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Neuron Ma Qiufu's lab discovered spinal cord pathways that selectively transmit affective visceral pain

 Last Update: 2023-02-03
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In early 2019, the National Institutes of Health hosted a working session to discuss the challenges facing
pain research.
At the time, the United States was dealing with a deadly opioid crisis
.
At the same time, the field of pain research has long been facing a transformation crisis
.
That said, advances in animal research have failed to translate into new painkillers
.
As one of the conference participants, Professor Ma Qiufu of Harvard University revisited the somatic sensory system architecture, pointing out that the pain field may use the wrong animal behavior to detect pain
for a long time.
Professor Ma Qiufu believes that the somatic sensory system can be functionally divided into two subsystems, which drive external sensation and internal sensory behavior
, respectively.
Simply put, exosensory nerve fibers are projected on the skin and other tissues that can be exposed to exogenous stimuli to sense threats from the outside world and produce reflexive or defensive behaviors to avoid injury; Endoceptive nerve fibers are found throughout the body to feel the persistent pain
caused by physical injury.
This anatomical and functional separation reveals that the long-used external reflex defense behavior in the pain community does not necessarily detect the loss
of emotional pain caused by physical injury.
For example, Ma Qiufu's team found in 2019 that mice that knocked out spinal cord neurons expressing the TAC1 gene retained the contraction-avoidance behavior caused by hot plate stimulation, but lost the self-licking and pain-reducing response caused by skin burns (Huang et al.
, Nature, 2019).

On December 29, 2022, Professor Ma Qiufu and his postdocs Qi Lu and Lin Xinghong published an article in Neuron Spinal VGLUT3 lineage neurons drive visceral mechanical allodynia but not sensitized Viscero motor reflexes, which studies visceral pain
from the intestines.
The paper also points out the existence of different types of spinal cord neurons that drive gut-related defense responses and emotional pain
.
This finding recalls for a re-examination of animal behavior
on how to measure affective pain.

Pain from internal organs is one of
the most prevalent clinical problems.
For example, 10-25% of the population suffers from irritable bowel syndrome (IBS), which still lacks effective treatment, resulting in long-term chronic pain
.
Still, research on visceral pain compared to skin pain is quite lacking
.
In 1988, Ness and Gebhart introduced two methods to study nociception and emotional pain
caused by colorectal distension (CRD).
They measure the nociception caused by CRD by electromyogram recordings of abdominal muscle contractions, called viscero motor response (VMR
).
The experience of emotional pain was measured by the real-time step-down avoidance learning assay.

The gastrointestinal tract represents half of the outside world, and VMR is a defensive response that helps get rid of gastrointestinal and external harmful substances
by increasing intra-abdominal pressure.
Brain injury experiments have shown that VMR can be adequately mediated by subcortical neural circuits, however human sensory and emotional experiences of pain require cerebral cortical structures such as the anterior cingulate cortex (ACC).

So VMR itself does not measure pain experience
.
In contrast, Li Ying's lab at City University of Hong Kong demonstrated several years ago that CRD-induced conditional location avoidance learning relies on ACC and may therefore represent a better way
to measure the emotional component of visceral pain.
Paradoxically, since 1988, the vast majority of visceral pain studies have used VMR to measure affective visceral pain
.
The basic assumption here is that the same primary sensory afferent or spinal cord transmitting neurons can connect different downstream circuits that drive both VMR and affective pain
.
It is hypothesized that loss of VMR indirectly indicates loss of affective visceral pain, at least for primary sensory afferents or spinal cord neuronal studies
.

