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Acta Pharmacologica Sinica 2005 May; 26 (5): 533–538
©2005 CPS and SIMM 533
Full-length article
Effects of l-tetrahydropalmatine on locomotor sensitization to oxycodone
in mice
Yan-li LIU1, 2, Jian-hui LIANG3, Ling-di YAN1, Rui-bin SU1, Chun-fu WU2, Ze-hui GONG1,4
1Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; 2Department of Pharmacology, Shenyang Pharmaceutica
l
University, Shenyang 110016, China; 3Department of Neuropharmacology, National Institute on Drug Dependence, Peking University,
B
eijing 100083, China
Abstract
Aim: Recent studies have shown that l-tetrahydropalmatine (l-THP), an active
component of Corydolis yanhusuo, can inhibit the development of the condi-
tional place preference induced by opioid receptor agonists, but the effects of l-
THP on locomotor sensitivity induced by opioid receptor agonists have not been
documented. In the present study, the effects of l-THP on locomotor sensitization
to oxycodone, which is an opioid receptor agonist, were studied. Methods: Mice
treated daily for 7 d with 5 mg/kg oxycodone and challenged with the same dose
after 5 days of washout showed locomotor sensitization. In order to study the
effects of l-THP on locomotor sensitization induced by oxycodone, l-THP was
administered at doses of 6.25, 12.5, and 18.75 mg/kg, 40 min prior to treatment o
f
oxycodone. Results: l-THP per se did not affect the locomotor activity at the
doses of 6.25, 12.5, and 18.75 mg/kg, but could antagonize the hyperactivity in-
duced by oxycodone (5 mg/kg). Co-administration of l-THP (18.75 mg/kg), 40 min
p
rior to oxycodone, could inhibit the development of sensitization to oxycodone.
In addition, l-THP (6.25, 12.5, and 18.75 mg/kg, ig) dose-dependently prevented
the expression of oxycodone sensitization. Conclusion: These results suggested
that l-THP could attenuate the locomotor-stimulating effects of oxycodone and
inhibit the development and expression of oxycodone behavioral sensitization.
Key words
l-tetrahydropalmatine; oxycodone; loco-
motor sensitization
4 Correspondence to Prof Ze-hui GONG.
Phn 86-10-6693-1620.
E-mail Gongzeh@yahoo.com.cn
Received 2004-07-17
Accepted 2004-12-30
doi: 10.1111/j.1745-7254.2005.00101.x
Introduction
The term ‘behavioral sensitization’ is used to describe
the augmented behavior activity produced by a given dose
of an opioid-drug after repeated intermittent injections[1].
Recently, the importance of behavioral sensitization in drug
abuse research has been realized. Studies have shown that
behavioral sensitization has a close relationship with relapse,
compulsive drug-seeking and drug-taking behaviors[2–5]. In-
vestigation of sensitization may be helpful for better under-
standing of the relapse mechanisms and for providing new
strategies for the treatment of drug addiction.
Oxycodone (4,5-epoxy-14-hydroxy-3-methoxy-17-methyl-
morphinan-6-one) is a semi-synthetic derivative of the natu-
rally occurring opium alkaloid, thebaine. Oxycodone is an
opioid receptor agonist similar to morphine[6–8]. It is reported
that the abuse potential of oxycodone is equivalent to that
of morphine[9]. It has been found that withdrawal syndrome
may occur in patients when high doses or the chronic treat-
ment of oxycodone is broken or weakened, but the effects of
oxycodone on locomotor behavior sensitivity in animals has
not been documented. Therefore, the present study was
designed to investigate whether acute injection of oxycodone
would induce hyperlocomotor activity and chronic adminis-
tration of oxycodone would induce locomotor sensitization
in mice.
l-Tetrahydropalmatine (l-THP) is an active principle of
Corydolis yanhusuo, a Chinese traditional herb used as an
analgesic[10]. It is reported that l-THP possesses a blocking
effect on dopamine D1 and D2 receptors and voltage-sensi-
tive Ca2+ channels[11]. It has been suggested in recent stud-
ies that l-THP can inhibit physical dependence in morphine-
534
Acta Pharmacologica Sinica ISSN 1671-4083Liu YL et al
dependent mice and significantly reduce the development
of the conditional place preference induced by morphine in
mice[12,13]. However, no research has been carried out on the
effects of l-THP on locomotor sensitization. Therefore, it is
interesting to determine whether pretreatment with l-THP
prior to administration of oxycodone would inhibit the hy-
peractivity induced by oxycodone and prevent the develop-
ment and expression of locomotor activity to oxycodone.
