Muscle pain – the neurochemical basis

Stimulated by Kazue Mizumura and Toru Taguchi 2024.[1]

IF – impact factor
GPT – generative pre-trained transformer
DRG – dorsal root ganglion
DOMS – delayed onset muscle soreness
LC – lengthening contraction
EDL – extensor digitorum longus
NGF – nerve growth factor
GDNF – glial cell line derived neurotrophic factor
ASIC – acid sensing ion channel
TRPV – transient receptor potential cation channel subfamily V member

– key to acronyms

This is a review paper in The Journal of Physiological Sciences (IF 2.6), which is an open access journal, currently in transition from Springer to Elsevier. JPS is the official journal of the Physiological Society of Japan and was first published in 1927. It joined Springer in 2008 to facilitate a worldwide digital readership.[2]

Luckily this paper showed up on my searches as I seem to have missed the main research paper on which it is based from the same team in 2021.[3]

I have been intrigued by muscle pain since I started daily exercise at the age of about 10, so it is hard to resist papers like this, despite their complexity.

The authors state that muscle is the largest organ of the body, weighing in at 40% or more of total body mass. I seem to remember that skin is generally given the title of the largest organ and ChatGPT also plumped for the skin initially (based on surface area). I pointed out that the gut has a much greater surface area and got the response that I am becoming very familiar with: “You’re absolutely right to call that out!”

Anyway, let’s get back to the paper, which runs to 24 pages and has a nice round 150 references. I learned a lot just from reading the introduction!

Nociceptive inputs from muscle have a stronger influence on spinal neurons than cutaneous inputs,[4] and are under stronger influence of the descending inhibitory system.[5] Nerve injury has a stronger influence on muscular afferents than cutaneous ones.[6,7] Due to these fundamental differences, Mizumura and Taguchi state that muscle pain must be studied independently, and I wholeheartedly agree with them (as if that makes any difference).

Another thing I learned from the introduction of this paper was that the distribution of DRG cell body sizes differs between cutaneous and muscle nerves. The former are skewed to an increased frequency of smaller DRG cell body sizes, whereas the latter form something more like a normal distribution ie the cells are bigger on average. Could that be because they do more neurochemical work?

The actual research on muscle pain focusses on DOMS, which is not really the same as myofascial pain, but at least it is a form of muscle pain, and may share similarities in terms of neurochemical physiology if not aetiology.

DOMS was first described by a chap called Theodore Hough at the beginning of the last century,[8] and most humans will have experienced it by the time they are old enough to have competed in school sports day (which I’m sure was mandatory in my day, although regrettably may not be anymore).

The best way to create DOMS is by eccentric loading of muscle. That means loading the muscle as it lengthens (lengthening contraction – LC). Running down hill is likely to do it for your quads, and running down steps will do it for your soleus, as I found to my cost when lecturing in a rather urban part of Manchester some years ago.

This team from Japan have developed a particularly sophisticated method for establishing DOMS in the extensor digitorum longus muscle (EDL) of a rat rodent hind limb. They have honed the model by studying precise ranges for joint movement and velocity.

Having optimised the model, they went on the study the neurochemical basis of the muscle pain created.

In brief it hinges on adenosine release from muscle, bradykinin release from vascular endothelium, and finally NGF and GDNF release from muscle or satellite cells. The subsequent increased mechanical sensitivity of muscle is mediated by ASIC3 and TRPV4 in Aδ fibres and by ASIC3 and TRPV1 in C fibres.

The major contribution of this team’s research has been to establish a synergism between NGF and GDNF in creating mechanical hyperalgesia. This was originally published in 2021,[3] but as I said previously, I missed it then.

I will show you all the lovely graphics and figures tonight on the blog webinar.

References

1          Mizumura K, Taguchi T. Neurochemical mechanism of muscular pain: Insight from the study on delayed onset muscle soreness. J Physiol Sci. 2024;74:4. doi: 10.1186/s12576-023-00896-y

2          Sakuma Y. A new beginning for The Journal of Physiological Sciences: a message from the editor-in-chief. J Physiol Sci JPS. 2009;59:1. doi: 10.1007/s12576-008-0009-3

3          Murase S, Kobayashi K, Nasu T, et al. Synergistic interaction of nerve growth factor and glial cell-line derived neurotrophic factor in muscular mechanical hyperalgesia in rats. J Physiol. 2021;599:1783–98. doi: 10.1113/JP280683

4          Woolf CJ, Wall PD. Relative effectiveness of C primary afferent fibers of different origins in evoking a prolonged facilitation of the flexor reflex in the rat. J Neurosci. 1986;6:1433–42. doi: 10.1523/jneurosci.06-05-01433.1986

5          Yu XM, Mense S. Response properties and descending control of rat dorsal horn neurons with deep receptive fields. Neuroscience. 1990;39:823–31. doi: 10.1016/0306-4522(90)90265-6

6          Michaelis M, Liu X, Jänig W. Axotomized and intact muscle afferents but no skin afferents develop ongoing discharges of dorsal root ganglion origin after peripheral nerve lesion. J Neurosci. 2000;20:2742–8. doi: 10.1523/jneurosci.20-07-02742.2000

7          Hu P, McLachlan EM. Selective reactions of cutaneous and muscle afferent neurons to peripheral nerve transection in rats. J Neurosci. 2003;23:10559–67. doi: 10.1523/jneurosci.23-33-10559.2003

8          Hough T. Ergographic studies in muscular soreness. Am J Physiol. 1902;7:76–92. doi: 10.1152/ajplegacy.1902.7.1.76

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Declaration of interests MC