Newborns who experience tissue injury and pain during critical periods of development may undergo a permanent rewiring of their nervous system that increases their sensitivity to pain later in life.
Working with an animal model, scientists at the National Institute of Dental and Craniofacial Research (NIDCR) have provided the first physical evidence that pain and inflammation in newborns alters the development of pain pathway circuitry, causing a stronger response to pain in adulthood. The study, which appears in the July 28 issue of Science, calls attention to the need to assess the long-term effects of pain and tissue injury on human newborns.
"Although we have yet to directly link animal research findings to what happens in human infants, one is tempted to speculate that similar changes as those identified in the animals may occur in newborn humans exposed to pain and inflammation," said Dr. M. A. Ruda, principal investigator on the study and chief of NIDCR's Cellular Neuroscience Section.
Each year, more than 400,000 babies in the U.S. are born either prematurely or at a low birth weight. Of these, 25,000 are considered to be extremely premature--born at 27 weeks of gestation or less. While 10 or 15 years ago most of these micropreemies did not live, it is no longer unusual for them to survive, thanks to advances in medical technology. Yet these tiny babies face a host of problems. Not only are they confronted with the trauma of living in the outside world too soon, but available medical procedures used to keep them alive and monitor their progress may cause pain and tissue injury. Heel sticks to draw blood, the insertion of IV lines and nasogastric tubes, and the use of ventilators are some of the modern technologies and procedures that are both miraculous and difficult.
"A premature infant can be thought of as still in the fetal time of their life when the basic elements of brain development are occurring," explained Dr. Ruda. "Abnormal stimulation during these critical developmental time points may abnormally wire the brain."
There has been considerable debate over the existence of pain in newborns and its management. As late as the mid-1980's, surgery was performed on infants without benefit of anesthesia, the belief being that even if babies did experience pain, they would forget about it. Since then, studies of the biological response to pain and the facial expressions of newborns during traumatic procedures document that they do indeed respond to pain. Today, pain from traumatic surgeries in newborns is carefully managed with anesthesia and analgesics.
Scientists have learned that by 24 weeks gestation, very immature pain transmission pathways are already in place. The development of these pathways continues postnatally. What newborns lack are fully developed and functional pain inhibitory systems. These typically develop several weeks after a full-term baby is born.
"Unlike other sensory modalities such as vision and hearing that require the input of sight and sound for their appropriate development, pain pathways normally develop in the absence of, or with little exposure to, painful stimulation. However, medical procedures shortly after birth can expose the nervous system to pain, the developmental effects of which we are just learning," said Dr. Ruda.
In their study, Dr. Ruda and her colleagues used newborn rat pups to explore the effect of tissue injury and pain on the development of pain pathways. An irritant was injected into the left hind paw of the pups to induce swelling. One group received the injection when they were 1 day old, an age equivalent to 24 weeks gestation in humans. A second group received the injection 14 days after birth, equivalent to adolescence in humans. Swelling and redness occurred shortly after the injection and persisted for 5-7 days in both groups.
When the animals were examined as adults, it was found that rats who received the left hind paw injection on day 1 had an increase in the density of nerve fibers on the left side of the dorsal horn, the layered structure in the spinal cord that propels pain signals up to the brain. Even at the level of individual nerve cells, the response to pain was increased. Spinal cord segments also exhibited an increase in pain input on the left neonatal treated side, including areas that normally would not be expected to display this. The picture was very different for the rats that received the injection on postnatal day 14. The patterns of nerve fibers in this group looked like those of normal rats. The researchers surmise that the critical time point responsible for a change in input had passed by day 14, so that neuronal circuits were not altered by the tissue injury and pain.
Adult rats that experienced left hind paw tissue injury and swelling on day 1 also reacted more strongly to pain as adults. When an irritant was injected into their left hind paw and the paw was exposed to heat, they were much quicker to withdraw it than normal rats. The changes that occurred because of tissue injury and pain are likely not limited to the spinal cord but could also involve higher centers of the brain that are part of pain pathways, suggest the researchers.
"Our study adds pain to the emerging list of early birth stimuli that we are discovering have a lifelong impact and suggests that further study is warranted to develop approaches to limit or prevent those effects," added Dr. Ruda.
Collaborating with Dr. Ruda on the study were Drs. Qing-Dong Ling, Andrea G. Hohmann, Yuan Bo Peng, and Toshiya Tachibana from the Cellular Neuroscience Section, Pain and Neurosensory Mechanisms Branch, NIDCR. The National Institute of Dental and Craniofacial Research is one of the federal National Institutes of Health, located in Bethesda, MD.
Journal
Science