Materials and methods
Animals Kunming mice, initially weighing 18–22 g, were
purchased from the Experimental Animal Center of Beijing
Institute of Pharmacology and Toxicology. The animals were
fed ad libitum and were housed in a room with a controlled
ambient temperature (22±2 oC), humidity (50%±10%), and a
12-h light/dark cycle. Animals were acclimated to the hous-
ing conditions and handled for 3–4 d before experiments. All
experiments were performed between 08.00 h and 16.00 h. All
experiments were conducted according to the NIH Guide for
the Care and Use of Laboratory Animals (NIH Publications
No. 80-23, revised 1996). The experimental procedures were
approved by the local Committee on Animal Care and Use.
Drugs Oxycodone, obtained from Beijing Four-Ring Phar-
maceutical Factory (Beijing), was dissolved in 0.9% saline
injected subcutaneously. l-THP, kindly provided by Profes-
sor Guo-zhang JIN (Shanghai Insititute of Materia Medica,
Chinese Academy of Sciences), was dissolved in distilled
water and administered intragastrically.
Apparatus Locomotor activity was counted automati-
cally with Small Animal Locomotion Recording Apparatus
(Institute of Materia Medica, Chinese Academy of Medical
Science), which consisted of four boxes (20 cm in diameter
and 15 cm in height) with six photoelectric infrared sensors 2
cm above the floor of each box. The sensors detect the
movements of the mice through infrared radiation.
Experimental procedures
Acute effects of oxycodone on locomotor activity in mice
Mice were put into the test boxes immediately after treat-
ment with saline or oxycodone (1.25, 2.5, and 5.0 mg/kg, sc).
Locomotor counts were measured every 10 min for 90 min.
Development of locomotor sensitivity to oxycodone in
mice Two groups of 10 mice each were given oxycodone or
saline for 7 consecutive days, and their activity was mea-
sured for 60 min immediately after each administration. The
experimental period for the 7 d remained at approximately the
same time everyday during the daytime.
Effects of acute and chronic l-THP on locomotor activity
in mice Four groups of mice were given l-THP (6.25, 12.5,
and 18.75 mg/kg) or saline, respectively, once per day for 7
consecutive days, followed by a 5-d withdrawal period. On
d 13, all animals were challenged with saline. On d 1, 7, and
13, after 40-min treatment with l-THP or saline, the mice were
put into the test boxes and locomotor activity was moni-
tored for 60 min.
Effects of l-THP on the acute oxycodone-induced hyper-
activity in mice Five groups of mice were administered with
one of the following drug pairs: saline+saline, saline+oxyco-
done, and l-THP (6.25, 12.5, and 18.75 mg/kg)+oxycodone
with a 40-min interval between the two treatments. After the
second treatment, the mice were put into the test boxes to
record their locomotor activity for 60 min.
Effects of l-THP on the development of oxycodone
sensitization To assess the effects of l-THP on the devel-
opment of oxycodone sensitization, five groups of mice were
administered for 7 consecutive days with one of the follow-
ing drug pairs: saline+saline, saline+oxycodone, and l-THP
(6.25, 12.5, and 18.75 mg/kg)+oxycodone. The interval be-
tween l-THP and oxycodone injections was 40 min, with
l-THP given prior to the oxycodone. After 5 washout periods,
all animals were injected with oxycodone (5 mg/kg) and then
put into the test chambers to record their locomotor activity
for 60 min.
Effects of l-THP on the expression of oxycodone sensitiza-
tion Mice were injected with 5 mg/kg oxycodone for 7 con-
secutive days to induce locomotor sensitization. After 5 days
of washout, the mice were challenged with 5 mg/kg oxyco-
done, and with either saline or l-THP (6.25, 12.5, and 18.75 mg/
kg), given 40 min prior to the oxycodone challenge. The
locomotor activity of the mice was then measured for 60 min.
Statistics The results were expressed as the mean±SEM.
In experiment acute effects of oxycodone on locomotor activity
in mice and development of locomotor sensitivity to oxycodone
in mice locomotor activity was analyzed using a two-way
ANOVA. Post hoc comparisons were performed using Tukey’s
test. For the other experiments, statistical analyses were per-
formed using one-way ANOVA and a post hoc Tukey’s test.
P<0.05 was considered statistically significant. Calculations
were performed using the SPSS statistical package.