In the newly published Neuron paper, Professor Ma Qiufu and colleagues challenge
these assumptions.
They found that in wild-type mice with gastrointestinal inflammation, low-threshold CRD was sufficient to cause real-time conditioned location avoidance, demonstrating that inflammation can cause mechanical dyspathic pain
.
BUT IN MICE THAT KNOCKED OUT NEURONS ON THE VGLUT3 LINEAGE OF THE SPINAL CORD, THIS LOW-THRESHOLD CRD WAS UNABLE TO INDUCE REAL-TIME CONDITIONAL POSITION AVOIDANCE, DEMONSTRATING THE DISAPPEARANCE
OF AFFECTIVE VISCERAL PAIN.
Conversely, hypersensitive VMR caused by inflammation was not affected, suggesting that spinal cord neurons that are not part of the VGLUT3 lineage can drive sensitized visceral motor reflexes
.
They further discovered that the VGLUT3 lineage of spinal cord neurons projects into the internal-lateral parabrachial nuclei (PBil).

Previous studies have revealed that PBil transmits sensory information induced by physical injury to the medial thalamic nucleus, which in turn passes to the anterior cingulate cortex and drives the experience
of emotional pain.
Optogenetic stimulation of peripheral neurons from the spinal VGLUT3 lineage near PBil can adequately drive real-time conditioned position avoidance, but not sufficient to drive visceral motor reflexes
.
These studies point to the existence of different types of spinal cord neurons that drive gut-related defense responses and emotional pain
.
In other words, measuring VMR alone cannot reveal the critical role
of spinal VGLUT3 neurons in processing affective visceral pain.
Even more troubling is that if only VMR is measured, it is possible in current preclinical studies to discard ideal painkillers
that can block emotional pain but retain a protective defense response.

In early 2022, Professor Ma Qiufu published a theoretical personal opinion article (Ma, Neuron, 2022), which considered the basic structure of the drive sensory system according to the basic structure of "external sensation" and "internal sensation" from the perspective of anatomy and function
.
This new article on intestinal pain provides further support
for this architecture.
It also explains to some extent why a considerable number of drugs seem to be effective in animals before, but stop clinically
.
In fact, these drugs may solve the "external feeling" of resisting external threats, and do not prevent the "internal feeling"
of emotional pain caused by internal injuries in the body.

In addition to behavioral measurement issues, Ma Qiufu's 2022 personal opinion article (Ma, Neuron, 2022) further points out that the translational success of pain research may face another challenge: redundant pain-causing pathways
at the molecular and circuit level.
To date, drugs that target a single pain-causing molecule rarely produce new painkillers, so new ideas, new strategies
are needed.
Since 2016, Professor Ma's lab has been studying how acupuncture regulates inflammation in an attempt to eliminate redundant pain pathways
at the source.
Professor Ma Qiufu's main goal of joining Westlake University full-time is to further explore the systematic physiology behind acupuncture and develop a new generation of bioelectronic medical methods to treat chronic diseases
including pain.
The lab is currently recruiting postdocs, research assistants, and lab assistants
.
Interested students and scholars, please submit resumes
.

Resume delivery </B140> ():

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References

1.
Huang, T.
, Lin, S.
H.
, Malewicz, N.
M.
, Zhang, Y.
, Zhang, Y.
, Goulding, M.
, LaMotte, R.
H.
, and Ma, Q.
(2019).
Identifying the pathways required for coping behaviours associated with sustained pain.
Nature 565, 86-90.

2.
Ness, T.
J.
, and Gebhart, G.
F.
(1988).
Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat.
Brain Res 450, 153-169.

3.
Yan, N.
, Cao, B.
, Xu, J.
, Hao, C.
, Zhang, X.
, and Li, Y.
(2012).
Glutamatergic activation of anterior cingulate cortex mediates the affective component of visceral pain memory in rats.
Neurobiol Learn Mem 97, 156-164.

4.
Ma, Q.
(2022).
A functional subdivision within the somatosensory system and its implications for pain research.
Neuron 110, 749-769.

5.
Qi, L.
, Lin, S.
H.
, Ma, Q.
Spinal VGLUT3 lineage neurons drive visceral mechanical allodynia but not sensitized visceromotor reflexes.
Neuron, 2022 Dec 20; S0896-6273(22)01076-5.
doi: 10.
1016/j.
neuron.
2022.
12.
003.

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