Oleanolic Acid Attenuates Morphine Withdrawal Symptoms in Rodents: Association with Regulation of Dopamine Function

Figures & data

Figure 1 The morphine-dependent rat model (Spontaneous withdrawal) and treatment of OA.

Figure 2 The morphine-dependent rat model (Naloxone-precipitated withdrawal) and treatment of OA.

Figure 3 The morphine-dependent mouse model (Naloxone-precipitated withdrawal) and treatment of OA.

Figure 4 The experimental steps of CPP.

Figure 5 Effect of OA on spontaneous withdrawal score of morphine dependent rats, presented as mean ± SEM. 2h after treatment on the 1st (d1), 3rd (d3), and 5th day (d5). **P<0.01 significant differences compared with the normal control group. ^##P<0.01 compared with the model group. ^∆∆P<0.01 compared with the clonidine group. ^☆☆P<0.01 compared with the Jitai group.

Figure 6 Effect of OA on the weight of spontaneous withdrawal morphine-dependent rats, presented as mean ± SEM. 2h after treatment on the 1st (d1), 3rd (d3), and 5thday (d5). “Before” means before administration of OA. **P<0.01 significant differences compared with the normal control group. ^#P<0.05, ^##P<0.01 compared with the model group.

Figure 7 Effect of OA on serum 5-HT and DA levels in morphine-dependent rats with spontaneous withdrawal, presented as mean ± SEM. **P<0.01 significant differences compared with the normal control group. ^##P<0.01 compared with the model group. ^∆P<0.05 compared with the clonidine group. ^☆P<0.05, ^☆☆P<0.01 compared with the Jitai group.

Figure 8 Effect of OA on withdrawal score of morphine dependent rats, presented as mean ± SEM. 2h after treatment on the 1st (d1), 3rd (d3), and 5th day (d5). “Before” means before administration of OA. **P<0.01 significant differences compared with the normal control group. ^#P<0.05, ^##P<0.01 compared with the model group. ^∆P<0.05, ^∆∆P<0.01 compared with the clonidine group. ^☆P<0.05, ^☆☆P<0.01 compared with theJitai group.

Table 1 The Effect of OA on the Content of NE, 5-HT and Endorphin in the Frontal Cortex of Morphine-Dependent Rats

Groups	NE	5-HT	Endorphin
	ng/mg	ng/mg	ng/mg
Normal control	0.46±0.04	0.42±0.08	0.13±0.01
Model	1.98±0.09**	1.74±0.15**	0.06±0.01**
Clonidine	0.73±0.09^##	0.97±0.11^##	0.11±0.01^##
Jitai Tablet	1.29±0.10^##∆	1.30±0.12^#	0.10±0.01^##
OA-hyper(28.0)	0.69±0.08^##☆☆	0.97±0.07^##	0.11±0.01^##
OA-high(14.0)	1.00±0.10^##☆	1.09±0.12^##	0.10±0.01^##
OA-Mid(7.0)	0.83±0.05^##☆☆	1.06±0.13^##	0.11±0.01^##
OA-Low(3.5)	1.30±0.09^##∆∆	1.12±0.15^##	0.10±0.01^##
OA-ultralow(1.75)	1.50±0.11^##∆∆	1.40±0.15^#	0.10±0.01^##

Notes: **P<0.01 significant differences compared with normal control group. ^#P<0.05, ^##P<0.01 compared with model group. ^∆P<0.05, ^∆∆P<0.01 compared with Clonidine group. ^☆P<0.05, ^☆☆P<0.01 compared with Jitai Tablet.

Table 2 Effect of OA on the Withdrawal of Morphine Dependent Mice

Groups	Times of Jump Response (Times)	Weight Loss (g)
Normal control	2.20±0.25	0.20±0.03
Model	48.00±2.99**	0.89±0.04**
Clonidine	40.00±2.50^#	0.53±0.04^##
Jitai Tablet	40.00±1.94^#	0.57±0.03^##
OA-high(20)	31.00±2.54^##∆∆☆☆	0.36±0.03^##∆∆☆☆
OA-Mid(10)	32.60±2.32^##∆∆☆☆	0.49±0.03^##
OA-Low(5)	37.80±2.27^##	0.53±0.03^##

Notes: **P<0.01 significant differences compared with normal control group. ^#P<0.05, ^##P<0.01 compared with model group. ^∆∆P<0.01 compared with Clonidine group. ^☆☆P<0.01 compared with Jitai Tablet.

Table 3 Effect of OA on the Acquisition of Morphine-Induced CPP

Groups	Time in the White Compartment	DA
	(s)	(ng/mL)
Normal control	391.12±16.44	67.63±3.01
Model	571.47±15.82**	196.11±8.14**
Clonidine	449.40±22.62^##	88.85±10.27^##
Jitai Tablet	492.02±17.06^#	149.69±10.40^##
OA-high(20)	455.89±29.11^##☆	99.92±5.41^##☆☆
OA- Mid(10)	439.54±26.36^##☆☆	84.55±8.89^##☆☆
OA- Low(5)	508.61±28.81^#∆	118.68±10.68^##∆∆☆☆

Notes: **P<0.01 significant differences compared with normal control group. ^#P<0.05, ^##P<0.01 compared with model group. ^∆P<0.05, ^∆∆P<0.01 compared with Clonidine group. ^☆P<0.05, ^☆☆P<0.01 compared with Jitai Tablet.