The mammalian fetus develops in a largely sterile environment, and direct exposure to a complex microbiota does not occur until birth. We took advantage of this to examine the effect of the microbiota on brain development during the first few days of life. The expression of anti- and pro-inflammatory cytokines, developmental cell death, and microglial colonization in the brain were compared between newborn conventionally colonized mice and mice born in sterile, germ-free (GF) conditions. Expression of the pro-inflammatory cytokines interleukin 1β and tumor necrosis factor α was markedly suppressed in GF newborns. GF mice also had altered cell death, with some regions exhibiting higher rates (paraventricular nucleus of the hypothalamus and the CA1 oriens layer of the hippocampus) and other regions exhibiting no change or lower rates (arcuate nucleus of the hypothalamus) of cell death. Microglial labeling was elevated in GF mice, due to an increase in both microglial cell size and number. The changes in cytokine expression, cell death and microglial labeling were evident on the day of birth, but were absent on embryonic day 18.5, approximately one-half day prior to expected delivery. Taken together, our results suggest that direct exposure to the microbiota at birth influences key neurodevelopmental events and does so within hours. These findings may help to explain some of the behavioral and neurochemical alterations previously seen in adult GF mice.

Chronic pain is a debilitating condition that impacts tens of millions each year, resulting in lost wages for workers and exacting considerable costs in health care and rehabilitation. A thorough understanding of the neural mechanisms underlying pain and analgesia is critical to facilitate the development of therapeutic strategies and personalized medicine. Clinical and epidemiological studies report that women experience greater levels of pain than men and have higher rates of pain-related disorders. Studies in both rodents and humans report sex differences in the anatomical and physiologic properties of the descending antinociceptive circuit, mu opioid receptor (MOR) expression and binding, morphine metabolism, and immune system activation, all of which likely contribute to the observed sex differences in pain and opioid analgesia. Although more research is needed to elucidate the underlying mechanisms, these sex differences present potential therapeutic targets to optimize pain management strategies for both sexes.

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The present study investigated the impact of advanced age on morphine modulation of persistent inflammatory pain in male and female rats. The impact of age, sex, and pain on μ-opioid receptor (MOR) expression and binding in the ventrolateral PAG (vlPAG) was also examined using immunohistochemistry and receptor autoradiography. Intraplantar administration of Complete Freund’s adjuvant induced comparable levels of edema and hyperalgesia in adult (2-3mos) and aged (16-18mos) male and female rats. Morphine potency was highest in adult males, with a two-fold decrease in morphine EC50 observed in aged versus adult males (10.22mg/kg versus 5.19mg/kg). Adult and aged female rats also exhibited significantly higher EC50 values (10.69 mg/kg and 9.00 mg/kg, respectively) compared to adult males. The upward shift in EC50 from adult to aged males was paralleled by a reduction in vlPAG MOR expression and binding. The observed age-related reductions in morphine potency and vlPAG MOR expression and binding have significant implications in pain management in the aged population.

Declarations of interest: JMS has an equity stake in Botanical Results, LLC and is co-founder and equity holder in Teleport Pharmaceuticals, LLC. No company products or interests were tested in this study.