up ...

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Depression is a debilitating psychiatric disorder that is highly comorbid with anxiety. Depression is twice as prevalent in women as in men, however, females remain underrepresented in preclinical research. The stress hyperresponsive Wistar-Kyoto (WKY) rat displays hypolocomotion in a novel aversive environment and depressive- and anxiety-like behaviours, which have been mostly characterised in males. The current study characterised behaviour in male and female rats in a battery of behavioural paradigms. Adult male and female WKY rats were tested in the open field and forced swim tests (tests with a locomotor component); and the marble burying, novelty-induced hypophagia and sucrose preference tests (tests with a minimal locomotor component) and 24h home-cage locomotor activity was also monitored. The tests were compared against the Sprague-Dawley (SD) strain, a commonly used "control" strain. SD, but not WKY, females exhibited higher home-cage locomotor activity compared to males. In the open field, WKY rats of both sexes exhibited a significant reduction in locomotor activity and increased anxiety-like behaviour as demonstrated by reduced time in the aversive inner zone of the open field, compared to SD counterparts. In the marble burying test, WKY females, but not males, exhibited a trend towards increased burying, indicative of anxiety-like/neophobic behaviour. In comparison, WKY males, but not females, exhibited enhanced novelty-induced hypophagia, indicative of increased anxiety-like behaviour compared to SD rats. In the forced swim test, WKY rats of both sexes spent more time immobile compared with SD counterparts, indicating depressive-like behaviour. However, in comparison to SD rats, WKY males, but not females, exhibited anhedonic-like behaviour. In conclusion, WKY rats exhibit depressive- and anxiety-like behaviours that are complex and nuanced depending on the sex of the rat and testing conditions. This study supports the use of a varied test battery to fully characterise depression/anxiety-like behaviour in male and female rats.