Table 1.
Summary table of studies on glia and oxaliplatin-induced neuropathic pain.
| Authors/ Years |
Animal Type (Investigated Site) | Oxaliplatin Dosing Schedule/Cumulative Dose | Glial Type | Findings: Behavioral Assessments |
|---|---|---|---|---|
| Findings: Glial Activation | ||||
| Zheng et al. (2011) [21] | SD rat (spinal cord) | D0–4 (5 times)/10 mg/kg (i.p.) | Mic. | Oxaliplatin-induced mechanical hypersensitivity (von Frey test): D35; p < 0.05 (4 g); p < 0.01 (15 g) versus control |
| No significant change in Iba1 expression after oxaliplatin treatment: D35; DH: 76.3 ± 4.2 (control) versus 67.9 ± 4.9; VH: 59.7 ± 5.3 (control) versus 55.3 ± 6.1 | ||||
| Warwick et al. (2012) [22] | Balb/c mice (DRG) | D0, D3 (twice)/8 mg/kg (i.p.) | SGCs | Oxaliplatin lowered the pain threshold by 70% (von Frey test): D7, p < 0.05 versus control Carbenoxolone (50 mg/kg, i.p.) increased the lowered pain threshold: p < 0.05 versus oxaliplatin |
| Oxaliplatin increased the number of DRG neurons surrounded by SGCs (more than 50% of their circumference): 15% (control); 35% (oxaliplatin, p < 0.05 versus control) Carbenoxolone (i.p.) lowered the increased incidence of coupling rate after oxaliplatin injection: 5/60 (control), 23/56 (oxaliplatin, p < 0.05 versus control), 10/40 (50 mg/kg, NS versus oxaliplatin), 6/53 (100 mg/kg, p < 0.05 versus oxaliplatin) | ||||
| Yoon et al. (2012) [25] | SD rat (spinal cord) | D1, D3, D5, D7 (4 times)/8 mg/kg (i.p.) | Ast. | Oxaliplatin decreased the pain threshold (von Frey test): D10, p < 0.05; D12 and D14, p < 0.01 versus control D0–7 carbenoxolone injection (25 μg, i.t.) prevented mechanical hypersensitivity D14–21 carbenoxolone injection (25 μg, i.t.) did not attenuate mechanical hypersensitivity |
| Increased GFAP expression in the spinal cord after oxaliplatin injection: D7, p < 0.05 versus control (Hypertrophied cell bodies with thickened and elongated processes); D14, NS versus control Increased expression of Cx43 in the spinal dorsal horn: D7 and 14, p < 0.05 versus control D0–7 carbenoxolone injection (25 μg, i.t.) prevented the increase of GFAP expression | ||||
| Mannelli et al. (2013) [23] | SD rat (brain, DRG, spinal cord) | D0–4, D7–11, D14–18 (15 times)/36 mg/kg (i.p.) | Ast. Mic. SGCs | Oxaliplatin induced cold hyperalgesia (cold plate test): 25.4 ± 0.9 s (control); 18.5 ± 0.8 s (D7, p < 0.05 versus control); 14 s (D14 and 21, p < 0.05 versus control) Oxaliplatin induced mechanical allodynia (von Frey test): 28.3 ± 1.2 g (control); 19.3 ± 1.3 g (D14, p < 0.05 versus control); 14.7 ± 1.5 g (D21, p < 0.05 versus control) Oxaliplatin induced mechanical hyperalgesia (paw-pressure test): 73.4 ± 2.1 g (control); 37.5 ± 2.8 g (D21, p < 0.05 versus control) |
| The number of SGCs increased in the DRG: D21, 31.4 ± 5.4 (control); 92.1 ± 7.9 (oxaliplatin, p < 0.01 versus control) Iba1 cell density increased in the dorsal horn of the spinal cord: D7, 73% higher versus control, p < 0.05 (cell body increased, and branches of the processes shortened); D14, NS versus control; D21, NS versus control GFAP cell density in spinal superficial laminae increased after oxaliplatin injection: D7, D14, and D21, p < 0.05 versus control, highest on D7; 54% higher versus control. No altered morphology Iba1 positive cells increased after oxaliplatin injection: thalamus, neostriatum, S1, DL-PAG, NRM: D7, D14 and D21, p < 0.05 versus control; ACC and VL-PAG: D14, p < 0.05 versus control; mfb: D7 and D14, p < 0.05 versus control GFAP expressing cells increased after oxaliplatin injection: neostriatum, ACC, S1: D7, D14, and D21, p < 0.05 versus control; thalamus: D7 and D14, p < 0.05 versus control; VL-PAG: D21, p < 0.05 versus control; NRM: D14 and D21, p < 0.05 versus control; DL-PAG and mfb: NS versus control | ||||
