The pain is good. It is the body’s way of preventing the animal from harming itself or repeating a dangerous mistake. But sometimes the debilitating feeling can get in the way. So evolution has devised ways to dampen that response under certain conditions.
Researchers at the University of California, Santa Barbara, have identified a pathway in fruit flies that reduces the sensation of pain caused by heat. Remarkably, only one neuron on each side of the animal’s brain controls the response. Moreover, the molecule responsible for suppressing this sensation in adult flies has the opposite role in fly larvae. Surprising results appear in Current Biology.
The fruit fly’s brain has about a million times fewer neurons than ours. “However, we did not expect that a single pair of neurons would have such an important role in pain suppression,” said senior author Craig Montell, Duggan Professor and Professor of Molecular, Cellular and Developmental Biology.
“We call them epiiones, or epi-neurons, for the Greek goddess of soothing pain,” said first author Jiangkou Liu, a postdoctoral fellow in Montel’s lab.
The writers are quick to make a point. “Pain is an explanation,” Montiel said. “A hard pat on the back of a teammate after a win may sound cool, but not from a bully in the field. Since we can’t ask fruit flies what they interpret for high temperatures, a more accurate term is ‘feeling the beat,’ which refers to how they sense body to a potentially harmful stimulus, then relays the information to induce an avoidance response.”
It is known that humans are able to suppress pain in some situations. However, scientists don’t know much about the suppression of pain in flies, which is a workhorse for sensory research. Montell and his lab wanted to determine whether flies have such a system, and if so, locate the neurons involved and understand the mechanism.
The researchers focused on the feeling of pain in response to heat. They first needed a way to measure how animals respond to high temperatures. They placed the flies on a hot plate and measured the number that jumped within 10 seconds. Almost all of the flies jumped between 38° and 44°C (about 100° to 111°F). The team is now setting out to see if they can identify neurons that suppress their aversion to high temperatures, and reduce their jump response.
The authors wondered whether neurons involved in thermal nociception might express a specific neuropeptide. Neuropeptides are somewhat similar to neurotransmitters, except that neurotransmitters mediate between neighboring neurons, whereas neuropeptides can have a more systemic effect. As a result, they influence many behaviours. Different groups of neurons tend to express different neuropeptides. Liu, Montiel and their co-authors used DNA segments that control the expression of 35 different neuropeptide genes to drive the expression of a protein that activates neurons.
Of the 35 different groups of neurons, one clearly reduced the flies’ tendency to jump off the hot plate. These neurons produce the neuropeptide AstC, which is associated with a mammalian compound that contributes to the suppression of pain in humans.
The researchers then expressed the gene coding for a light-sensitive channel in this group of neurons. This enabled them to activate neurons using light. As expected, stimulating these neurons reduced the flies’ tendency to jump off the hot plate.
The authors then used the DNA section controlling the expression of AstC to control the GFP gene instead. Now they can finally see which neurons are firing. That’s when they discovered that turning on just one neuron on each side of the brain (Epi neurons) dampens the nociceptive response.
Find the trigger
Once the team found the neurons responsible for suppressing heat pain, they were curious to see if the Epi neurons were sensitive to heat, or if they were receiving a signal from some other neuron.
The researchers showed a gene coding for a protein that fluoresces when calcium ions flood into Epi neurons. They found that calcium levels increased with the temperature, even when they used a chemical to block communication between nerve cells. These results indicated that Epi neurons were directly sensing the elevated temperature.
The researchers determined that a specific ion channel in the cell membrane of Epi neurons was responsible for heat detection. This channel, called “painless”, is a member of the TRP family of channels. TRP channels have broad roles in sensation, including temperature sensation. In fact, painlessness is also required for thermal pain in fly larvae. “So ‘painless’ could have opposite roles in the noxious heat response,” Montiel said. “In some neurons, the channel is required for the animal to escape high temperatures, while in Epi neurons, painlessness is needed to suppress the feeling of pain. This is an interesting and surprising development.”
“This is the first time, to my knowledge, that the TRP channel has been found to sense noxious heat not to trigger a nociceptive response, but to suppress it,” Montiel added.
To summarize: the authors found that there is a mechanism for suppressing the feeling of thermal pain in flies, and discovered that it is mediated by a single pair of neurons, called Epi neurons. They also found that Epi neurons respond directly to heat, and that this ability relies on a previously known TRP channel called painless, which can actually trigger pain in fly larvae. The team also found that heat directly activates Epi neurons, causing them to release the neuropeptide AstC. This complex then binds to the AstC-R1 receptor in other neurons associated with ovioid receptors in mammals.
The team plans to investigate further the pathways involved in this nociceptive response. For example, they hope to identify neurons that function downstream of those expressing AstC-R1. Their work raises the question of whether a thermally activated TRP channel might prevent pain perception in mammals as well. If so, Montell suspects it’s in our limbs rather than the brain, because mammals maintain a constant internal temperature, unlike fruit flies.