​Sci Adv | Explore the neural mechanism of "pain first"

Written | Edited by Pan Xiuzhen | Enzyme American Roman statesman Cicero said in "The End of Good and Evil": "No one loves pain, and no one seeks desire because it is pain.

" (Rackham 1931) In the conflict of motivations caused by pain and other behaviors, the disgust for pain often occupies our main attention, making us not in the mood to do other things, such as whether you don't want to eat.

Under normal circumstances, pain represents a dangerous thing, such as injury, so prioritizing pain generally helps to improve animal survival.

This kind of priority attention and treatment of pain is called "pain priority".

However, continuous attention to pain under pathological conditions such as chronic pain is believed to lead to a weakened motivation for other things and even depression and other mental illnesses, while the existing painkillers generally cannot treat these mental illnesses that accompany chronic pain.
.

Patients with chronic long-term pain often have no appetite.

In fact, the neural mechanism of why pain is prioritized in motivational conflicts is not clear.

The latest developments reported by Dr.
Fu Yu from the Agency for Science and Technology Research of Singapore in Science Advances recently provided a new perspective on understanding the neural mechanisms of “pain priority” and published a paper entitled A distinct parabrachial-to-lateral hypothalamus circuit for motivational suppression of feeding by nociception.

In order to study the neural mechanism of "pain priority", postdoctoral researcher Siew Cheng Phua and student Yu Lin Tan of Dr.
Fu's research group focused on a brain region called the parabrachial nucleus in the brainstem of mammals.

Previous studies have shown that the parabrachial nucleus is an important pain signal transmission center in the mammalian brain, responsible for transmitting pain and itch signals from the spinal nerves to the higher brain regions (Navratilova and Porreca, 2014).

Nerve cells in the parabrachial nucleus project to many different brain areas including the central amygdala and lateral hypothalamus.

Because eating behavior is an instinctive behavior that is vital to survival for animals, studying the changes in appetite under pain is a good starting point for studying "pain first".

Studies of nerve cells in the parabrachial nucleus that project to the central amygdala (CeA) have shown that these nerve cells encode fear responses that include pain, and they can reduce appetite when activated (Campos et al.
, 2018; Han et al.
, 2015; Palmiter, 2018).

However, there is no evidence that these parabrachial nucleus nerve cells that project to CeA play any role in the "pain priority" phenomenon.

Because the lateral hypothalamus (LH) has an important regulatory function for appetite, and earlier studies have shown that certain lateral hypothalamic nerve cells also respond to pain, and certain lateral hypothalamic nerve cells also play an important role in behavioral motivation.
(Petrovich, 2018), the author speculates that the parabrachial nucleus nerve cells that project to the lateral inferior colliculus (called LHPBN nerve cells) may be involved in the regulation of "pain priority".

Using a variety of tracing tools, the researchers found that the parabrachial nucleus cells (LHPBN) projected to LH and CeA (CeAPBN) projected to CeA are significantly different in location distribution and gene expression, indicating that these two pathways It is possible to mediate different functions.

The results of retroviral tracing and in vivo calcium imaging experiments show that LHPBN neurons directly receive input from the spinal cord and have obvious responses to a variety of acute pain.

Previous studies have shown that activating CeAPBN neurons reduces the average eating time of eating, but activating LHPBN neurons specifically reduces the frequency of eating, suggesting that the desire to eat may be reduced.

Through the task behavior experiment of the progressive ratio of rewards, activating LHPBN neurons significantly reduces the behavioral motivation to obtain food rewards, verifying the adequacy of these neurons in suppressing appetite in the "pain priority"; in order to further test the LHPBN neurons in the "pain priority" In the “necessity of suppressing appetite”, researchers first perfected and studied in detail the classic “conflict avoidance” behavior paradigm (Bower et al.
, 1960; Champion, 1961).

In this behavioral paradigm, normal hungry mice cannot overcome the pain caused by a weak electric shock to obtain food, and exhibit behaviors similar to human hesitation, walking back and forth in front of the electric shock area but cannot obtain food through the electric shock area.
.

However, after inhibiting the LHPBN neurons, although the perception of pain in these mice did not change, these mice significantly reduced the "hesitating behavior" and were able to get more food through the shock area, indicating that the pain caused by the electric shock needs to activate LHPBN Neurons to achieve the effect of "pain first".

Interestingly, although activating CeAPBN neurons also reduces food intake, inhibiting these neurons does not increase mice overcoming the pain caused by weak electric shocks and increasing food intake, which further illustrates that different parabrachial nucleus neurons are involved in pain-mediated conditions.
Different behavioral responses have different functions.

Interestingly, the commonly used painkillers can not increase appetite under painful conditions, indicating that the inhibition of pain on other instinctive behavioral motivations and the reduction of behavioral motivation under chronic pain cannot be well alleviated by existing painkillers.

Figure 1 An overview of the conflict avoidance behavior paradigm that studies pain priority and the projection and function of different neurons in the parabrachial nucleus.

Through a series of system neurobiology methods, detailed experimental data proves the important role of LHPBN neurons in pain priority, reveals important differences in projection and function between different neurons in the parabrachial nucleus, which is useful for understanding pain.
A better understanding of the effects of a variety of negative emotions has also provided a new neural circuit basis for understanding the loss of appetite and depression in patients with long-term chronic pain.

And it puts forward new requirements and ideas for the development of better control and relief of mental diseases caused by chronic pain.

Full text link: https://advances.
sciencemag.
org/content/7/19/eabe4323 Platemaker: 11 References 1.
Campos, CA, Bowen, AJ, Roman, CW, and Palmiter, RD (2018).
Encoding of danger by parabrachial CGRP neurons.
Nature 555, 617–622.
2.
Han, S.
, Soleiman, MT, Soden, ME, Zweifel, LS, and Palmiter, RD (2015).
Elucidating an Affective Pain Circuit that Creates a Threat Memory.
Cell 162, 363–374.
3.
Navratilova, E.
, and Porreca, F.
(2014).
Reward and motivation in pain and pain relief.
Nat.
Neurosci.
17, 1304–1312.
4.
Palmiter, RD (2018).
The Parabrachial Nucleus : CGRP Neurons Function as a General Alarm.
Trends Neurosci.
41, 280–293.
5.
Petrovich, GD (2018).
Lateral Hypothalamus as a Motivation-Cognition Interface in the Control of Feeding Behavior.
Front.
Syst.
Neurosci.
12, 14.
6.
Rackham, H.
(1931).
Cicero.
De finibus bonorum et malorum (London; New York:William Heinemann; GP Putnam's Sons).
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