Results
Acute effects of oxycodone on locomotor activity in mice
Mice were given saline, oxycodone (1.25, 2.5, or 5 mg/kg),
then locomotor activity was monitored for 90 min. Locomo-
tor acounts showed a great difference between saline-treated
Http://www.chinaphar.com Liu YL et al
535
mice and oxycodone-treated mice. Oxycodone dose-depen-
dently induced locomotor response in mice during the 90-
min test session [F (treatment) (3, 33)=16.598, P<0.01; F
(treatment×time) (24, 424)=6.080, P<0.01]. During the first
and the last 10 min, there was a significant difference be-
tween the saline-treated and oxycodone-treated group (5
mg/kg, sc). The climax of oxycodone-induced hyperactivity
appeared approximately 30–40 min after the treatment of
oxycodone. The psychomotor effect of 5 mg/kg oxycodone
lasted about 90 min, and 1.25, 2.5 mg/kg oxycodone increased
locomotor activity only at some time points (Figure 1).
Development of locomotor sensitivity to oxycodone in
mice Figure 2 showed the total 60-min activity counts after
7 repeated administrations of oxycodone or saline to the
mice in the test boxes. The activity counts were dependent
on the drug [F (1,126) =20.764, P<0.01] and number of admin-
istrations [F (6,126)=73.246, P<0.01]. There was a significant
interaction between the drug given and the number of ad-
ministrations [F (6,126)=45.00, P<0.01]. The locomotor ac-
tivity showed significant enhancement in the fourth injec-
tion compared to the initial injection. There was no signifi-
cant difference among saline groups.
Effects of acute and chronic l-THP on locomotor activity
in mice Mice were given l-THP (6.25, 12.5, and 18.75 mg/kg,
ig) for 7 consecutive days, then subjected to withdrawal from
l-THP for 5 d. On d 13, all animals were challenged with saline.
On d 1, 7, and 13, 40 min after injection of l-THP or saline, the
mice were put into the test boxes and locomotor counts were
measured for 60 min. On d 1 and 7, there was no difference
between the l-THP groups (6.25, 12.5, and 18.75 mg/kg) and
saline group [F (3, 37)=1.360, P>0.05, F (3, 37)=0.348, P>
0.05, respectively]. On d 13, there was also no significant
difference between l-THP groups and saline groups after
administration of saline [F (3, 37)=1.532, P>0.05]. These
results indicated that acute or chronic pretreatment with
l-THP at the dose of 6.25, 12.5, and 18.75 mg/kg might not
affect locomotor activity in mice (Figure 3).
Effects of l-THP on acute oxycodone-induced hyperactiv-
ity in mice Locomotor counts were greatly increased in the
oxycodone group compared with the saline group. l-THP at
doses of 6.25, 12.5, and 18.75 mg/kg antagonized hyperac-
tivity induced by oxycodone [F (4, 60)=15.76, P<0.01]
(Figure 4).
Effects of l-THP on the development of oxycodone sensi-
tization Figure 5 showed that the psychomotor effect of
oxycodone was significantly enhanced in mice pretreated
with oxycodone (5 mg/kg×7, sc), 5 d cessation of treatment.
l-THP (6.25, 12.5 mg/kg) did not affect the magnitude of
sensitization, but there was a marked difference between
oxycodone+oxycodone group and l-THP (18.75 mg/kg)
+oxycodone+oxycodone group, indicating that l-THP
(18.75 mg/kg) greatly inhibited the development of
oxycodone sensitization [F (4, 62) =8.766, P<0.01].
Effects of l-THP on expression of oxycodone sensitiza-
tion Our protocol induced great locomotor sensitization to
oxycodone in oxycodone+oxycodone group compared to the
saline+oxycodone group. There were great differences
between oxycodone+oxycodone group and l-THP (6.25, 12.5,
18.75 mg/kg)+oxycodone+oxycodone groups [F (4, 65)=
Figure 1. Acute effects of oxycodone on locomotion in mice. Mice were
put into the test boxes immediately after treatment with saline or
oxycodone (1.25, 2.5, and 5.0 mg/kg, sc). Locomotor counts were
measured for 90 min. Mean±SEM. n=10–12. bP<0.05, cP<0.01 vs
saline group.
Figure 2. The development of locomotion sensitivity to oxycodone in
mice. Two groups of 10 mice each were given oxycodone or saline for 7
consecutive days and their locomotor activity was measured immediately
for 60 min after each administration. The experimental time remained
approximately at the same time everyday during the daytime. Mean±SEM.
n=10. cP<0.01 vs saline group. eP<0.05, fP<0.01 vs the first admin-
istration within group.
