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Review
. 2024 Jan 24;74(1):4.
doi: 10.1186/s12576-023-00896-y.

Neurochemical mechanism of muscular pain: Insight from the study on delayed onset muscle soreness

Kazue Mizumura  1   2 , Toru Taguchi  3   4
Affiliations
Review

Neurochemical mechanism of muscular pain: Insight from the study on delayed onset muscle soreness

Kazue Mizumura et al. J Physiol Sci. .

Abstract

We reviewed fundamental studies on muscular pain, encompassing the characteristics of primary afferent fibers and neurons, spinal and thalamic projections, several muscular pain models, and possible neurochemical mechanisms of muscle pain. Most parts of this review were based on data obtained from animal experiments, and some researches on humans were also introduced. We focused on delayed-onset muscle soreness (DOMS) induced by lengthening contractions (LC), suitable for studying myofascial pain syndromes. The muscular mechanical withdrawal threshold (MMWT) decreased 1-3 days after LC in rats. Changing the speed and range of stretching showed that muscle injury seldom occurred, except in extreme conditions, and that DOMS occurred in parameters without muscle damage. The B2 bradykinin receptor-nerve growth factor (NGF) route and COX-2-glial cell line-derived neurotrophic factor (GDNF) route were involved in the development of DOMS. The interactions between these routes occurred at two levels. A repeated-bout effect was observed in MMWT and NGF upregulation, and this study showed that adaptation possibly occurred before B2 bradykinin receptor activation. We have also briefly discussed the prevention and treatment of DOMS.