| Ahn et al. (2014) [18] | SD rat (spinal cord) | D0 (single)/6 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced cold allodynia (TWL, 4 °C): D3 and D5, p < 0.001 versus control) Oxaliplatin induced mechanical hypersensitivity (von Frey test): D3, p < 0.05 versus control; D5, p < 0.001 versus control GBT (400 and 600 mg/kg, p.o.) attenuated the cold allodynia and mechanical hypersensitivity: D5, p < 0.001 and p < 0.01 versus oxaliplatin, respectively |
| Oxaliplatin increased GFAP and OX-42 expression in the spinal cord: D5, 135.0 ± 13.5 (control); 216.3 ± 2.8 (oxaliplatin, p < 0.001 versus control); and 106.7 ± 11.9 (control); 204.0 ± 2.2 (oxaliplatin, p < 0.001 versus control) Hypertrophic with thick processes (astrocytes) and hypertrophic amoeboid shape with short processes (microglia) GBT (400 mg/kg, p.o.) suppressed the increase in the number of spinal GFAP and OX-42-positive cells: D5, p < 0.001 versus oxaliplatin | ||||
| Mannelli et al. (2014) [26] | SD rat (brain, spinal cord) | D0–4, D7–11, D14–18 (15 times)/36 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced cold hyperalgesia (cold plate test): 23.8 ± 1.2 s (control); 14.1 ± 0.8 s (D21, p < 0.01 versus control) Oxaliplatin induced mechanical allodynia (von Frey test): 21.0 ± 0.5 g (control); 13.8 ± 0.3 g (D21, p < 0.01 versus control) Oxaliplatin induced mechanical hyperalgesia (paw-pressure test): 68.3 ± 1.6 g (control); 41.7 ± 2.1 g (D21, p < 0.01 versus control) D0-20 α7 nAChR agonists (PNU-282987 and (R)-ICH3, 30 mg/kg, p.o.) injection prevented the pain behavior evoked by oxaliplatin (p < 0.01 versus oxaliplatin) |
| No change in Iba1 positive cell number in the spinal cord after oxaliplatin treatment: D21 Iba1 expression increased in the brain after oxaliplatin: thalamus, S1, and DL-PAG (p < 0.05 versus control) PNU or (R)-ICH3 per se enhanced Iba1 cell density: in the thalamus by 60% and S1 by 108% (p < 0.05 versus control) Increase in GFAP-positive cell number in the spinal cord after oxaliplatin injection: D21 GFAP expression increased in the brain after oxaliplatin: S1 by 49% and VL-PAG by 50% (p < 0.05 versus control) PNU or (R)-ICH3 (30 mg/kg, p.o.) failed to reduce increased GFAP expression in the spinal cord PNU or (R)-ICH3 injection increased GFAP cell number in the thalamus and S1, but decreased in the VL-PAG (p < 0.05 versus oxaliplatin) | ||||
| Mannelli et al. (2014) [24] | SD rat (spinal cord, DRG) | D0–4, D7–11, D14–18 (15 times)/36 mg/kg (i.p.) | Ast. Mic. SGCs | Oxaliplatin induced mechanical hyperalgesia (paw-pressure test): ± 70 g (control); 56.6 ± 1.9 g (D7, p < 0.05 versus control); 45.0 ± 4.1 g (D14, p < 0.01 versus control); 43.5 ± 1.9 g (D21, p < 0.01 versus control); Minocycline (12.5 nmol/h, i.t.) prevented mechanical hyperalgesia: by 50% (D7, p < 0.05); by 33% (D14, p < 0.05); by 60% (D21, p < 0.01); Fluorocitrate (1 nmol/h, i.t.) prevented hyperalgesia: by 100% (D7, p < 0.01); by 80% (D14, p < 0.01); 87% (D21, p < 0.01) Oxaliplatin induced mechanical allodynia (von Frey test): ± 28 g (control); 19.2 ± 0.6 g (D14, p < 0.05); 14.2 ± 0.5 g (D21, p < 0.01). Minocycline prevented by 60% (D14, p < 0.05); 90% (D21, p < 0.01); Fluorocitrate prevented by 93% (D14, p < 0.01); 94% (D21, p < 0.01). Oxaliplatin induced cold hyperalgesia (cold plate test): ± 23 s (control), 17.0 ± 1.5 g (D7, p < 0.05), 16.1 ± 0.8 g (D14, p < 0.01), and 12.4 ± 1.1 g (D21, p < 0.01); Minocycline prevented by 80% (D21, p < 0.01); Fluorocitrate prevented by 100% (D7, p < 0.01), by 90% (D14, p < 0.01), and by 95% (D21, p < 0.01) |
| Oxaliplatin increased Iba1 positive cells in the spinal cord: D7, p < 0.01 versus control. Minocycline prevented this increased: D7, p < 0.01 versus oxaliplatin; D14, NS versus control; D21, NS versus control Oxaliplatin increased GFAP expressing cell number in the superficial laminae of the dorsal horn: D7, D14, and D21, p < 0.01 versus control. Fluorocitrate prevented this increase: D7, D14, and D21, p < 0.01 versus oxaliplatin Minocycline and fluorocitrate did not decrease the number of SGCs increased in DRG after oxaliplatin treatment: D21; 10.7 ± 1.3 (control); 23.5 ± 2.7 (oxaliplatin, p < 0.05 versus control); 20.4 ± 3.6 (minocycline, NS versus oxaliplatin); 22.7 ± 4.1(fluorocitrate, NS versus oxaliplatin) | ||||
| Robinson et al. (2014) [27] | SD rat (spinal cord) | D1, D3, D5, D7 (4 times)/8 mg/kg (i.p.) | Ast. | Oxaliplatin induced mechanical allodynia (von Frey test): D14, 20.6 ± 1.8 g (control); 12.0 ± 1.4 g (oxaliplatin, p < 0.05 versus control); D0-8 treatment of minocycline (25 mg/kg, i.p.) prevented this change: D14 |
| Oxaliplatin increased GFAP fluorescence intensity in the spinal cord: D7, 131 ± 9.4% of control (p < 0.001); D14, 122 ± 4.7% of control (p < 0.001) D0–8 treatment of minocycline showed an increase of intensity at D7, 115 ± 13.5% of control (NS) and decrease at D14, 91 ± 20.2% of control (NS) | ||||
| Janes et al. (2015) [28] | SD rat (spinal cord) | D0–4 (5 times)/10 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced mechanical hypersensitivity (von Frey test): D11, D17, and D25 (p < 0.05 versus control) D0–4 A3AR agonists MRS5698 (0.1 mg/kg/day, i.p.) injection prevented the development of mechanical hypersensitivity: D11, D17, and D25 (p < 0.05 versus oxaliplatin) |
| No change in spinal expression of OX42 after oxaliplatin treatment: D25 GFAP expression increased bilaterally within the superficial dorsal horn: p < 0.05 versus control Enhanced expression of GFAP was suppressed by treatment of MRS5698: p < 0.05 versus oxaliplatin | ||||
| Kim et al. (2015) [29] | SD rat (spinal cord) | Twice a week for 4 weeks (8 times)/32 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced mechanical allodynia (von Frey test): D21, p < 0.05; D28, p < 0.01 versus control Oxaliplatin induced thermal pain (hot plate test, tail-flick test): D14, p < 0.01 versus control; D21, p < 0.05 versus control; D28, p < 0.001 versus control PC (300 mg/kg, p.o.) treatment decrease mechanical allodynia induced by oxaliplatin: D28, p < 0.05 versus oxaliplatin Increased thermal pain reduced after PC treatment: D21, p < 0.05; D28, p < 0.01 versus oxaliplatin |
