Neuroscience
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Maternal deprivation (MD) in rhesus monkeys has been demonstrated to be an effective model to mimic early adversity in humans because of the close phylogenetic similarity affinity. Although behavioral and hormonal abnormalities have been observed in MD monkeys, the neurobiological underpinning of the long-term deleterious effect of MD on monkeys is still unclear. In this study, we assessed emotional changes and socio-behavioral abnormalities induced by long-term MD and assessed structural alterations of gray matter volume (GMV) and white matter integrity (WMI) in 15 MD rhesus monkeys and in 15 age-, gender-matched normal controls (NC) using voxel-based morphology and voxel-based analysis methods. ⋯ Moreover, the mean FA values in pSTS showed positive correlation with the stereotypical behavioral durations in MD monkeys and negative correlation with social grooming durations in NC monkeys. Our findings indicated that the deleterious effects of MD on rhesus monkeys resulted in structural abnormalities in the visual cortex and premature myelination in the pSTS. These findings provide new insights into understanding the impact of maternal deprivation on the neurological basis of brain development.
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Many persistent pain conditions occur predominantly in women making pain a major women's health issue. One theory for the prevalence in females is hormone modulation of pain mechanisms. The peripheral release of the neurotransmitter serotonin (5HT) has been implicated in various sexually dimorphic pain conditions; yet no studies have examined the effect of ovarian hormones on peripheral 5HT-evoked pain behaviors. ⋯ There were no significant sex differences or estrous cycle effects on 5HT-evoked edema or 5HT content in inflamed hindpaws. Local pretreatment with the 5HT2A receptor antagonist blocked 5HT-evoked thermal hyperalgesia and edema. These data provide evidence of a modulatory role of hormones on peripheral 5HT-evoked pain occurring via the 5HT2A receptor.
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Endothelin-1 (ET-1) and its receptors (ETAR/ETBR) emerge to be a key signaling axis in neuropathic pain processing and are recognized as new therapeutic targets. Yet, little is known on the functional regulation of ET-1 axis during neuropathic pain. Bioinformatics analysis indicated that paired box gene 2 (Pax2) or nuclear factor of activated T-cells 5 (NFAT5), two transcription factors involved in the modulation of neurotransmission, may regulate ET-1. ⋯ At molecular level, Pax2 siRNA, but not NFAT5 siRNA, downregulated ET-1 and ETAR, while ETAR inhibitor reduced NFAT5, indicating Pax2 in the upstream of ET-1 axis with NFAT5 in the downstream. Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling. These findings demonstrate that Pax2 targeting ET-1-ETAR-NFAT5 is a novel regulatory mechanism underlying neuropathic pain.
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Besides physical insult, spinal cord injury (SCI) can also result from transient ischemia, such as ischemia-reperfusion SCI (I/R SCI) as a postoperative complication. Increasing evidence has suggested that oxidative stress and related reactive aldehyde species are key contributors to cellular injury after SCI. Previous work in spinal cord contusion injury has demonstrated that acrolein, both a key product and an instigator of oxidative stress, contributes to post-traumatic hyperalgesia. ⋯ Taken together, these results support the causal role of acrolein in inducing hyperalgesia after I/R SCI via activation and upregulation of TRPA1 channels. Furthermore, endogenously produced acrolein resulting from metabolic abnormality in the absence of mechanical insults appears to be capable of heightening pain sensitivity after SCI. Our data also further supports the notion of acrolein scavenging as an effective analgesic as well neuroprotective strategy in conditions where oxidative stress and aldehyde toxicity is implicated.
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In the visual cortex, sensory deprivation causes global augmentation of the amplitude of AMPA receptor-mediated miniature EPSCs in layer 2/3 pyramidal cells and enhancement of NMDA receptor-dependent long-term potentiation (LTP) in cells activated in layer 4, effects that are both rapidly reversed by light exposure. Layer 2/3 pyramidal cells receive both feedforward input from layer 4 and intra-cortical lateral input from the same layer, LTP is mainly induced by the former input. ⋯ However, inhibition of NMDA receptors by CPP or mGluR5 by MPEP, prevented the effect of light exposure on the mice reared in the dark from birth, while only inhibition of NMDAR prevented the effect of light exposure on dark-exposed mice. These results suggested that the activation of both NMDAR and mGluR5 are essential in the light exposure reversal of feedforward excitatory synaptic strength in the dark reared mice from birth; while in the dark exposed mice, only activation of NMDAR is required.