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Do Post-Surgical Opioids Actually Lead to Chronic Pain?

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Giving opioids to animals to quell pain after surgery prolongs pain for more than three weeks and primes specialized immune cells in the spinal cord to be more reactive to pain, according to a new study by the University of Colorado Boulder.

The authors say the paradoxical findings, if replicated in humans, could have far-reaching implications for patient pain management and add a new wrinkle to the conversation about the national opioid epidemic.

“This indicates that there is another dark side of opiates that many people don’t suspect,” said senior author Linda Watkins, a professor in the Department of Psychology and Neuroscience. “It shows that trauma, including surgery, in combination with opiates can lead to chronic pain.”

For the study, Watkins and co-author Peter Grace, then an assistant research professor at CU Boulder, performed exploratory abdominal surgery, or laparotomy, on male rats. A similar procedure is done tens of thousands of times annually in the United States in humans, and opiates are routinely used after surgery.

“Opiates are really effective for acute pain relief. There is no drug that works better. But very little research has been done to look at what it is doing in the weeks to months after it’s withdrawn,” said Grace, now an assistant professor at MD Anderson Cancer Center in Houston.

In one experiment, half the rats were given the equivalent of what would be a “moderate” dose of morphine in people for seven days postsurgery. Half were given a saline solution.

In another experiment, the rats were given morphine for eight days and then tapered off by day 10. In a third, the animals were given morphine until day 10 and then it was abruptly withdrawn.

Before and after the treatments, the researchers measured the animal’s sensitivity to touch as well as activity of genes that express inflammatory proteins in the spinal cord.

They found that rats given morphine experienced postoperative pain for more than three weeks longer. The longer they received morphine, the longer their pain lasted. And gradual tapering made no difference.

“This tells us that this is not a phenomenon related to opioid withdrawal, which we know can cause pain. Something else is going on here,” Grace said.

Watkins describes that something as a “one-two hit” on specialized immune system cells called glial cells in the central nervous system. The first hit, the surgery, stimulates what she calls the “not me, not right, not OK” receptor, Toll-like receptor 4 on the cells, igniting the release of a cascade of inflammatory proteins and “priming” them to be on guard for a second hit.

Morphine, which also stimulates that receptor, is the second hit.

“With that second hit, the primed glial cells respond faster, stronger and longer than before, creating a much more enduring state of inflammation and sometimes local tissue damage,” she said.

In a previous study, published in the Proceedings of the National Academy of Sciences in 2016, the researchers showed that just a few days of treatment with opiates to treat peripheral nerve pain, such as sciatica, could exacerbate and prolong pain for months in animals, in part by increasing expression of inflammatory genes.

A few small studies in humans have associated postsurgical opioid administration with chronic pain as much as one year later.

“An unusually high number of people end up with postoperative chronic pain. This new study lends insight into one explanation for that,” Watkins said.

The researchers, acknowledging that animal studies cannot directly translate to humans, are now calling for more clinical studies on opioids and chronic pain.

More than 50 million U.S. adults experience chronic pain, according to the National Institutes of Health.

Watkins is also studying novel compounds that could be given with opioids to mute the exaggerated immune response they are believed to trigger, as well as alternative painkillers, including cannabinoids, for pain.

“There is surely a dark side in terms of addiction when it comes to opioids, but this is a very different idea — that we think we are treating the pain with these drugs and we may actually be prolonging it,” she said.

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Paternal Transmission Of Epigenetic Memory Via Sperm

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Studies of human populations and animal models suggest that a father’s experiences such as diet or environmental stress can influence the health and development of his descendants. How these effects are transmitted across generations, however, remains mysterious.

Susan Strome’s lab at UC Santa Cruz has been making steady progress in unraveling the mechanisms behind this phenomenon, using a tiny roundworm called Caenorhabditis elegans to show how marks on chromosomes that affect gene expression, called “epigenetic” marks, can be transmitted from parents to offspring. Her team’s most recent paper, published October 17 in Nature Communications, focuses on transmission of epigenetic marks by C. elegans sperm.

In addition to documenting the transmission of epigenetic memory by sperm, the new study shows that the epigenetic information delivered by sperm to the embryo is both necessary and sufficient to guide proper development of germ cells in the offspring (germ cells give rise to eggs and sperm).

“We decided to look at C. elegans because it is such a good model for asking epigenetic questions using powerful genetic approaches,” said Strome, a distinguished professor of molecular, cell, and developmental biology.

Epigenetic changes do not alter the DNA sequences of genes, but instead involve chemical modifications to either the DNA itself or the histone proteins with which DNA is packaged in the chromosomes. These modifications influence gene expression, turning genes on or off in different cells and at different stages of development. The idea that epigenetic modifications can cause changes in gene expression that are transmitted from one generation to the next, known as “transgenerational epigenetic inheritance,” is now the focus of intense scientific investigation.

For many years, it was thought that sperm do not retain any histone packaging and therefore could not transmit histone-based epigenetic information to offspring. Recent studies, however, have shown that about 10 percent of histone packaging is retained in both human and mouse sperm.

“Furthermore, where the chromosomes retain histone packaging of DNA is in developmentally important regions, so those findings raised awareness of the possibility that sperm may transmit important epigenetic information to embryos,” Strome said.

When her lab looked at C. elegans sperm, they found the sperm genome fully retains histone packaging. Other researchers had found the same is true for another commonly studied organism, the zebrafish.

“Like zebrafish, worms represent an extreme form of histone retention by sperm, which makes them a great system to see if this packaging really matters,” Strome said.