| No change in GFAP expression in the spinal cord after oxaliplatin treatment: D28 PC administration decreased the number of Iba1 positive cells increased after oxaliplatin treatment in the spinal cord: D28, 10.00 ± 2.12 (control); 16.67 ± 4.27 (oxaliplatin, p < 0.01 versus control); 11.80 ± 3.11 (PC, p < 0.05 versus oxaliplatin) | ||||
| Mannelli et al. (2015) [30] | SD rat (brain, spinal cord) | D0–4, D7–11, D14–18 (15 times)/36 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced cold hyperalgesia (cold plate test): 21.3 ± 0.8 s (control); 11.5 ± 0.6 s (D21, p < 0.01 versus control) Single PEA (30 mg/kg, i.p.) injection relieved pain for 30–60 min after administration (p < 0.01 versus oxaliplatin) D0–20 PEA (30 mg/kg/day, i.p.) administration decreased mechanical allodynia about 40% (p < 0.05 versus oxaliplatin) Oxaliplatin induced mechanical allodynia (von Frey test): 32.1 ± 1.1 g (control), 21.6 ± 1.1 g (D21, p < 0.01 versus control) D0-20 PEA treatment prevented pain threshold alteration by 55% (p < 0.01 versus oxaliplatin) Oxaliplatin induced mechanical hyperalgesia (paw-pressure test): 69.2 ± 1.7 g (control), 40.5 ± 1.3 g (D21, p < 0.01 versus control); D0-20 PEA treatment, prevented mechanical hyperalgesia by 62% (p < 0.01 versus oxaliplatin) |
| D0–20 PEA treatment decreased increased expression of GFAP-positive cells by 66% in the dorsal horn of the spinal cord: D21, p < 0.05 versus oxaliplatin. Iba1 expression was not changed after oxaliplatin In S1, both GFAP and Iba1 positive cell number increased after oxaliplatin: D21, p < 0.05 versus control D0-20 PEA treatment decreased GFAP and Iba1 positive cell number: D21, p < 0.05 versus oxaliplatin | ||||
| Deng et al. (2016) [31] | Wistar rat (spinal cord) | Twice a week (not mentioned)/36 mg/kg (i.p.) | Ast. | WLT decrease oxaliplatin induced mechanical allodynia (von Frey test, 4 g): D31, 5.00 ± 5.35 (control); 46.25 ± 20.65 (oxaliplatin, p < 0.01 versus control); 16.25 ± 10.61 (WLT, p < 0.05 versus oxaliplatin) WLT decrease oxaliplatin induced mechanical hyperalgesia (von Frey test, 15g): D31, 18.75 ± 8.35 (control); 60.00 ± 16.04 (oxaliplatin, p < 0.01 versus control); 33.75 ± 15.06 (WLT, p < 0.01 versus oxaliplatin) |
| GFAP-positive cell density change (IOD) after oxaliplatin and WLT treatment in the spinal dorsal horn: D31, 0.55 ± 0.07 (control); 1.27 ± 0.33 (oxaliplatin, p < 0.01 versus control); 0.61 ± 0.11 (WLT, p < 0.01 versus oxaliplatin) GFAP-positive cell density change (area μm2) after oxaliplatin and WLT treatment in the spinal dorsal horn: D31, 191.44 ± 171.04 (control); 1366.17 ± 486.86 (oxaliplatin, p < 0.01 versus control); 129.85 ± 54.31 (WLT, p < 0.01 versus oxaliplatin) | ||||
| Kim et al. (2016) [19] | SD rat (spinal cord) | D0 (single)/6 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced cold allodynia (TWL, 4 °C): D3–5, p < 0.001 versus control D0-4 WECC (200, 400 mg/kg, p.o.) administration showed potent analgesic effects: D3–5, p < 0.001 versus oxaliplatin Coumarin decreased oxaliplatin induced cold allodynia: D3 and 5, p < 0.001; D4, p < 0.01 versus oxaliplatin |
| GFAP and Iba1 positive cells in spinal cord (laminae I–II) increased after oxaliplatin injection: p < 0.001 versus control D0–4 WECC (200 mg/kg, p.o.) administration suppressed the change in GFAP and Iba1 positive cells: GFAP (p < 0.001 versus oxaliplatin); Iba1 (p < 0.05 versus oxaliplatin) | ||||
