Effects of rapamycin on the neuropathic pain complicated with nucleoside reverse transcriptase inhibitors treatment of human immunodeficiency virus infection

doi:10.3877/cma.j.issn.1674-1358.2021.04.006

Abstract

Abstract:

Objective

To investigate the effect of rapamycin on neuropathic pain complicated with nucleoside reverse transcriptase inhibitors (NRTIs) treatment of human immunodeficiency virus (HIV) infection.

Methods

Forty male mice were divided into control group, stavudine group, rapamycin + stavudine group and sodium carboxymethyl cellulose (CMC-Na) group (n = 10), randomly. Mice in sastavidine group and rapamycin + stavidine group were intragastrically administered corresponding dose of drug every 24 h, and equivalent dose of saline and 0.5% CMC-Na were given to mice of control and CMC-Na groups, respectively. Behavioral tests were conducted at 7, 14, 21, 28, 35 and 42 days after drug administration, and the expression of mammalian target of rapamycin (mTOR) in spinal cord of mice was detected by Western blot.

Results

The mechanical sensitivity and dramatic thermal hyperalgesia to noxious plantar heat stimulation decreased significantly in mice at 7, 14, 21, 28, 35 and 42 days after stetafudine administration (all P < 0.01). The mechanical threshold in mice was significantly increased and thermal hyperalgesia was reversed in rapamycin + stavudine group at 7, 14, 21, 28, 35, 42 days after stetafudine administration compared with stavudine group (all P < 0.05); among which, on the 42nd day after stetafudine administration, the effect of rapamycin on mechanical allodynia [(8.41 ± 0.17) vs. (7.40 ± 0.13); t = 4.89, P = 0.034] and thermal hyperalgesia [(6.25 ± 0.16) vs. (4.43 ± 0.21); t = 13.32, P < 0.001] in mice were both at the maximum level, with significant differences. Western blot result showed that rapamycin significantly reversed the increased expression of phospho-mTOR in the spinal cord of mice caused by stavudine compared with stavudine group [0.72 ± 0.04) vs. (0.86 ± 0.03); t = 4.24, P = 0.045].

Conclusion

Rapamycin could relieve the neuropathic pain associated with NRTIs treatment of HIV by inhibiting the phosphorylation of mTOR.

Key words: Rapamycin, Nucleoside reverse transcriptase inhibitors, Human immunodeficiency virus, Neuropathic pain, Mammalian target of rapamycin

Liangyu Wu, Hao Cheng. Effects of rapamycin on the neuropathic pain complicated with nucleoside reverse transcriptase inhibitors treatment of human immunodeficiency virus infection[J]. Chinese Journal of Experimental and Clinical Infectious Diseases(Electronic Edition), 2021, 15(04): 250-256.

