Stress in the Adult Rat Exacerbates Muscle Pain Induced by Early-Life Stress

Abstract

Background Early-life stress and exposure to stressful stimuli play a major role in the development of chronic widespread pain in adults. However, how they interact in chronic pain syndromes remains unclear. Methods Dams and neonatal litters were submitted to a restriction of nesting material (neonatal limited bedding, NLB) for one week. As adults, these rats were exposed to a painless sound stress protocol. The involvement of sympathoadrenal catecholamines, interleukin 6 (IL-6) and tumor necrosis alpha (TNFα) in nociception, was evaluated through of behavioral and ELISA assays, surgical interventions and intrathecal antisense treatments. Results Adult NLB rats exhibited mild muscle hyperalgesia, which was markedly aggravated by sound stress (peaking 15 days after exposure). Adrenal medullectomy did not modify hyperalgesia in NLB rats but prevented its aggravation by sound stress. Sustained administration of epinephrine to NLB rats mimicked sound stress effect. Intrathecal treatment with antisense directed to IL-6-receptor subunit gp130, but not to TNFα type 1 receptor (TNFR1), inhibited hyperalgesia in NLB rats. However, antisense against either gp130 or TNFR1 inhibited sound stress-induced enhancement of hyperalgesia. Compared to control rats, NLB rats exhibit increased plasma levels of IL-6 but decreased levels of TNFα, whereas sound stress increases IL-6 plasma levels in control but not in NLB rats. Conclusions Early-life stress induces a persistent elevation of IL-6, hyperalgesia and susceptibility to chronic muscle pain, which is unveiled by exposure to stress in adults. This probably depends on an interaction between adrenal catecholamines and pro-inflammatory cytokines acting at muscle nociceptor level.

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

“…The contribution of the sympathoadrenal system to bradykinin-induced hyperalgesia was demonstrated by the absence of cutaneous and muscle hyperalgesia in unpredictable sound-stressed rats subjected to adrenal medullectomy (Khasar et al, 2009). Neonatal limited bedding (nesting material) for 1 week induced mild muscle hyperalgesia, which was inhibited following intrathecal treatment with antisense oligonucleotide (Alvarez et al, 2013). These studies suggest that hyperalgesia associated with negative affect is influenced by the sympathetic adrenomedullary and peripheral nervous systems.…”

“…Digital force transducer Mechanical hyperalgesia (Alvarez et al, 2013;Green et al, 2011a) Noise Stress Male SpragueDawley rats 105 dB tone of mixed frequencies, ranging from 11 to 19 kHz over 30 minutes over 3 to 4 days Paw-withdrawal threshold Enhanced inflammatory pain (Khasar et al, 2009(Khasar et al, , 2005 …”

Laboratory environmental factors and pain behavior: the relevance of unknown unknowns to reproducibility and translation

“…Postnatal stressors during development can have long-lasting effects as well. Failure to provide bedding material for a rat to make a nest for her pups can lead to hyperalgesia in those pups when they become adults 55,56 , and the handling of young animals (for example, related to injections, and involving the stress of maternal separation) can cause long-term alterations in pain sensitivity 41,[57][58][59][60][61][62][63] . A growing literature also documents the effect of diet on pain sensitivity [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] .…”

Anatomical and Physiological Factors Contributing to Chronic Muscle Pain

“…Common methods for inducing stress are exposure to water (Green et al 2011), unexpected blasts of noise (Strausbaugh et al 2003; Khasar et al 2005; Khasar et al 2009), and cooling of ambient temperature (Nasu et al 2010). These approaches produce long lasting mechanical hypersensitivity in the muscle and exaggerated responses to subsequent mild muscle insults (Alvarez et al 2013). …”

“…Sustained exposure to epinephrine, either from stress or exogenous sources, switches intracellular signaling via EP receptors from Gs to Gi/o, resulting in activation of PCKε (Khasar et al 2008). Prolonged exposure to epinephrine also triggers elevated expression of IL-6 and TNFR1 (Alvarez et al 2013). …”