A channel involved in pain sensation can also suppress it.

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UC Santa Barbara researchers identified a pathway in fruit flies that reduces the sensation of pain from heat. Surprisingly, only a single neuron on each side of the animal’s brain controls the response. Furthermore, the molecule responsible for suppressing this sensation in adult flies has the opposite role in fly larvae. The surprising results appear in current biology.

The brain of a fruit fly has about a million fewer neurons than ours. “However, we did not anticipate that a single pair of neurons would have such an important role in pain suppression,” said lead author Craig Montell, the Duggan Professor and Distinguished Professor of Molecular, Cellular, and Developmental Biology.

“We call them ‘Epione,’ or Epi neurons, after the Greek goddess of pain reliever,” said first author Jiangqu Liu, a postdoctoral fellow in Montell’s lab.

The authors are quick to clarify one point. “Pain is an interpretation,” Montell said. “A hard smack to the back from a teammate after a win might feel good, but not from a playground bully. Since we can’t ask fruit flies about their interpretation of high temperatures, a more precise term is ‘nociception’.” which refers to how the body detects a potentially harmful stimulus and then relays the information to induce an avoidance response.”

Humans are well known for being able to suppress pain in some situations. However, scientists don’t know much about the suppression of nociception in flies, which are workhorses for sensory research. Montell and his lab wanted to determine if flies have such a system, and if so, locate the neurons involved and understand the mechanism.

The researchers focused on nociception in response to heat. First they needed a way to measure how animals responded to high temperatures. They placed flies on a hot plate and measured the number that jumped in 10 seconds. Almost all the flies jumped between 38° and 44° Celsius (approximately 100° to 111° Fahrenheit). Now, the team set out to see if they could identify the neurons that suppress their aversion to high temperatures and reduce the jumping response.

Location of neurons

The authors wondered if neurons involved in the suppression of thermal pain might express a particular neuropeptide. Neuropeptides are a bit like neurotransmitters, except that neurotransmitters mediate between adjacent neurons, whereas neuropeptides can have a more systemic effect. As a result, they impact many behaviors. Different sets of neurons tend to express different neuropeptides. Liu, Montell, and their co-authors used the 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 tendency of flies to jump off the hot plate. These neurons produce the neuropeptide AstC, which is related to a mammalian compound that contributes to pain suppression in humans.

The researchers then expressed the gene encoding a light-sensitive channel in this group of neurons. This allowed them to activate the neurons using light. As expected, stimulating these neurons reduced the flies’ tendency to jump off the hot plate.

The authors then used the section of DNA that controls AstC expression to control a green fluorescent protein gene. Now they could finally see which neurons were firing. It was then that they discovered that activating a single neuron on each side of the brain (the Epi neurons) suppressed the nociceptive response.

find the trigger

Once the team found the neurons responsible for suppressing thermal pain, they wondered if the Epi neurons were thermosensitive or if they received a signal from other neurons.

The researchers expressed a gene that encodes a protein that fluoresces when calcium ions flood Epi neurons. They found that calcium levels increased as the temperature increased, even when they used a chemical to block communication between neurons. These findings indicated that Epi neurons were directly sensing high temperature.

The researchers determined that a specific ion channel in the cell membrane of the Epi neurons was responsible for detecting heat. This channel, called “Painless”, is a member of the TRP family of channels. TRP channels have extensive functions in sensation, including temperature sensation. In fact, Painless is also required for thermal nociception in fly larvae. “So Painless may have opposing roles in the response to noxious heat,” Montell said. “In some neurons, the channel is required for the animal to escape high temperatures, whereas in Epi neurons, Painless is needed to suppress nociception. That’s an interesting and surprising twist.”

“This is the first time, to my knowledge, that a TRP channel has been found to detect noxious heat, not to induce a nociceptive response, but to suppress it,” Montell added.

In summary: the authors found that there is a mechanism to suppress thermal nociception in flies, and found 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 depends on a previously known TRP channel called Painless, which can actually trigger nociception in fly larvae. The team also discovered that heat activates Epi neurons directly, causing them to release the neuropeptide AstC. This compound then binds to the AstC-R1 receptor on other neurons that is related to mammalian opioid receptors.

The team plans to further investigate the pathways involved in this anti-nociceptive response. For example, they hope to identify neurons that function downstream of those that express AstC-R1. Their work raises the question of whether a thermally activated TRP channel could also suppress nociception in mammals. If so, Montell suspects it would be in our extremities and not in our brains, since mammals maintain a constant internal temperature, unlike fruit flies.