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References 26

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指标		只数	给药前	给药后7 d	给药后14 d	给药后21 d	给药后28天	给药后35天	给药后42天
PWMT（g）
对照组		10	15.93 ± 0.53	15.63 ± 0.52	15.37 ± 0.46	15.68 ± 0.39	15.42 ± 0.36	15.38 ± 0.42	15.62 ± 0.33
	CMC-Na组	10	15.55 ± 0.29	15.44 ± 0.35	15.45 ± 0.34	15.36 ± 1.53	15.52 ± 0.35	15.50 ± 0.38	15.68 ± 0.34
	雷帕霉素+司他夫定组	10	15.49 ± 0.40	13.44 ± 0.25	10.51 ± 0.27	10.12 ± 0.29	9.51 ± 0.20	8.69 ± 0.20	8.41 ± 0.17
	司他夫定组	10	15.45 ± 0.30	12.35 ± 0.36	9.98 ± 0.50	9.16 ± 1.39	8.54 ± 0.22	7.64 ± 1.03	7.40 ± 0.13
F值			1.45	20.63	34.68	35.76	22.56	18.96	29.18
P值			0.180	0.008	0.004	0.003	0.007	0.008	0.005
t_{对照组 vs. CMC-Na组}			0.48	1.21	0.56	0.89	0.79	1.16	1.23
P_{对照组 vs. CMC-Na组}			0.640	0.28	0.59	0.42	0.56	0.31	0.23
t_{对照组 vs.雷帕霉素+司他夫定组}			0.85	17.16	24.61	32.16	37.18	30.12	19.21
P_{对照组 vs.雷帕霉素+司他夫定组}			0.490	0.009	0.007	0.004	0.003	0.005	0.008
t_{对照组 vs.司他夫定组}			1.12	28.17	34.24	25.12	38.12	22.23	35.17
P_{对照组 vs.司他夫定组}			0.380	0.006	0.004	0.007	0.003	0.007	0.003
t_{CMC-Na组 vs.司他夫定组}			1.25	32.23	33.17	17.73	29.16	37.69	38.69
P_{CMC-Na组 vs.司他夫定组}			0.210	0.004	0.004	0.009	0.005	0.003	0.002
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.63	21.12	27.16	36.21	31.16	18.61	23.14
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.580	0.008	0.006	0.003	0.005	0.009	0.007
t_{司他夫定组 vs.雷帕霉素+司他夫定组}			1.56	5.71	1.64	4.12	4.36	5.06	4.89
P_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.190	0.026	0.12	0.046	0.042	0.031	0.034
PWTL（s）
	对照组	10	10.14 ± 0.17	10.28 ± 0.18	10.15 ± 0.23	10.18 ± 0.20	10.27 ± 0.20	10.21 ± 0.33	10.25 ± 0.21
	CMC-Na组	10	10.59 ± 1.43	10.36 ± 0.14	10.43 ± 0.15	10.44 ± 0.20	10.39 ± 0.14	10.35 ± 0.24	10.39 ± 0.16
	雷帕霉素+司他夫定组	10	10.31 ± 0.17	8.56 ± 0.23	8.29 ± 0.14	7.88 ± 0.19	7.27 ± 0.11	6.90 ± 0.14	6.25 ± 0.16
	司他夫定组	10	10.39 ± 0.16	7.56 ± 0.35	7.12 ± 0.32	6.54 ± 0.20	5.89 ± 0.16	5.26 ± 0.23	4.43 ± 0.21
F值			1.66	20.63	33.96	25.63	18.83	30.28	24.71
P值			0.150	0.008	0.004	0.006	0.008	0.005	0.007
t_{对照组 vs. CMC-Na组}			0.98	0.64	0.96	1.24	1.36	1.07	0.52
P_{对照组 vs. CMC-Na组}			0.470	0.57	0.45	0.26	0.21	0.41	0.62
t_{对照组 vs.雷帕霉素+司他夫定组}			0.86	18.72	23.17	28.81	22.18	33.69	31.21
P_{对照组 vs.雷帕霉素+司他夫定组}			0.510	0.008	0.007	0.006	0.007	0.004	0.005
t_{对照组 vs.司他夫定组}			1.18	29.12	27.18	32.38	19.23	21.17	35.56
P_{对照组 vs.司他夫定组}			0.360	0.005	0.006	0.004	0.008	0.008	0.003
t_{CMC-Na组 vs.司他夫定组}			1.28	30.16	34.71	28.63	22.32	18.12	25.07
P_{CMC-Na组 vs.司他夫定组}			0.240	0.005	0.004	0.006	0.007	0.009	0.007
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}			1.61	31.12	26.18	20.26	15.71	21.21	24.16
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.170	0.005	0.007	0.008	0.009	0.008	0.007
t_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.81	4.57	5.92	6.23	6.68	15.79	16.68
P_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.530	0.039	0.023	0.017	0.013	0.009	0.009