| Pacini et al. (2016) [32] | SD rat (brain, spinal cord) | D0–4, D7–11, D14–18 (15 times)/36 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced mechanical hyperalgesia (paw-pressure test): ± 75 g (control); 60.1 ± 2.0 g (D7, p < 0.05 versus control); 47.4 ± 1.2 g (D14, p < 0.01 versus control); 44.6 ± 2.9 g (D21, p < 0.01 versus control); D0-21 RgIA (10 nmol/100 μL, i.m.) injection prevented pain development: D7, p < 0.05; D14 and D21; p < 0.01 versus oxaliplatin Oxaliplatin induced mechanical allodynia (von Frey test): ± 35 g (control); 20.2 ± 2.3 g (D14, p < 0.01 versus control); 15.0 ± 2.0 g (D21, p < 0.01 versus control); D0–21 RgIA injection increased the threshold (D14 and D21, p < 0.01 versus oxaliplatin) Oxaliplatin induced cold hyperalgesia (cold plate test): ± 23 s (control); 14.7 ± 0.9 g (D7, p < 0.01 versus control); 15.0 ± 0.6 g (D14, p < 0.01 versus control); 10.7 ± 1.6 g (D21, p < 0.01 versus control); D0–21 RgIA significantly delayed the latency (D7, p < 0.05 versus oxaliplatin; D14 and D21, p < 0.01 versus oxaliplatin group) |
| No change in spinal expression of Iba1 after oxaliplatin treatment: D21, 40.7 ± 2.7 (control); 37.0 ± 4.4 (NS versus control) D0–21 RgIA (10 nmol) treatment prevented oxaliplatin-induced GFAP expression increase: 185.1 ± 21.3 (control); 303.0 ± 14.1 (p < 0.05 versus control); 201.3 ± 28.4 (p < 0.05 versus oxaliplatin) RgIA treated rats showed increase in the density of both Iba1 and GFAP expression in the brain: Cg1, Cg2, M1, M2, S1, S2, GI, VPL, mfb, PAG, CA2/CA3 (p < 0.05 versus control) | ||||
| Jung et al. (2017) [20] | SD rat (spinal cord) | D0 (single)/6 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced cold allodynia (TWL, 4 °C): D3, p < 0.05; D5, p < 0.001 versus control Oxaliplatin induced mechanical hypersensitivity (von Frey test): D3 and D5, p < 0.001 versus control D0-5 Buja (300 mg/kg, p.o.) administration prevented the development of cold allodynia (D5, p < 0.001 versus oxaliplatin) and mechanical hypersensitivity (D3 and D5, p < 0.001 versus oxaliplatin) |
| GFAP and Iba1-positive cells increased in the spinal cord after oxaliplatin injection (p < 0.001 versus control) Buja only suppressed GFAP expressions (p < 0.001), but not Iba1 expression in cells increased by oxaliplatin | ||||
| Makker et al. (2017) [33] | C57BL/6J mice (spinal cord) | D0, D2, D4, D6 (4 times)/20 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced mechanical allodynia (von Frey test): D8, p < 0.01 versus control; D13, p < 0.001 versus control; and D16, p < 0.001 versus control |
| No change of GFAP and Iba1 expression in the spinal cord after oxaliplatin injection: D13 Reduction in P2ry12 + homeostatic microglia in the spinal cord: p < 0.001 versus control | ||||
| Mannelli et al. (2017) [34] | SD rat (BrainSpinal cord) | D0–4, D7–11, D14–18 (15 times)/36 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced cold hyperalgesia (cold plate test): 24.1 ± 1.2 s (control); 16.2 ± 0.8 s (oxaliplatin, p < 0.05) Oxaliplatin induced mechanical allodynia (von Frey test): 23.7 ± 1.2 g (control); 13.8 ± 0.9 g (oxaliplatin, p < 0.05) Oxaliplatin induced mechanical hyperalgesia (paw-pressure test): 66.5 ± 1.9 g (control); 40.7 ± 1.8 g (oxaliplatin, p < 0.05 versus control) D0–21 treatment of 50% HA (300 mg/kg, p.o.) attenuated oxaliplatin-induced pain: D21, p < 0.01 versus oxaliplatin |
