A report from researchers at the University of Chicago, published early online in the Proceedings of the National Academy of Sciences, shows that by activating "OFF" cells and shutting down "ON" cells in the ventromedial medulla (VMM) – a small region in the brain stem – animals provide themselves with a form of "eating-induced analgesia," allowing them to complete essential tasks even in a difficult situation.
"Escaping pain and potential dangers may be important protective behaviors, but eating, drinking, and eliminating wastes are absolutely essential," said study author Peggy Mason, Ph.D., professor in the department of neurobiology, pharmacology and physiology (NPP) at the University of Chicago. "What we found was a very effective system that lets these animals focus on the essentials and postpone concerns that are slightly less pressing. It's as if they could give themselves a six-second dose of morphine, allowing hunger to override pain."
Mason and colleague Hayley Foo, research associate in NPP, studied adult male rats in containers with a wire mesh floor that enabled them to deliver radiant heat to one hind paw. The heat caused no damage but was annoying enough to make the animal withdraw that paw within seconds.
When the rats ate, however, they postponed retracting the heated paw for six to eight seconds and continued to eat.
Food choice made no difference. Rats focused just as intently on standard rat chow as when munching chocolate chips, yogurt drops or butter cookies.
Although earlier studies found that eating took precedence over pain in food-deprived animals, this is the first study to show that feeding suppressed pain in well-fed animals.
To understand the neural basis of this form of pain suppression, the researchers next inserted electrodes to monitor brain activity in feeding rats.
The suspected source of pain relief was a cluster of cells in the VMM. In 1979, Howard Fields of the University of California at San Francisco identified two groups of neurons in the brain stem that could enhance or inhibit pain. Neurons that "facilitate" pain, which he labeled "ON cells, fire in bursts when animals are awake and are inactive during slow-wave sleep. "OFF" cells, which suppress pain, are active during slow-wave sleep.
Foo and Mason, who completed her post-doctoral training in Fields' laboratory, found that the pain-enhancing ON cells were inhibited and the pain-suppressing OFF cells were excited during feeding, results that duplicated the effects of morphine. The changes occurred only during selected portions of eating, while the animal was both holding and chewing the food. A similar response took place when the animals drank water or urinated.
This response "protects critical behaviors from disruption," the authors note, "allowing an animal to nourish itself without being distracted." (Animals that don't urinate are at high-risk for infections.)
As a final test the authors used drugs to inactivate the VMM. This completely eliminated the delayed response to pain.
"This is the best evidence so far on the biological significance of OFF cell activity," said UCSF's Fields, who was not connected with the study. "It is a major step in understanding the neurobiological mechanisms of decision making in the face of conflict -- in this case the choice between whether to feed or flee. Off cells help you feed instead of flee."
Mason and Foo also found, however, that in situations that might be more dangerous, the feed-or-flee balance could be tipped the other way. Given just before feeding, a strong puff of air – perhaps indicating a nearby predator -- activated ON cells, and restored pain sensation. Such "predation-related stimuli," the authors speculate, "activate ON cells and thereby evoke a state of vigilant eating without concurrent sensory suppression."
"We have known for a long time that these cells could be manipulated by opioids, such as morphine," said Mason, "but we had no good explanation of what their natural role might be." Their prime location -- in the brain stem, the "Gold Coast of neuroanatomical property" -- suggests that they "must do something crucial." This study indicates that they "protect against distraction. They give precedence to essential behaviors."
Defects in this system could be linked to various disorders, Mason suggests, such as sudden infant death syndrome. Overactive OFF cells during sleep could mask the discomfort of oxygen deprivation.
Fields suspects that the link between eating and pain relief, in a society where the risks of caloric plenty far exceeds those of predation, may even be related to obesity. "Are OFF cells promoting bravery," he asked, "or gluttony?"
The National Institute of Mental Health and the Women's Council of the Brain Research Foundation supported this research.
Journal
Proceedings of the National Academy of Sciences