指标		只数	给药前	给药后7 d	给药后14 d	给药后21 d	给药后28天	给药后35天	给药后42天
PWMT（g）
对照组		10	15.93 ± 0.53	15.63 ± 0.52	15.37 ± 0.46	15.68 ± 0.39	15.42 ± 0.36	15.38 ± 0.42	15.62 ± 0.33
	CMC-Na组	10	15.55 ± 0.29	15.44 ± 0.35	15.45 ± 0.34	15.36 ± 1.53	15.52 ± 0.35	15.50 ± 0.38	15.68 ± 0.34
	雷帕霉素+司他夫定组	10	15.49 ± 0.40	13.44 ± 0.25	10.51 ± 0.27	10.12 ± 0.29	9.51 ± 0.20	8.69 ± 0.20	8.41 ± 0.17
	司他夫定组	10	15.45 ± 0.30	12.35 ± 0.36	9.98 ± 0.50	9.16 ± 1.39	8.54 ± 0.22	7.64 ± 1.03	7.40 ± 0.13
F值			1.45	20.63	34.68	35.76	22.56	18.96	29.18
P值			0.180	0.008	0.004	0.003	0.007	0.008	0.005
t_{对照组 vs. CMC-Na组}			0.48	1.21	0.56	0.89	0.79	1.16	1.23
P_{对照组 vs. CMC-Na组}			0.640	0.28	0.59	0.42	0.56	0.31	0.23
t_{对照组 vs.雷帕霉素+司他夫定组}			0.85	17.16	24.61	32.16	37.18	30.12	19.21
P_{对照组 vs.雷帕霉素+司他夫定组}			0.490	0.009	0.007	0.004	0.003	0.005	0.008
t_{对照组 vs.司他夫定组}			1.12	28.17	34.24	25.12	38.12	22.23	35.17
P_{对照组 vs.司他夫定组}			0.380	0.006	0.004	0.007	0.003	0.007	0.003
t_{CMC-Na组 vs.司他夫定组}			1.25	32.23	33.17	17.73	29.16	37.69	38.69
P_{CMC-Na组 vs.司他夫定组}			0.210	0.004	0.004	0.009	0.005	0.003	0.002
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.63	21.12	27.16	36.21	31.16	18.61	23.14
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.580	0.008	0.006	0.003	0.005	0.009	0.007
t_{司他夫定组 vs.雷帕霉素+司他夫定组}			1.56	5.71	1.64	4.12	4.36	5.06	4.89
P_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.190	0.026	0.12	0.046	0.042	0.031	0.034
PWTL（s）
	对照组	10	10.14 ± 0.17	10.28 ± 0.18	10.15 ± 0.23	10.18 ± 0.20	10.27 ± 0.20	10.21 ± 0.33	10.25 ± 0.21
	CMC-Na组	10	10.59 ± 1.43	10.36 ± 0.14	10.43 ± 0.15	10.44 ± 0.20	10.39 ± 0.14	10.35 ± 0.24	10.39 ± 0.16
	雷帕霉素+司他夫定组	10	10.31 ± 0.17	8.56 ± 0.23	8.29 ± 0.14	7.88 ± 0.19	7.27 ± 0.11	6.90 ± 0.14	6.25 ± 0.16
	司他夫定组	10	10.39 ± 0.16	7.56 ± 0.35	7.12 ± 0.32	6.54 ± 0.20	5.89 ± 0.16	5.26 ± 0.23	4.43 ± 0.21
F值			1.66	20.63	33.96	25.63	18.83	30.28	24.71
P值			0.150	0.008	0.004	0.006	0.008	0.005	0.007
t_{对照组 vs. CMC-Na组}			0.98	0.64	0.96	1.24	1.36	1.07	0.52
P_{对照组 vs. CMC-Na组}			0.470	0.57	0.45	0.26	0.21	0.41	0.62
t_{对照组 vs.雷帕霉素+司他夫定组}			0.86	18.72	23.17	28.81	22.18	33.69	31.21
P_{对照组 vs.雷帕霉素+司他夫定组}			0.510	0.008	0.007	0.006	0.007	0.004	0.005
t_{对照组 vs.司他夫定组}			1.18	29.12	27.18	32.38	19.23	21.17	35.56
P_{对照组 vs.司他夫定组}			0.360	0.005	0.006	0.004	0.008	0.008	0.003
t_{CMC-Na组 vs.司他夫定组}			1.28	30.16	34.71	28.63	22.32	18.12	25.07
P_{CMC-Na组 vs.司他夫定组}			0.240	0.005	0.004	0.006	0.007	0.009	0.007
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}			1.61	31.12	26.18	20.26	15.71	21.21	24.16
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}			0.170	0.005	0.007	0.008	0.009	0.008	0.007
t_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.81	4.57	5.92	6.23	6.68	15.79	16.68
P_{司他夫定组 vs.雷帕霉素+司他夫定组}			0.530	0.039	0.023	0.017	0.013	0.009	0.009

组别	只数	phospho-mTOR/β-actin
对照组	10	0.58 ± 0.03
CMC-Na组	10	0.61 ± 0.01
雷帕霉素+司他夫定组	10	0.72 ± 0.04
司他夫定组	10	0.86 ± 0.03
F值		6.19
P值		0.018
t_{对照组 vs. CMC-Na组}		1.75
P_{对照组 vs. CMC-Na组}		0.120
t_{对照组 vs.雷帕霉素+司他夫定组}		6.05
P_{对照组 vs.雷帕霉素+司他夫定组}		0.021
t_{对照组 vs.司他夫定组}		12.13
P_{对照组 vs.司他夫定组}		0.008
t_{CMC-Na组 vs.司他夫定组}		13.25
P_{CMC-Na组 vs.司他夫定组}		0.006
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}		7.12
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}		0.018
t_{司他夫定组 vs.雷帕霉素+司他夫定组}		4.24
P_{司他夫定组 vs.雷帕霉素+司他夫定组}		0.045

组别	只数	phospho-mTOR/β-actin
对照组	10	0.58 ± 0.03
CMC-Na组	10	0.61 ± 0.01
雷帕霉素+司他夫定组	10	0.72 ± 0.04
司他夫定组	10	0.86 ± 0.03
F值		6.19
P值		0.018
t_{对照组 vs. CMC-Na组}		1.75
P_{对照组 vs. CMC-Na组}		0.120
t_{对照组 vs.雷帕霉素+司他夫定组}		6.05
P_{对照组 vs.雷帕霉素+司他夫定组}		0.021
t_{对照组 vs.司他夫定组}		12.13
P_{对照组 vs.司他夫定组}		0.008
t_{CMC-Na组 vs.司他夫定组}		13.25
P_{CMC-Na组 vs.司他夫定组}		0.006
t_{CMC-Na组 vs.雷帕霉素+司他夫定组}		7.12
P_{CMC-Na组 vs.雷帕霉素+司他夫定组}		0.018
t_{司他夫定组 vs.雷帕霉素+司他夫定组}		4.24
P_{司他夫定组 vs.雷帕霉素+司他夫定组}		0.045

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