536
Acta Pharmacologica Sinica ISSN 1671-4083Liu YL et al
over 80 years, but its pharmacological properties are still poorly
characterized. The present results showed that the repeated
administration of oxycodone in mice induced behavioral loco-
motor sensitization similar to morphine.
l-THP, an active principle of Corydolis yanhusuo, at doses
of 6.25, 12.5, and 18.75 mg/kg per se did not affect locomotor
activity in mice treated with acute or chronic administration,
but inhibited hyperactivity, and the development and ex-
pression of locomotor sensitivity induced by oxycodone (5
mg/kg, sc).
Figure 3. Effects of acute and chronic l-THP on locomotor activity in
mice. Mice were given l-THP (6.25, 12.5, and 18.75 mg/kg) or saline
once per day for 7 consecutive days, followed by a 5-d withdrawal
period. On d 13, all mice were challenged with saline. On d 1, 7, and
13, 40 min after treatment with l-THP or saline, the mice were put
into test boxes and locomotor activity was monitored for 60 min.
n=10 in each group. Mean±SEM.
Figure 4. Effects of l-THP on the acute oxycodone-induced hyperactiv-
ity in mice. Five groups of mice were administered with one of the fol-
lowing drug pairs: saline+saline, saline+oxycodone, and l-THP (6.25,
12.5, and 18.75 mg/kg)+oxycodone with a 40-min interval between
the two treatments. After the second treatment, the mice were put
into the test boxes for recording of their locomotor activity for 60
min. n=10–12. Mean±SEM. cP<0.01 vs saline+saline group. eP<0.05,
fP<0.01 vs saline+oxycodone group.
Figure 5. Effects of l-THP on the development of oxycodone
locomotor sensitization. Mice were administered for 7 consecutive
days with one of the following drug pairs: saline+saline, saline+
oxycodone, and l-THP (6.25, 12.5, and 18.75 mg/kg)+oxycodone.
The interval between l-THP and oxycodone injections was 40 min,
with l-THP given prior to the oxycodone. After 5 washout period,
all animals were injected with oxycodone (5 mg/kg) and then put into
the test chambers to record their locomotor activity for 60 min.
n=12–14. Mean±SEM. bP<0.05, cP<0.01 vs saline+oxycodone group.
eP<0.05 vs oxycodone+oxycodone group.
Figure 6. Effects of l-THP on the expression of oxycodone
sensitization. Mice were injected with 5 mg/kg oxycodone for 7
consecutive days to induce behavioral sensitization. After 5 d of
washout, all mice were challenged with 5 mg/kg oxycodone, and with
either saline or l-THP (6.25, 12.5, 18.75 mg/kg), given 40 min prior
to the oxycodone challenge. The locomotor activity of the mice
was then measured for 60 min. n=12–14. Mean±SEM. bP<0.05 vs
saline+oxycodone group. fP<0.01 vs oxycodone+oxycodone group.
24.128, P<0.01]. In all, l-THP (6.25, 12.5, and 18.75 mg/kg),
administered 40 min before the challenge doses of oxycodone,
inhibited the expression of oxycodone sensitization (Figure 6).
Discussion
In our research, acute administration of oxycodone in-
creased locomotor activities in mice and those effects were
progressively enhanced by the repeated injection of
oxycodone, indicated by the development of behavioral loco-
motor activity (Figure 1). In addition, locomotor activities
were increased when the mice were treated with oxycodone
after a 7-d period of washout, which attributed to the expres-
sion phase (Figure 2). Oxycodone has been used clinically for
Http://www.chinaphar.com Liu YL et al
537
Behavioral sensitization consists of two phases: devel-
opment/induction and expression. There is evidence sug-
gesting that the induction and the expression of sensitiza-
tion to opioids involve different anatomical and physiologi-
cal mechanisms. The development of sensitization consists
of the immediate molecular and/or cellular effects that in-
duce behavioral sensitization and are altered by drug ac-
tions in the somatodendritic regions of the A10/A9 dopam-
ine neurons[14]. Changes in dopamine transmission within
the nucleus accumbens seems to be responsible for the ex-
pression of sensitization, which refers to the long-term con-
sequences of molecular and/or cellular effects that induce
behavioral sensitization[14]. The present results demonstrated
that pretreatment with l-THP not only inhibited the
development, but also inhibited the expression of oxycodone.
It has been hypothesized that dopamine (DA) is one of
the important neurotransmitters involved in locomotion.
