Scientists at Georgia State University have uncovered the mechanisms of how pain in infancy alters how the brain processes pain in adulthood.

Research is now indicating that infants who spent time in the neonatal intensive care unit (NICU) show altered pain sensitivity in adolescence. These results have profound implications and highlight the need for pre-emptive and post-operative pain medicine for newborn infants.

The study, published online in the journal Frontiers in Behavioral Neuroscience, sheds light on how the mechanisms of pain are altered after infant injury in a region of the brain called the periaqueductal gray, which is involved in the perception of pain.

Using Sprague-Dawley rats, Jamie LaPrairie, a graduate student in associate professor Anne Murphy's laboratory, examined why the brief experience of pain at the time of birth permanently decreased pain sensitivity in adulthood.

Endogenous opioid peptides, such as beta-endorphin and enkephalin, function to inhibit pain. They're also the 'feel good' substances that are released following high levels of exercise or love. Since these peptides are released following injury and act like morphine to dampen the experience of pain, LaPrairie and Murphy tested to see if the rats, who were injured at birth, had unusually high levels of endogenous opioids in adulthood.

To test this hypothesis, LaPrairie and Murphy gave adult animals that were injured at the time of birth a drug called naloxone. This drug blocks the actions of endogenous opioids. After animals received an injection of naloxone, they behaved just like an uninjured animal.

The scientists then focused on the periaqueductal gray region to see if inflammation at birth altered the natural opioid protein expression in this brain region. Using a variety of anatomical techniques, the investigators showed that animals that were injured at birth had endogenous opioid levels that were two times higher than normal.

While it's beneficial to decrease pain sensitivity in some cases, it's not good to be completely resilient to pain.

"Pain is a warning sign that something is wrong," Murphy explained. "For example, if your hand is in water that's too hot, pain warns you to remove it before tissue damage occurs."

Interestingly, while there is an increase in endorphin and enkephalin proteins in adults, there is also a big decrease in the availability of mu and delta opioid receptors. These receptors are necessary in order for pain medications, such as morphine, to work. This means that it takes more pain-relieving medications in order to provide relief as there are fewer available receptors in the brain. Studies in humans are reporting the same phenomenon.

The number of invasive procedures an infant experienced in the NICU is negatively correlated with how responsive the child is to morphine later in life; the more painful procedures an infant experienced, the less effective morphine is in alleviating pain.

The study by LaPrairie and Murphy has major implications for the treatment of infants in neonatal intensive care. On average, a prematurely born infant in a neonatal intensive care unit will experience 14 to 21 invasive procedures a day, including heel lance, insertion of intravenous lines, and intubation. All of these procedures are quite painful and are routinely conducted without prior analgesics or anesthetics.

"It's imperative that pain be treated," Murphy said. "We once assumed that a newborn infant is insensitive to pain, and this is clearly not the case. Even at that period of time, the central nervous system is able to respond to pain, and our studies show that the experience of pain completely changes the wiring of the brain in adulthood."

The next steps in Murphy's research include the study of how neonatal injury at birth alters stress responses, as well as the affects of infant injury on long-term learning and memory.

LaPrairie's and Murphy's work was supported by the National Institutes of Health, the Center for Behavioral neuroscience, a consortium of seven universities at Georgia State, and the Georgia State Brains and Behavior Program.

The article, titled "Neonatal injury alters adult pain sensitivity by increasing opioid tone in the periaqueductal gray," appears in the September 2009 edition of journal Frontiers in Behavioral Neuroscience, Vol. 3, p. 1-11.

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