Chinese Tuina remodels the synaptic structure in neuropathic pain rats by downregulating the expression of N-methyl D-aspartate receptor subtype 2B and postsynaptic density protein-95 in the spinal cord dorsal horn

doi:10.19852/j.cnki.jtcm.20221214.002

Journal of Traditional Chinese Medicine ›› 2023, Vol. 43 ›› Issue (4): 715-724.DOI: 10.19852/j.cnki.jtcm.20221214.002

• Original Articles • Previous Articles Next Articles

Chinese Tuina remodels the synaptic structure in neuropathic pain rats by downregulating the expression of N-methyl D-aspartate receptor subtype 2B and postsynaptic density protein-95 in the spinal cord dorsal horn

HUANG Hongye¹, WANG Bingqian⁴, CHEN Shuijin²^,³, FANG Jiayu¹, WANG Xiaohua¹, CHEN Lechun²^,³, JIANG Yu²^,³, ZHANG Huanzhen²^,³, CHEN Jincheng²^,³, LIN Zhigang²^,³()

1 College of Rehabilitation Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
2 Fujian University of Traditional Chinese Medicine Subsidiary Rehabilitation Hospital, Fuzhou 350003, China
3 Fujian Provincial Key Laboratory of Rehabilitation Technology, Fuzhou 350003, China
4 Peking University International Hospital, Beijing 102206, China

Received:2022-02-23 Accepted:2022-07-08 Online:2022-12-14 Published:2022-12-14
Contact: LIN Zhigang
About author:Dr. LIN Zhigang, Fujian University of Traditional Chinese Medicine Subsidiary Rehabilitation Hospital, Fuzhou 350003, China. linzhigang@fjtcm.edu.cn. Telephone: +86-18159191681
Supported by:
Natural Science Foundation-funded Project: Study on the Mechanism of Tuina and Tuina in Regulating the Synaptic Plasticity of Spinal Dorsal Horn in Lumbar Disc Herniation Based on LncRNA-HOTAIR/miR-219 Mediated NMDAR Pathway(82174523);Natural Science Foundation of Fujian Province: Study on the Mechanism of Tuina Regulating the Synaptic Plasticity of Spinal Dorsal Horn in Lumbar Disc Herniation based on NMDAR-CAMK2-CREB Pathway(2020J01757);Study on Analgesic Mechanism of Tuina on Neuropathic Pain in Spinal Dorsal Horn/ACC Brain Region based on PKA-NMDA-NR2B Pathway(2020J01758);Fujian Health Science and Technology Program: Study on the Analgesic Mechanism of Tuina Manipulation On Lumbar Disc Herniation from the Efficacy of miR-219/NR2B Mediated Synaptic Transmission(2020GGA070);Effects of Tuina Point Press on AMPA/NMDA Receptor Scaffold Protein and Synaptic Plasticity in Spinal Dorsal Horn of Rats with Neuropathic Pain(2020CXA052)

Abstract

Abstract:

OBJECTIVE: To investigate whether the Chinese massage system, Tuina, exerts analgesic effects in a rat model of chronic constriction injury (CCI) by remodeling the synaptic structure in the spinal cord dorsal horn (SCDH).

METHODS: Sixty-nine male Sprague-Dawley rats were randomly and evenly divided into the normal group, sham group, CCI group, CCI + Tuina group, CCI + MK-801 [an N-methyl D-aspartate receptor subtype 2B (NR2B) antagonist] group, and CCI + MK-801 + Tuina group. The neuropathic pain model was established using CCI with right sciatic nerve ligation. Tuina was administered 4 d after CCI surgery, using pressing manipulation for 10 min, once daily. Motor function was observed with the inclined plate test, and pain behaviors were observed by the Von Frey test and acetone spray test. At 19 d after surgery, the L3-L5 spinal cord segments were removed. Glutamate, interleukin 1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels were detected by enzyme-linked immunosorbent assay. The protein expression levels of NR2B and postsynaptic density protein-95 (PSD-95) were detected by Western blot, and the synaptic structure was observed by transmission electron microscopy (TEM).