Keywords: Delayed onset muscle soreness; Glial cell line-derived neurotrophic factor; Lengthening contraction; Mechanical hyperalgesia; Muscle pain; Nerve growth factor.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Size distribution of muscle innervating DRG neurons and expression of NGF and GDNF receptors. Muscle-innervating DRG neurons were traced by the retrograde transport of Fluorogold (FG). Upper column: Blue, FG+ and TrkA− neurons; green, FG+/TrkA+ neurons; yellow, triple positive neurons (FG+/TrkA+/GFRα1+). Lower column: blue, FG+/GFRα1− neurons; orange, FG+/GFRα1+ neurons: yellow, triple positive neurons (FG+/TrkA+/GFRα1+). Numbers of cells expressing TrkA, GFRα1 and both in each size range are cumulatively presented in each bar. The addition of all three in each size range provided the number of cells innervating the GC in that size range. Modified from Murase et al. [19]
Fig. 2
Fig. 2
A rat model of DOMS. a: Method applying lengthening contractions mainly to the extensor digitorum longus (EDL) muscle. One pair of insulated needle electrodes, except for their tips, was inserted near the common peroneal and sciatic nerves. While the muscle was contracted by electrical stimulation (50 Hz for 1 s), it was stretched. This was repeated 500 times with a 3 s resting period. b: Change in withdrawal threshold after lengthening contraction (LC). The withdrawal threshold decreased for three days after LC. c: c-Fos expression in the superficial dorsal horn. A significant increase in the number of c-Fos-positive neurons was observed only when the muscle was compressed after LC at L4, where the nerve innervating the EDL terminated. d: Time course of discharges of muscle thin-fibers in response to ramp mechanical stimulation (0–196 mN in 10 s, lower-most trace). The discharge rate was significantly higher in the fibers recorded from rats two days after LC (orange triangles) than in those recorded from control animals (blue circles). a and c: Modified from Taguchi et al. [78]; b: Modified from Taguchi et al. [147]; d: Modified from Taguchi et al. [83]
Fig. 3
Fig. 3
Muscular mechanical hyperalgesia after lengthening contractions in rats depends on stretch velocity (VEL) (a–e) and range of motion (ROM) (f–j), and muscle fiber damage such as necrotic fibers (k) and Evans Blue dye-positive fibers seldom observed (k–p). AAC area above the curve. Modified from Hayashi et al. [89]
Fig. 4
Fig. 4
Effect of B2 bradykinin receptor antagonist HOE 140 and NGF expression in the muscle. The B2 bradykinin receptor antagonist HOE 140 completely blocked the development of DOMS when subcutaneously (s.c.) injected (a) but had no effect when injected in the midst of DOMS 2 days after LC (b). NGF mRNA (c) and protein (d) levels in exercised muscle increased 12 h–1 or 2 days after LC and were blocked by HOE 140 (e). Modified from Murase et al. [37]
Fig. 5
Fig. 5
B2 bradykinin receptor–NGF route in DOMS. a: Dark-field (left) and bright-field (right) photomicrographs of in situ hybridization on the LC side (left pair) and contralateral side (right pair). White dots in bright-field photos and black dots in bright-field photos represent signals of in situ hybridization of NGF mRNA. Signals were observed around myofiber/satellite cell nuclei in LC side. b: Injection of anti-NGF antibody (30 μg) into the muscle at the time point marked with a symbol of injector almost completely reversed the decreased withdrawal threshold in 3 h (#). c: NGF dose-dependently decreased the withdrawal threshold 2 or 3 h after injection. Comparison was made with – 1 day. Modified from Murase et al. [37]
Fig. 6
Fig. 6
NGF-induced mechanical sensitization of muscular thin-fiber receptors. Single-fiber recordings were performed from the common peroneal nerve-extensor digitorum longus muscle preparation ex vivo. a: Sample recordings from C-fibers before and 120 min after intramuscular injection of PBS (left) and NGF (right) near the receptive field. The mechanical response of the fibers that received the NGF injection increased 120 min after NGF injection. b: Time course of the change in the response threshold to ramp mechanical stimulation after injection. c: Time course of the change in the response magnitude (no. of discharges induced by ramp mechanical stimulation) after the injection. * Compared with the PBS group at each time point. Modified from Murase et al. [37]
Fig. 7
Fig. 7
Involvement of GDNF in DOMS. a: Time course of change in GDNF mRNA expression in exercised muscle, * compared with the control (CTR). b: Photomicrograph of the in situ hybridization of GDNF mRNA. Dark field pictures (left) were taken from transverse sections at low magnification to show the mRNA signals (white dots) over a wide area. Bright field pictures (right) were taken from longitudinal sections to show the relationship between signals (black dots) and muscle cells. White arrows in bright fields photos indicate dense signals around the nuclei of muscle/satellite cells. c: GDNF mRNA upregulation was suppressed by COX-2 inhibitors (p.o.) prior to LC. * Compared to no drug treatment. d: Intramuscular injection of anti-GDNF antibody (10 μg) injected 2 days after LC reversed decreased withdrawal threshold. * Compared to pre-injection 2 days after LC. Modified from Murase et al. [88]
Fig. 8
Fig. 8