| Increased number of GFAP but not Iba1 positive cells in the spinal cord after oxaliplatin injection: D21, p < 0.05 versus control; 50% HA reduced the number of GFAP-positive cells: p < 0.05 versus oxaliplatin Oxaliplatin increased both GFAP and Iba1 positive cells in the brain: Cg, S1, M1, PAG, and mfb (p < 0.05 versus control) D0–21 treatment of 50% HA (300 mg/kg, p.o.) reduced the number of the GFAP and Iba1 positive cells except in Cg (Iba1): p < 0.05 versus oxaliplatin | ||||
| Wang et al. (2017) [35] | SD rat (spinal cord) | D0–3 (4 times)/20 mg/kg (i.p.) | Ast. | Oxaliplatin induced mechanical allodynia (von Frey test): D7, p < 0.05 versus control Oxaliplatin induced thermal pain (hot plate test, tail-flick test): D7, p < 0.05 versus control Single melatonin (20 mg/kg, i.p.) injection alleviated pain: D1 and D3, p < 0.05 versus oxaliplatin |
| Enhanced GFAP expression after oxaliplatin treatment: p < 0.05 versus control; hypertrophic with thicker processes Melatonin (20 mg/kg, i.p.) decreased oxaliplatin-induced upregulation of GFAP expressions: p < 0.05 versus oxaliplatin | ||||
| Areti et al. (2018) [36] | SD rat (spinal cord) | Twice a week for 4 weeks (8 times)/32 mg/kg (i.p.) | Ast. | Oxaliplatin induced cold allodynia (acetone spray test): D14–28, p < 0.001 versus control Oxaliplatin induced thermal hyperalgesia (hot/cold plate test): D14–28, p < 0.001 versus control Oxaliplatin induced mechanical hypersensitivity (von Frey test): D14–28, p < 0.001 versus control D0-28 RA (25 and 50 mg/kg, i.p.) treatment attenuated pain: D21–28, p < 0.001 versus oxaliplatin |
| Oxaliplatin increased the GFAP expression in the L4-L6 spinal cord: p < 0.001 versus control D0-28 RA (25 and 50 mg/kg, i.p.) treatment significantly attenuated this increase: p < 0.01 versus oxaliplatin group | ||||
| Tonkin et al. (2018) [37] | C57BL/6J mice (spinal cord) | D0, D2, D4, D6 (4 times)/20 mg/kg (i.p.) | Ast. | Oxaliplatin induced mechanical allodynia (von Frey test, 4g): D13, 2.1 folds; D16, 1.5 folds (p < 0.05 versus control) Cx43 mimetic (Peptide 5, 20 μM) injection had no effect on response rate: p > 0.05 versus control |
| A significant increase in Cx43 protein levels in oxaliplatin treated mice:D13, 2.2 folds, p < 0.05 versus control | ||||
| Wahlman et al. (2018) [38] | SD rat & C57BL/6J mice | D0–4 (5 times)/10 mg/kg (rats, i.p.), D0–4, D10–14 (10 times)/30 mg/kg (mice, i.p.) | Ast. | Oxaliplatin induced mechanical allodynia (von Frey test): D11, D17, and D25, p < 0.05 versus control Oxaliplatin induced mechanical hyperalgesia (paw pressure test): D11, D17, and D25, p < 0.05 versus control ABT-702 (30 nmol, i.t.) injection prevented these pain signs, but A3AR antagonist injection (MRS1523, 1 nmol, i.t.) blocked the effect: D11, D17, and D25, p < 0.05 versus oxaliplatin |
| Increased GFAP expression after oxaliplatin treatment in the spinal dorsal horn: D25, p < 0.05 versus control Increased ADK expression in spinal dorsal horn after oxaliplatin injection: D11 and D25, p < 0.05 versus control No change in the percentage of ADK+ GFAP (co-localization) expression in the spinal cord: 44.49% ± 5.72 (control); 44.97% ± 12.23 (oxaliplatin, p = 0.95 versus control); but the cellular volume of astrocytes occupied by ADK (ADK+ voxels/GFAP+ voxels) increased: 0.20 ± 0.09 (control); 0.42 ± 0.08 (p < 0.05 versus control) Increased ADK signal was found in the astrocyte nucleus and cytoplasm in somas that expanded into processes | ||||