RESULTS: CCI reduced motor function and caused mechanical and cold allodynia in rats, increased glutamate concentration and TNF-α and IL-1β levels, and increased expression of synapse-related proteins NR2B and PSD-95 in the SCDH. TEM revealed that the synaptic structure of SCDH neurons was altered. Most of these disease-induced changes were reversed by Tuina and intrathecal injection of MK-801 (P < 0.05 or < 0.01). For the majority of experiments, no significant differences were found between the CCI + MK-801 and CCI + MK-801 + Tuina groups.

CONCLUSIONS: Chinese Tuina can alleviate pain by remodeling the synaptic structure, and NR2B and PSD-95 receptors in the SCDH may be among its targets.

Key words: neuralgia, spinal cord dorsal horn, receptors, N-Methyl-D-aspartate, disks large homolog 4 protein, neuronal plasticity, Chinese Tuina

HUANG Hongye, WANG Bingqian, CHEN Shuijin, FANG Jiayu, WANG Xiaohua, CHEN Lechun, JIANG Yu, ZHANG Huanzhen, CHEN Jincheng, LIN Zhigang. Chinese Tuina remodels the synaptic structure in neuropathic pain rats by downregulating the expression of N-methyl D-aspartate receptor subtype 2B and postsynaptic density protein-95 in the spinal cord dorsal horn[J]. Journal of Traditional Chinese Medicine, 2023, 43(4): 715-724.

Figures/Tables 9

Figure 1 Experimental process Inclined-plate test and Von Frey test were performed on days 4, 11, 14, 18 after CCI surgery; acetone spray test was performed on days 5, 12, 15, 19 after CCI surgery; spinal cord dorsal horn was isolated on day 19; CCI + MK-801 and CCI + MK-801 + Tuina group received intrathecal injection of MK-801 once daily from days 4-19 after CCI surgery, CCI + Tuina and CCI + MK-801 + Tuina group received Tuina treatment once daily from day 4-19 after CCI surgery. Tuina started half an hour after receiving intrathecal injection. DRG: dorsal root ganglia; CCI: chronic constriction injury; BL40: bladder meridian 40.

Figure 2 Tuina manipulation emulator with micro pressure sensor simulates the effect of Tuina manipulation on the body surface of rats A: photograph of Tuina manipulation emulator equipped with a pressure sensor and demonstration of rat fixation; B: control board can display and collect real-time mechanical information through corresponding software which can be immediately transmitted to a computer; C: real-time force display in a 15 s interval included pressing and circular rubbing manipulation (5 ± 1N).

Table 1 Inclined plate test results at different intervention times (

\bar{x} \pm s

)

Group	n	Baseline	Day 4	Day 11	Day 14	Day 18
Normal	5	53.7±2.2	52.7±1.9	53.3±1.7	54.0±2.8	53.3±1.7
Sham	5	51.7±1.2	45.3±1.8^a	45.7±1.9^a	50.7±2.8	50.7±3.0
CCI	5	51.7±2.0	32.7±0.9^ab	32.3±1.5^ab	34.0±1.9^ab	38.0±4.0^ab
CCI+Tuina	5	52.0±0.7	33.7±1.8	37.3±1.9^c	40.3±1.8^c	43.4±1.7
CCI+MK-801	4	51.2±0.8	34.6±1.6	36.2±1.6	41.7±1.4^c	41.2±3.5
CCI+MK-801+Tuina	5	53.0±1.4	33.0±1.4	36.0±2.2	44.0±1.5^c	45.7±3.8^d

Table 1 Inclined plate test results at different intervention times ( $\bar{x} \pm s$ )

