Inspired by Liu et al 2020.
ST36 – an acupuncture point location in upper tibialis anterior (L4/L5 myotome)
ST25 – an acupuncture point location in rectus abdominis (T10 myotome)
EA – Electroacupuncture
LPS – lipopolysaccharide (basically this is chopped up E coli cell walls)
LD – lethal dose
LD80 – dose at which 80% of subjects are expected to die
NPY – neuropeptide Y
DBH – dopamine beta-hydroxylasekey to acronyms
I overlooked this paper when it was published online on 12th August. It must have come up on my daily searches, but the title is not exactly inviting for a clinician and fails to reveal the really interesting aspects of this rather complex paper.
We have known for some years that EA at ST36 can reduce mortality (in mice) with LPS-induced endotoxemia (septic shock). This paper is rather similar, but it elaborates the mechanisms somewhat further (hence NPY in the title of the paper), and also demonstrates that EA can enhance lethality as well as reduce it.
This is a rather complex paper that opens explaining how the team managed to target certain cell lines that expressed NPY and DBH, and then created a mouse line in which cells that expressed both NPY and DBH also had diphtheria toxin receptor added to them. This meant that a dose of diphtheria toxin would ablate these cells selectively.
The reason for doing all this was to examine the role of these cells in the mechanism of EA to influence survival in endotoxemia. But what was more interesting to me was the results in terms of mice surviving injection of LPS at LD80.
They found that the timing, intensity and location of EA affected outcomes. If EA was performed before LPS injection then it always reduced mortality, although the intensity at ST25 needed to be over 1.0mA and ideally 3.0mA, and at the marvellous ST36 both low intensity (0.5mA) and higher intensity (3.0mA) resulted in significantly reduced mortality.
If EA was performed 1.5 hours after LPS injection (at the height of the cytokine storm) 3.0mA EA at ST25 and ST36 both increased mortality, but 0.5mA at ST36 reduced mortality. The increased mortality at 3.0mA could be flipped to a significantly reduced mortality with the addition of yohimbine pre-treatment (an a2 blocker).
Adrenergic a2 receptors are upregulated in endotoxemia, and their effect in promoting inflammation then outweighs the anti-inflammatory effect of the b2 receptors on NPY and DBH expressing splenic cells, which had mediated the reduced inflammation from ST25 (segmental for the spleen) EA.
The effects at ST25 were absent in mice with their NPY and DBH expressing splenic sympathetic nerves ablated, and the effects at ST36 were absent in mice with their NPY and DBH expressing adrenal chromaffin cells ablated. The latter mechanism involved a brainstem connection to vagal efferent nerves, rather than a segmental connection to sympathetic efferent nerves involved at ST25.
It is a huge piece of work, involving many individual experiments, and perhaps opens a door to the possibility of important site and intensity-specific effects of EA.
I was intrigued by the team that was predominantly from Harvard and Shanghai, but also Beijing and Houston. I noticed the name of my new research friend from Beijing (Xiang-Hong Jing), who has written in Chinese about Western medical acupuncture. I decided I should look up the boss – the last author, and found a number of interesting papers on pain and aspects of the sensory gating in the dorsal horn, including a recent paper in Nature. That reminds me to acknowledge the recent passing of Ron Melzack, one of the famous pair that proposed the Gate Theory of pain in 1965. I met Ron in Oxford at a fancy conference on phantom limb pain, and helped him find his way back to the hotel. Later on we had dinner, and I sat opposite him and his wife. He entertained me with his first experiences with acupuncture some 40 years before, when he had a needle break in LR3. As far as he knew it was still there.
Whilst I’m on the subject of the Gate Theory, one paper from the last author of Lui et al (ie the boss), led me to two others on a similar subject in the same journal.[7,8] They both have some great images of the complexity of spinal gating, which I will show you on the blog webinar tonight.
1 Liu S, Wang Z-F, Su Y-S, et al. Somatotopic Organization and Intensity Dependence in Driving Distinct NPY-Expressing Sympathetic Pathways by Electroacupuncture. Neuron 2020;:1–15. doi:10.1016/j.neuron.2020.07.015
2 Torres-Rosas R, Yehia G, Peña G, et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat Med 2014;20:291–5. doi:10.1038/nm.3479
3 Zhang Y, Liu S, Zhang YQ, et al. Timing Mechanisms Underlying Gate Control by Feedforward Inhibition. Neuron 2018;99:941-955.e4. doi:10.1016/j.neuron.2018.07.026
4 Huang T, Lin S-H, Malewicz NM, et al. Identifying the pathways required for coping behaviours associated with sustained pain. Nature 2019;565:86–90. doi:10.1038/s41586-018-0793-8
5 Basbaum AI. In Memoriam. Pain 2020;161:877–9. doi:10.1097/j.pain.0000000000001835
6 Melzack R, Wall PD. Pain Mechanisms: A New Theory. Science (80- ) 1965;150:971–8. doi:10.1126/science.150.3699.971
7 Braz J, Solorzano C, Wang X, et al. Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 2014;82:522–36. doi:10.1016/j.neuron.2014.01.018
8 Cui L, Miao X, Liang L, et al. Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain. Neuron 2016;91:1137–53. doi:10.1016/j.neuron.2016.07.038