GDNF-induced mechanical sensitization occurs in muscle Aδ-fibers. a: Response threshold (left) and response magnitude (right) to a ramp mechanical stimulation from 0 to 196 mN in 10 s in Aδ-fibers (n = 14 each). Significant changes were observed after 60 (threshold) and 30 min (magnitude). b: Those of C-fibers (n = 30 each). No changes were observed in either the mechanical threshold or response magnitude. Modified from Murase et al. [38]
Fig. 9
Fig. 9
NGF and GDNF synergistically amplifies muscular hypersensitivity. a: Dose–response relationship of the NGF-induced decrease of MMWT (mechanical hypersensitivity). n = 6 except 0.2 μM and 0.8 μM NGF (n = 8). b: Dose–response relationship of the GDNF-induced decrease in MMWT. n = 6 each. c: A mixture of NGF (0.1 μM) and GDNF (0.008 M), which alone did not induce a decrease in MMWT, induces a pronounced decrease in MMWT. n = 6. d: Sample photograph of pERK immunohistochemistry of the DRG (L5) after compression (1500 mN) of the muscle treated with PBS (left) or a mixture of low NGF (0.1 μM) and low GDNF (0.008 μM) (right). e: Percentage of pERK+ DRG neurons after each treatment. Neither low NGF nor low GDNF induced a larger percentage of pERK+ neurons compared with PBS, but a mixture of both (Low Mix) induced a significantly larger increase. Modified from Murase et al. [19]
Fig. 10
Fig. 10
Involvement of TRPV1 and ASICs in NGF- and GDNF-induced hypersensitivity. High NGF (0.8 μM, 20 μL, i.m.)-induced decrease in MMWT was reversed by capsazepine (50 μM, 20 μL) but not by amiloride (50 mM, 20 μL) (a), whereas high GDNF (0.03 μM)-induced decrease in MMWT was reversed by amiloride but not capsazepine (b), suggesting that TRPV1 is involved in high NGF-induced hypersensitivity, whereas ASICs are involved in high GDNF-induced hypersensitivity. A mixture of low NGF- and low-GDNF-induced decrease in MMWT was reversed by both capsazepine (c) and amiloride (d), suggesting that both receptor channels are involved in low mixture-induced hypersensitivity. Mean ± SD. a, c, and d: Modified from Murase et al. [19]; b: Modified from Murase et al. [38]
Fig. 11
Fig. 11
Mechanical sensitization of thin-fiber receptors after LC is mediated by ASIC3. Single-fiber recordings from Aδ- and C-fibers were performed from the common peroneal nerve-extensor digitorum longus muscle preparation ex vivo. Average time histograms of the mechanical responses of Aδ- (a) and C-fibers (b) from control rats and rats that underwent LC. Thus, the response of the LC group was facilitated. The ASIC3 inhibitor APETx2 (2.2 μM) injected near the receptive field reversed the decreased mechanical threshold (left) and increased the response magnitude (right) of both Aδ- (c) and C-fibers (d). Modified from Matsubara et al. [126]
Fig. 12
Fig. 12
Neurochemical mechanisms for the development of DOMS. The starting point of this schema is based on the report by Boix et al. [92] that a bradykinin-like substance (Arg-bradykinin) is produced and released from blood vessels by the adenosine released by muscle contraction [148, 149]. Arg-bradykinin binds to and activates the B2 bradykinin receptor (B2R) in muscle cells to stimulate NGF production. NGF sensitizes C-fibers only when high concentrations are used, and both Aδ- and C-fibers when a low mix is used or in DOMS involving TRPV1 and ASIC3. In addition, the activation of B2R upregulates COX-2. Another route involves the upregulation of COX-2 in muscle fibers, resulting in increased production of prostaglandin (PG) E2. PGE2 rapidly spreads from the cells and binds to the EP2 receptor [150] to stimulate GDNF production. GDNF sensitizes nociceptors (Aδ-fibers only when high concentration was used, and both Aδ- and C-fibers when low mix was used or in DOMS) involving TRPV4 and ASIC3. A synergistic interaction has been observed between NGF and GDNF at the primary afferent level. The mechanism of this synergistic interaction is open to future studies
Fig. 13
Fig. 13
DOMS is attenuated by repeated LC. a: A Decrease in MMWT after LC did not occur after the second bout of LC with a 5-day-interval. b: NGF mRNA increased after 1st LC but not after 2nd LC, corresponding to the absence of DOMS after 2nd LC. c: Subcutaneous injection of the B2 receptor antagonist HOE140 before 1st LC suppressed DOMS not only after 1st LC but also after 2nd LC, although the effect of HOE 140 lasts for several hours. Consistent with this observation, NGF mRNA levels did not increase in either group (d). These results suggest that adaptation to LC occurs prior to B2 bradykinin receptor activation. Modified from Urai et al. [132]
Fig. 14
Fig. 14
Human model of DOMS in the thoracolumbar paraspinal muscles. a Distribution of pressure pain thresholds. In the CTR group (n = 12), there were no remarkable changes in the pressure pain threshold maps at 0 (before LC), 24, and 48 h after LC. In the LC group (n = 12), the pressure pain thresholds remarkably decreased 24 h after LC, and the decreased threshold appeared to recover 48 h after LC. Heatmap images were obtained from the mean pressure pain threshold values at each measurement point (ranging from 294 to 588 kPa). b: Magnitude of DOMS in the thoracolumbar area after LC. Note the significantly higher magnitude of DOMS in the LC group than in the CTR group at segments Th11–L5 (*p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001; CTR vs. LC, two-way repeated-measures analysis of variance followed by Sidak’s multiple comparison test). Modified from Hanada et al. [137]
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