Group	n	Baseline	Day 4	Day 11	Day 14	Day 18
Normal	5	53.7±2.2	52.7±1.9	53.3±1.7	54.0±2.8	53.3±1.7
Sham	5	51.7±1.2	45.3±1.8^a	45.7±1.9^a	50.7±2.8	50.7±3.0
CCI	5	51.7±2.0	32.7±0.9^ab	32.3±1.5^ab	34.0±1.9^ab	38.0±4.0^ab
CCI+Tuina	5	52.0±0.7	33.7±1.8	37.3±1.9^c	40.3±1.8^c	43.4±1.7
CCI+MK-801	4	51.2±0.8	34.6±1.6	36.2±1.6	41.7±1.4^c	41.2±3.5
CCI+MK-801+Tuina	5	53.0±1.4	33.0±1.4	36.0±2.2	44.0±1.5^c	45.7±3.8^d

Table 2 Time-course changes of PWTs in the hind paw of rats (g,

\bar{x} \pm s

)

Group	n	Baseline	Day 4	Day 11	Day 14	Day 18
Normal	5	12.0±2.7	11.6±3.2	13.0±2.7	12.0±1.2	14.0±2.2
Sham	8	11.9±2.6	11.2±2.3	12.2±3.0	11.9±2.6	13.1±2.6
CCI	8	13.1±2.6	5.0±2.4^ab	3.7±2.0^ab	3.2±1.0^ab	2.2±0.7^ab
CCI+Tuina	8	11.9±2.9	4.7±1.5	7.0±1.8^c	8.0±1.1^d	9.0±1.1^d
CCI+MK-801	8	14.2±5.6	5.5±2.1	9.0±1.1^d	9.2±1.0^d	12.5±2.7^d
CCI+MK-801+Tuina	8	14.5±5.3	4.7±2.1	9.0±1.1^d	9.4±1.6^d	11.9±2.6^d

Table 2 Time-course changes of PWTs in the hind paw of rats (g, $\bar{x} \pm s$ )

Group	n	Baseline	Day 4	Day 11	Day 14	Day 18
Normal	5	12.0±2.7	11.6±3.2	13.0±2.7	12.0±1.2	14.0±2.2
Sham	8	11.9±2.6	11.2±2.3	12.2±3.0	11.9±2.6	13.1±2.6
CCI	8	13.1±2.6	5.0±2.4^ab	3.7±2.0^ab	3.2±1.0^ab	2.2±0.7^ab
CCI+Tuina	8	11.9±2.9	4.7±1.5	7.0±1.8^c	8.0±1.1^d	9.0±1.1^d
CCI+MK-801	8	14.2±5.6	5.5±2.1	9.0±1.1^d	9.2±1.0^d	12.5±2.7^d
CCI+MK-801+Tuina	8	14.5±5.3	4.7±2.1	9.0±1.1^d	9.4±1.6^d	11.9±2.6^d

Table 3 Time-course changes of cold spray scores in the hind paw of rats (

\bar{x} \pm s

)

Group	n	Baseline	Day 5	Day 12	Day 15	Day 19
Normal	5	0.80±0.14	0.76±0.17	0.60±0.14	0.62±0.06	0.48±0.23
Sham	8	0.83±0.13	0.78±0.27	0.83±0.20	0.75±0.21	0.70±0.15
CCI	8	0.88±0.15	2.73±0.15^ab	2.85±0.09^ab	2.85±0.03^ab	2.90±0.17^ab
CCI+Tuina	8	0.83±0.23	2.72±0.10	2.40±0.17	2.15±0.18^c	1.75±0.09^c
CCI+MK-801	8	0.95±0.09	1.93±0.15^c	1.45±0.14^c	1.30±0.17^c	1.13±0.10^c
CCI+MK-801+Tuina	8	0.93±0.10	1.40±0.11^cd	1.40±0.16^c	1.18±0.20^c	1.05±0.09^c

Table 3 Time-course changes of cold spray scores in the hind paw of rats ( $\bar{x} \pm s$ )