| Hao et al. (2019) [39] | SD rat (spinal cord) | D0–4, D7–11, D14–18 (15 times)/36 mg/kg (i.p.) | Ast. Mic. | Oxaliplatin induced cold allodynia (acetone spray test): D7–21, p < 0.01 versus control Oxaliplatin induced thermal hyperalgesia (hot plate test): D7–21, p < 0.01 versus control Oxaliplatin induced mechanical allodynia (von Frey test): D7–21, p < 0.01 versus control Single Huachansu (2.5 g/kg, i.p.) injection alleviated cold allodynia (D21, p < 0.01 versus oxaliplatin), mechanical allodynia (D7, D14, D21, p < 0.01 versus oxaliplatin), and thermal hyperalgesia (D7, D14, D21, p < 0.01 versus oxaliplatin) D0–19 Huachansu (2.5 g/kg, i.p.) treatment alleviated cold allodynia (D21, p < 0.01 versus oxaliplatin), mechanical allodynia (D21, p < 0.01 versus oxaliplatin), and thermal hyperalgesia (D21, p < 0.01 versus oxaliplatin) |
| Increased GFAP expression in the spinal cord after oxaliplatin injection: D21, p < 0.001 versus control Increased Iba1 expression in the spinal cord after oxaliplatin injection: D21, p < 0.001 versus control D0-19 Huachansu (2.5 g/kg, i.p.) treatment decreased upregulated GFAP expression: p < 0.01 versus oxaliplatin Huachansu failed to block the activation of Iba1 positive cells: p > 0.01 versus oxaliplatin | ||||
| Saika et al. (2019) [40] | Transgenic mice (spinal cord) | D0, D2, D4, D6 (4 times)/20 mg/kg (i.p.) | Mic. | Oxaliplatin-induced mechanical allodynia (von Frey test) Single CNO (10 mg/kg, i.p.) injection did not prevent pain development in male and female CX3CR1-hM4Di mice |
| HA-hM4Di was highly expressed in the SDH of CX3CR1-hM4Di mice In CX3CR1-hM4Di mice, HA-hM4Di overlapped with Iba1 |
Abbreviations: A3AR: A3 adenosine receptor, ABT-702: ABT 702 hydrochloride; 5-(3-Bromophenyl)-7-[6-(4-morpholinyl)-3-pyrido[2,3-d]byrimidin-4-amine hydrochloride, ACC: anterior cingulate cortex, ADK: adenosine kinase, Ast.: astrocytes, CA2: cornu ammonis 2 of hippocampus, CA3: cornu ammonis 3 of hippocampus, CNO: clozapine N-oxide, Cg1: cyngulate cortex area 1, Cg2: cyngulate cortex area 2, CX3CR1-hM4Di: CX3C chemokine receptor 1-human Gi coupled M4 muscarinic receptors, Cx43: connexin43, DL-PAG: dorsolateral periaqueductal grey, DH: dorsal horn, DRG: dorsal root ganglion, GBT: Gyejigachulbu-tang, GFAP: glial fibrillary acidic protein, GI: granular insular cortex, HA: 50% hydroalcoholic 50% extracts of Astragali radix, HA-hM4Di: Hemagglutinin A-human Gi coupled M4 muscarinic receptors Iba1: Ionized calcium binding adaptor molecule 1, IOD: integral optical density, i.p.: intraperitoneal, LPS: lipopolysaccharide, M1: primary motorcortex, M2: secondary motor cortex, Mic.: microglia, mfb: medial forebrain bundle, α7 nAChR: α7 nicotinic acetylcholine receptor, NRM: nucleus raphe magnus, mfb: medial forebrain bundle, NS: non-significant, OX-42: oxycocin-42, p2ry12: purinergic receptor P2Y12, PAG: periaqueductal grey, PC: phosphatidylcholine, PEA: N-Palmitoylethanolamine, (R)-ICH3: (R)-(−)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate, RA: Rosmarinic acid, S1: primary somatosensory cortex, S2: secondary somatosensory cortex, SD rat: Sprague–Dawley rat, SGCs: satellite glial cells, TWL: tail withdrawal latency, VH: ventral horn, VL-PAG: ventrolateral periaqueductal grey, VPL: ventral posterolateral thalamic nucleus, WECC: water extract of cinnamomi cortex, WLT: Wen-luo-tong.