Her lab focused on a particular epigenetic mark (designated H3K27me3) that has been well established as a mark of repressed gene expression in a wide range of organisms. The researchers found that removing this mark from sperm chromosomes causes the majority of the offspring to be sterile. Having established that the mark is important, they wanted to see if it is sufficient to guide normal germline development.

The researchers addressed this by analyzing a mutant worm in which the chromosomes from sperm and egg are separated in the first cell division after fertilization, so that one cell of the embryo inherits only sperm chromosomes and the other cell inherits only egg chromosomes (normally, each cell of an embryo inherits chromosomes from both egg and sperm). This unusual chromosome segregation pattern allowed the researchers to generate worms whose germ line inherited only sperm chromosomes and therefore only sperm epigenetic marks. Those worms turned out to be fertile and to have normal gene expression patterns.

“These findings show that the DNA packaging in sperm is important, because offspring that did not inherit normal sperm epigenetic marks were sterile, and it is sufficient for normal germline development,” Strome said.

While the study shows that epigenetic information transmitted by sperm is important for normal development, it does not directly address how the life experience of a father can affect the health of his descendants. Strome’s lab is investigating this question with experiments in which worms are treated with alcohol or starved before reproducing.

“The goal is to analyze how the chromatin packaging changes in the parent,” she said.

“Whatever gets passed on to the offspring has to go through the germ cells. We want to know which cells experience the environmental factors, how they transmit that information to the germ cells, what changes in the germ cells, and how that impacts the offspring.”

By demonstrating the importance of epigenetic information carried by sperm, the current study establishes that if the environment experienced by the father changes the epigenetics of sperm chromosomes, it could affect the offspring.

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Father’s Nicotine Use Can Cause Cognitive Problems In Children And Grandchildren

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A father’s exposure to nicotine may cause cognitive deficits in his children and even grandchildren, according to a study in mice publishing on October 16 in the open-access journal PLOS Biology by Pradeep Bhide of Florida State University in Tallahassee and colleagues. The effect, which was not caused by direct secondhand exposure, may be due to epigenetic changes in key genes in the father’s sperm.

Exposure of mothers to nicotine and other components of cigarette smoke is recognized as a significant risk factor for behavioral disorders, including attention deficit hyperactivity disorder, (or ADHD) in multiple generations of descendants. Whether the same applies to fathers has been less clear, in part because in human studies it has been difficult to separate genetic factors (such as a genetic predisposition to ADHD) from environmental factors, such as direct exposure to cigarette smoke.

To overcome this difficulty, Deirdre McCarthy, Pradeep Bhide and colleagues exposed male mice to low-dose nicotine in their drinking water during the stage of life in which the mice produce sperm. They then bred these mice with females that had never been exposed to nicotine. While the fathers were behaviorally normal, both sexes of offspring displayed hyperactivity, attention deficit, and cognitive inflexibility. When female (but not male) mice from this generation were bred with nicotine-naïve mates, male offspring displayed fewer, but still significant, deficits in cognitive flexibility. Analysis of spermatozoa from the original nicotine-exposed males indicated that promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning, suggesting that these modifications likely contributed to the cognitive deficits in the descendants.

Nicotine and cigarette smoke have been previously shown to cause widespread epigenetic changes, Bhide said.

“The fact that men smoke more than women makes the effects in males especially important from a public health perspective. Our findings underscore the need for more research on the effects of smoking by the father, rather than just the mother, on the health of their children.”

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Nutrition Has A Greater Impact On Bone Strength Than Exercise

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ANN ARBOR—One question that scientists and fitness experts alike would love to answer is whether exercise or nutrition has a bigger positive impact on bone strength. University of Michigan researchers looked at mineral supplementation and exercise in mice, and found surprising results–nutrition has a greater impact on bone mass and strength than exercise. Further, even after the exercise training stopped, the mice retained bone strength gains as long as they ate a mineral-supplemented diet.

“The longer-term mineral-supplemented diet leads to not only increases in bone mass and strength, but the ability to maintain those increases even after detraining,” said David Kohn, a U-M professor in the schools of dentistry and engineering.

“This was done in mice, but if you think about the progression to humans, diet is easier for someone to carry on as they get older and stop exercising, rather than the continuation of exercise itself.”

The second important finding is that the diet alone has beneficial effects on bone, even without exercising. This surprised Kohn, who expected exercise with a normal diet to fuel greater gains in bone strength, but that wasn’t the case.

“The data suggests the long-term consumption of the mineral-supplemented diet could be beneficial in preventing the loss of bone and strength with age, even if you don’t do exercise training,” he said.

Combining the two amplifies the effect.

Most other studies look at effects of increasing dietary calcium, Kohn said. The U-M study increased calcium and phosphorous, and found benefits to increasing both.

This isn’t to suggest that people run out and buy calcium and phosphorus supplements, Kohn said. The findings don’t translate directly from mice to humans, but they do give researchers a conceptual place to start.

It’s known that humans achieve peak bone mass in their early 20s, and after that it declines. The question becomes how to maximize the amount of bone when young, so that when declines do begin, people start from a better position, Kohn said.

In addition to testing bone mass and strength, Kohn and colleagues performed a full battery of mechanical assessments on the bone, which is important because the amount of bone doesn’t always scale with or predict the mechanical quality of the tissue.

They tested the mice after eight weeks of training and supplemented diet or normal diet, and then after eight weeks of detraining.

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