Group	n	Baseline	Day 5	Day 12	Day 15	Day 19
Normal	5	0.80±0.14	0.76±0.17	0.60±0.14	0.62±0.06	0.48±0.23
Sham	8	0.83±0.13	0.78±0.27	0.83±0.20	0.75±0.21	0.70±0.15
CCI	8	0.88±0.15	2.73±0.15^ab	2.85±0.09^ab	2.85±0.03^ab	2.90±0.17^ab
CCI+Tuina	8	0.83±0.23	2.72±0.10	2.40±0.17	2.15±0.18^c	1.75±0.09^c
CCI+MK-801	8	0.95±0.09	1.93±0.15^c	1.45±0.14^c	1.30±0.17^c	1.13±0.10^c
CCI+MK-801+Tuina	8	0.93±0.10	1.40±0.11^cd	1.40±0.16^c	1.18±0.20^c	1.05±0.09^c

Table 4 Glutamate concentrations, TNF-α and IL-1β levels in the SCDH

Group	n	Glutamate concentrations (ng/mL)	TNF-α level (pg/100 μg)	IL-1β level (pg/100 μg)
Sham	4	726.7±34.5	16.4±1.8	186.8±11.7
CCI	4	1061.6±85.7^a	26.3±5.6^a	342.7±19.4^a
CCI+Tuina	4	807.6±14.2^b	16.3±2.0^b	227.1±7.4^b
CCI+MK-801	4	865.7±72.8^c	20.1±2.1	229.0±8.5^b
CCI+MK-801+Tuina	4	617.1±22.5^bd	18.3±2.9^c	212.5±11.3^b

Figure 3 NR2B and PSD-95 protein expression levels in the SCDH A-C: protein expression of NR2B and PSD-95 in the SCDH from rats detected by Western blot. Rats in the sham group were performed with sham surgery without knotting; the CCI group were received chronic constriction injury surgery; the CCI + Tuina group were treat with Tuina manipulation once daily; the CCI + MK-801 group were given intrathecal injection of MK-801 once daily; the CCI + MK-801 + Tuina group, the above two treatments were given once daily. Each group was treated for 14 d. CCI: chronic constriction injury; NR2B: N-methyl D-aspartate receptor subtype 2B; PSD-95: postsynaptic density protein-95; SCDH: spinal cord dorsal horn. Data were expressed as the mean ± standard error of the mean (n = 5). aP < 0.01 compared with the sham group; bP < 0.01 compared with the CCI group.

Figure 4 Synaptic ultrastructure changes and quantitative summary of synaptic ultrastructure in the SCDH (Transmission electronic microscopy staining method, × 20 000) The red arrow indicates the synapse. A: sham group; B: CCI group; C: CCI + Tuina group; D: CCI + MK-801 group; E: CCI + MK-801 + Tuina group; F: synaptic active zone length of rats in each group; G: mean PSD thickness of rats in each group; H: synaptic cleft width of rats in each group. Rats in the sham group were performed with sham surgery without knotting; the CCI group were received chronic constriction injury surgery; the CCI + Tuina group were treat with Tuina manipulation once daily; the CCI + MK-801 group were given intrathecal injection of MK-801 once daily; the CCI + MK-801 + Tuina group, the above two treatments were given once daily. Each group was treated for 14 d. SCDH: spinal cord dorsal horn; CCI: chronic constriction injury; PSD: postsynaptic density. Data were expressed as the mean ± standard error of the mean (n = 3). aP < 0.01 compared with the sham group; bP < 0.01 compared with the CCI group; cP < 0.05 compared with the CCI + MK-801 group.

Table 5 Quantitative summary of synaptic ultrastructure in the SCDH (nm)

Group	n	Active zone length	PSD thickness	Synaptic cleft
Sham	3	177.7±45.1	22.0±5.4	26.1±1.7
CCI	3	541.0±98.9^a	77.9±21.4^a	18.2±4.1^a
CCI+Tuina	3	232.5±48.1^b	25.0±6.6^b	23.8±0.7^b
CCI+MK-801	3	273.5±20.2^b	19.7±3.0^b	23.4±1.8^b
CCI+MK-801+Tuina	3	205.8±61.2^b	24.5±6.2^b	27.9±2.7^bc

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Chinese Tuina remodels the synaptic structure in neuropathic pain rats by downregulating the expression of N-methyl D-aspartate receptor subtype 2B and postsynaptic density protein-95 in the spinal cord dorsal horn

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