Early Maternal Separation And Pain Of Rodent Offspring:A Meta-Analysis And Animal Experiment

In their early lives, mammals show high sensitivity to changes in maternal environments. Disrupted early attachment relationships have potentially negative consequences for offspring including the development of anxiety-like behaviors,depressive-like responses, cognitive deficits, and changes of pain sensitivity. One of the most widely used methods used to assess causal effects of disrupted attachment on responses to painful stimulation has been to separate rodent pups from their dams for specific durations during pre-weaning and to compare their responses to those of non-separated controls.Although numerous animal studies have assessed the impact of maternal separation upon pain sensitivity, overall conclusions are difficult to draw about such studies in light of mixed patterns of findings. In Study 1, meta-analysis, a procedure that supports conclusions through synthesizing data from multiple studies rather than possibly idiosyncratic results of individual studies, was performed to assess effects of early maternal separation on sensitivity to nociceptive thermal stimulation in rodent offspring and to identify moderators that might explain variable results between studies. Fifteen studies comprising 19 rodent offspring samples(N = 1642) fulfilled all selection criteria.Analyses indicated that rodent offspring exposed to early maternal separation had longer response latencies(RLs) reflecting lower sensitivity to nociceptive thermal stimulation compared to non-separated controls. Heightened effect size heterogeneity was also evident.Moderator analyses indicated variable findings between studies were partially or fully explained by several methodological factors and sample characteristics.Specifically, reduced pain sensitivity in separated samples was associated with operationalizations of maternal separation on the basis of early handling(EH) of 15 minutes per separation episode instead of prolonged maternal separation(MS) of an hour or longer. Pain sensitivity was also reduced in separated samples exposed to the tail flick test rather than the hot plate test or other nociceptive tests, older rather than younger samples, those that had not received injections during separation compared to those that had, in samples comprising proportionately more male than female rodent pups and in more recent publications compared to early publications.The meta-analysis highlighted conditions under which maternal separation affects one facet of exposure to nociceptive stimulation, pain sensitivity. However, less is known about effects of MS and EH on other responses to nociception such as healing from injuries. Multiple studies have found psychological stressors can have significant negative effects on speed of wound healing both in humans and rodents. However,researchers have yet to evaluate effects of disrupted early mother-offspring attachments on wound healing of rat pups or potentially interactive effects of disrupted attachments and early injuries on responsiveness to nociceptive stimuli after pups have reached adulthood. Therefor, meta analysis can provide certain theory and knowledge for study 2. And the factors that have significant moderating effect found in the meta analysis can be used to instruct the experimental conduction in study2.In Study 2, the impact of maternal separation conditions on cutaneous wound healing was assessed in a rat sample. Furthermore, effects of both early separation and cutaneous wounding on adult rat responses to nociception were assessed. Sprague Dawley rat offspring(N=30) were subjected to different maternal conditions, including maternal separation(MS), early handling(EH) and left undisturbed(Control) from postnatal day 2(PND2) to PND20, and weaning on PND21. Skin excisions(i.e., smallpuncture wounds) were made on PND10. In addition, von Frey filaments were used to test hind-paw withdraw thresholds of 21 previously wounded pups and 16 non-wounded controls on PND 60 and 67.First, using photography and image analysis, the rate of healing was compared between wounded pups in different maternal conditions. MS rats showed a significantly slower healing rate during the healing period [eight days post-wounding] compared to EH group rats. Group differences in healing rates were most evident during the first three days after injury. Differential involvement of the hypothalamic–pituitary– adrenal(HPA) axis between separation conditions was one plausible mechanism contributing to the observed effect.Second, regarding adult rat withdrawal responses to von Frey filaments, no significant difference was found between the three maternal separation conditions.However, rats wounded in infancy showed significantly higher pain sensitivity levels based on lower withdrawal thresholds compared to non-wounded rats. The withdrawal threshold was significantly lower in the former group during the second von Frey test(PND67) while no group difference was evident for the initial test on PND60. This finding underscored how early injuries may have interfered with habituation following initial exposure to aversive stimulation.