Peripheral receptors and neuromediators

Stimulated by Trento et al 2021.[1]

IF – impact factor
APs – acupuncture points
NE – norepinephrine (aka noradrenaline)
NO – nitric oxide

key to acronyms

This paper was sent to me by Ari (second author) the day before it appeared on my PubMed searches. Ari has lectured to the BMAS in the past, and I met him first in 2009 at a Brazilian conference when I was introduced to a group of acupuncture residents. That was the first time I realised that Brazil had a residency programme for physicians in acupuncture. He finished that programme along with an MSc in neuroscience and then a PhD. Well that is a bit about Ari, but who is the first author of this epic review paper?

The first author, Maísa Trento has recently graduated from her medical studies at the Federal University of Santa Catarina (UFSC) in Florianopolis, yes I said recently graduated. This review of peripheral receptors and neuromediators involved in the antihyperalgesic effects of acupuncture took over 2 years to complete, so Maísa did the work in her final 2 years of medical studies. All medical students at UFSC have to complete a monograph (long essay) as part of their degree. Ari was her mentor and she ran the medical students ‘Acupuncture League’, so it is not a surprise that acupuncture was a potential topic, but this was a hugely ambitious project. They had help from Elisa, a professor of anatomy and Daniel, a professor of neuroscience, so Maísa had a good team in her corner.

an integrative review

This paper runs to 21 pages of Pflugers Archiv European Journal of Physiology (IF 3.27) with 77 references, and it is described by the authors as an integrative review. This sort of review has apparently become popular within the basic sciences as a way to summarise the current knowledge in the field and identify areas for further research.

Twenty-nine studies were included in the review from a total of 463 that were found from searches or manual selection. After 180 duplicates were removed there were 283 left, of which 242 were excluded, the majority (n=176) because the receptor studied was not at either the site of needling or hyperalgesia. A further 12 were excluded on reading the full texts for essentially the same reason, which left them with 29. Nine of these were related to opioid receptors, 5 to adenosine and 5 to cannabinoid receptors, with a sprinkling of others to make up the rest.

The neuromediators included in the studies were as follows:

  • opioid peptides
  • adenosine
  • histamine
  • substance P (SP)
  • calcitonin gene-related peptide (CGRP)
  • anandamide (an endocannabinoid)
  • nitric oxide (NO)
  • norepinephrine

These neuromediators are involved in some way in the vicinity of the needling site in order to mediate an antihyperalgesic effect of acupuncture. Apart from the first two on the above list, the rest all only had a single paper describing their role. I was intrigued by norepinephrine (NE). I knew there was a wealth of data describing the effects of acupuncture on the autonomic nervous system, including the release of catecholamines such as NE, but I was not aware of a strictly local effect at the site of needling. So, I got hold of the paper concerned.[2]

Life Sciences (IF 3.53) is a pretty good journal, but this paper from 2006 did not involve either acupuncture needles or the measurement of antihyperalgesic effects. Curious I thought, and certainly it might raise a question about inclusion in this review, but the nature of the review means that it is not really critical to any pooled result, and therefore one could argue for inclusivity based on location alone.

NE production at acupuncture points?

I dug further to find that the paper used quite sophisticated methods to assess NE production at acupuncture points (APs). They found NE in higher concentrations in rat skin at APs compared with non-points on meridians and with non-points off meridians. They also determined the role of nitric oxide (NO) in promoting NE production.

This is all well and good until you find out how they determined APs from non-APs, beyond the approximate anatomical considerations. They used skin impedance. Since the only points with lowered skin impedance were the APs and there were no differences in outcomes between non-points on meridians with non-points off meridians, it seems as though this research really only examines the differences between skin in areas of low impedance compared with skin of more normal impedance. There was one other paper using the same method to find points, and it examined NO concentrations.[3] So, the only thing that relates these papers to acupuncture is the theoretical concept of AP locations, which have always been rather tenuous, and since lowered skin impedance has not been reliably correlated with APs,[4] these papers are on even more dodgy ground in trying to imply that this has anything at all to do with acupuncture effects.

the peripheral milieu

The other 27 papers actually involved acupuncture needle stimulation, many with electrical stimulation, and so are another matter entirely. The review includes a long and detailed table summarising the included papers and 3 figures summarising the findings. They are a handy summary and guide to navigate the review, making this a really useful reference text for the peripheral milieu involved in acupuncture effects.


1          Trento MMS, Moré AOO, Duarte ECW, et al. Peripheral receptors and neuromediators involved in the antihyperalgesic effects of acupuncture: a state-of-the-art review. Pflüg Arch – Eur J Physiol Published Online First: 20 January 2021. doi:10.1007/s00424-020-02503-0

2          Chen J-X, Ibe BO, Ma S-X. Nitric oxide modulation of norepinephrine production in acupuncture points. Life Sci 2006;79:2157–64. doi:10.1016/j.lfs.2006.07.009

3          Ma S-X. Enhanced nitric oxide concentrations and expression of nitric oxide synthase in acupuncture points/meridians. J Altern Complement Med N Y N 2003;9:207–15. doi:10.1089/10755530360623329

4          Ahn AC, Colbert AP, Anderson BJ, et al. Electrical properties of acupuncture points and meridians: a systematic review. Bioelectromagnetics 2008;29:245–56. doi:10.1002/bem.20403

Declaration of interests MC