Measurement of spontaneous locomotor activity has been
used to obtain preliminary information on the behavioral prop-
erties of drugs acting on dopaminergic system[15,16]. Mor-
phine is known to activate ventral tegmental area dopamine
neurons indirectly as a consequence of inhibiting non-
dopamine, presumably γ-GABA, neurons of the ventral teg-
mental area, leading to increased dopamine release in the
nucleus accumbens[17]. Direct infusions of morphine or µ-
receptor-selective peptides into the ventral tegmental area
elicit locomotion, which can be blocked by DA receptor an-
tagonist administration into the nucleus accumbens. Fol-
lowing repeated administration of morphine, there is a marked
increase in the induction of locomotor-stimulating effects of
morphine, there is general agreement that the mesoac-
cumbens DA system is the anatornical locos for sensitized
locomotion[18]. Kalivas and Stewart (1991) presented pre-
liminary results showing that either systemic or intra-ventral
tegmental area administration of sch23390 prevented sensi-
tization to systemic morphine, when the combinations were
given every other day for 8 d. They also suggested DA D1
receptor involvement in the development of morphine sensi-
tization[14]. In other studies, the blockade of the dopamine D2
receptor by haloperidol significantly antagonized the effects
of opioid on locomotor activity[19]. Thus, dopamine D1 and
D2 receptors play important roles in the acceleration of opioid
sensitization[20]. Although the mechanisms of action through
which l-THP attenuates the psychomotor effect of oxycodone
are not clear, one reason maybe relevant to dopamine D1 and
D2 receptors, which are involved in oxycodone-induced hy-
peractivity and locomotor sensitivity. l-THP, which has af-
finity for D1 as well as D2 receptors, is a dopamine receptor
antagonist[11]. l-THP may inhibit mesolimbic dopamine D1
and D2 receptors and attenuate psychomotor effects of
oxycodone. Our recent studies also showed that oxycodone
(2.5 mg/kg, sc) increased dopamine concentrations of dialy-
sates with microdialysis in the striatum of rat. l-THP (25 mg/
kg, ig) per se, did not affect dopamine release, but pretreat-
ment of rats with l-THP (25 mg/kg, ig) significantly inhibited
oxycodone-induced increases in extraceullar dopamine con-
centrations [F(3,18)=5.068, P<0.05] (Liu et al, unpublished data,
2004). These results indicate that the inhibiting locomotor
sensitivity effect of l-THP might be connected with the DA
system. l-THP could inhibit dopamine release in the
mesolimbic system, induced by oxycodone, and then inhibit
the development and expression of locomotor sensitization.
Another reason might be connected with L-type Ca2+
channels. Recent reports show that L-type Ca2+ channels
may play an important role in the development of morphine
behavioral sensitization. Co-administration with L-type Ca2+
channel blockers attenuates the development of morphine
tolerance, dependence, and sensitization, suggesting that
the L-type Ca2+ channel might play a role in morphine-in-
duced neural and behavioral plasticity[21,22]. In contrast,
L-type Ca2+ channel blockers have antidopaminergic prop-
erties[23]. L-type Ca2+ channel blockers such as nimodipine,
nifedipine, and verapamil, dose-dependently antagonize apo-
morphine-induced yawning and penile erections in rats[24,25].
Nimodipine and verapamil inhibits locomotor activity induced
by morphine[26]. Therefore, L-type Ca2+ channel blockers
could attenuate morphine-induced hyperactivity through an
antidopaminergic action. The inhibitory effect of l-THP on
the development and expression of sensitivity of oxycodone
might also be a result of the inhibitory effect of l-THP on
L-type Ca2+ channel. Previous studies show that l-THP is
also an L-type calcium antagonist. Using the patch-clamp
technique, l-THP causes both tonic and use-dependent re-
duction of Ca2+ current in single ventricular myocytes of
guinea pigs, has a moderate inhibitory effect on L-type Ca2+
current, and has inhibitory effects on [Ca2+]i in myocytes by
blocking voltage-dependent calcium channels similar to
verapamil[27–29]. Therefore, the inhibitory effect of l-THP on
L-type Ca2+ channel might be included in mechanisms of
action through which l-THP attenuated locomotor sensitiza-
tion to oxycodone.
In conclusion, the present data indicates that l-THP at-
tenuated psychomotor effects of oxycodone, and the devel-
opment and expression of locomotor sensitivity of oxyco-
done. The exact mechanisms of the inhibitory effect of
l-THP on oxycodone sensitivity need further investigation.
538
Acta Pharmacologica Sinica ISSN 1671-4083Liu YL et al
Acknowledgement
We thank Prof Guo-zhang JIN for kindly providing l-THP.
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