Vinpocetine and piracetam exert antinociceptive effect in visceral

Vinpocetine and piracetam exert antinociceptive

effect in visceral pain model in mice

Omar M.E. Abdel Salam

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Abstract:

The effect of vinpocetine or piracetam on thermal and visceral pain was studied in mice. In the hot plate test, vinpocetine (0.9 and

1.8 mg/kg), but not piracetam, produced a reduction in nociceptive response. Vinpocetine (0.45–1.8 mg/kg, ip) or piracetam

(75–300 mg/kg, ip) caused dose-dependent inhibition of the abdominal constrictions evoked by ip injection of acetic acid. The effect

of vinpocetine or piracetam was markedly potentiated by co-administration of propranolol, guanethidine, atropine, naloxone,

yohimbine or prazosin. The marked potentiation of antinociception occurred upon a co-administration of vinpocetine and baclofen

(5 or 10 mg/kg). In contrast, piracetam antagonized antinociception caused by the low (5 mg/kg), but not the high (10 mg/kg) dose of

baclofen. The antinociception caused by vinpocetine was reduced by sulpiride; while that of piracetam was enhanced by haloperidol

or sulpiride. Either vinpocetine or piracetam enhanced antinociception caused by imipramine. The antinociceptive effects of

vinpocetine or piracetam were blocked by prior administration of theophylline. Low doses of either vinpocetine or piracetam

reduced immobility time in the Porsolt’s forced-swimming test. This study indicates that vinpocetine and piracetam possess visceral

antinociceptive properties. This effect depends on activation of adenosine receptors. Piracetam in addition inhibits GABA-mediated

antinociception.

Key words:

vinpocetine, piracetam, thermal pain, visceral pain, mice

Introduction

Piracetam, the first of the pyrrolidone derivatives

(2-oxopyrrolidine), is a widely used drug in the treat-

ment of cerebral stroke [20], dementia or cognitive

impairment in the elderly [41], and myoclonus epi-

lepsy [10]. The drug reverses hippocampal membrane

alterations in Alzheimer’s disease [8]. Vinpocetine,

a synthetic derivative of the alkaloid vincamine hav-

ing antianoxic, antiischemic and neuroprotective

properties, is frequently used in the therapy of cere-

bral disorders of vascular origin [11]. Although both

drugs belong to distinct chemical classes, they share

the name nootropic, the term introduced by Giurgea

[16], to indicate this category of drugs that enhance

memory, facilitate learning and protect memory pro-

cesses against conditions which tend to disrupt them.

Despite the fact that piracetam and vinpocetine

have been used in clinical practice for around three

decades, their precise mechanism of action within the

brain remains largely unknown. Enhancement of oxi-

dative glycolysis, anticholinergic effects, positive ef-

fects on the cerebral circulation, effects on membrane

physics, and also reduction of platelet aggregation

and improvement in erythrocyte function are likely to

account for a cognition-enhancing effect and a neuro-

protective effect of piracetam in stroke [36]. On the

other hand, vinpocetine is a potent vasodilator at the

cerebral vascular bed, increasing cerebral blood flow,

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that increases the regional cerebral glucose uptake

and, to a certain extent, glucose metabolism in the

so-called peri-stroke region as well as in the relatively

intact brain tissue [40]. Vinpocetine has been found to

interfere with various stages of the ischemic cascade:

adenosine triphosphate (ATP) depletion, activation of

voltage-sensitive Na+- and Ca++-channels, glutamate

and free radicals release [17].

Apart from their cognitive enhancing properties,

both drugs are likely to possess other important phar-

macological properties. Gastric protective effects

have been described for vinpocetine [28], whereas pi-

racetam has been suggested to exert anti-inflammatory

properties [27]. Prolonged consumption of piracetam

resulted in a 3-fold decrease in beta-endorphin con-

centration in plasma of rats [39], but its ip administra-

tion (100 mg/kg) inhibited gamma aminobutyric acid

(GABAergic) antinociception caused by baclofen

[13]. Nefiracetam, a new member of the piracetam

group of cognition enhancers, reversed the thermal hyper-

algesia observed in nerve-injured mice and the thermal

hyperalgesia observed in streptozotocin-induced diabetic

mice [33].

Vinpocetine is capable of blocking NaV1.8 sodium

channel activity, which suggests a potential additional

utility of the drug in various sensory abnormalities

arising from abnormal peripheral nerve activity [44].

The above data suggest that these nootropic drugs are

likely to modulate nociception and might prove useful

in certain types of pain. In the light of the above and

since the nootropic agents vinpocetine and piracetam

are widely prescribed for the pharmacotherapy of

memory and neurodegenerative disorders, it, there-

fore, looked pertinent to investigate and compare the

pharmacological effects of piracetam and vinpocetine

in two experimental pain models in mice: the acetic

acid-induced writhing response, a model of visceral

inflammatory pain (chemonociception), and the tail-

flick test, a model of supraspinal analgesia. Moreover,

the effect of the two drugs on locomotor activity and

their potential antidepressant effect were evaluated.

Materials and Methods

Animals

Male albino Swiss mice 20–22 g of body weight were

used. Standard laboratory food and water were pro-

vided ad libitum. All experimental procedures were

conducted in accordance with the guide for the care

and use of laboratory animals and were reviewed by

the Local Animal Care and Use Committee. The

doses of vinpocetine or piracetam used in the study

were based upon the human dose after conversion to

that of rat [31].

Hot-plate assay

The hot-plate test was performed by using an elec-

tronically controlled hot plate (Ugo Basile, Italy)

heated to 52 ± 0.1°C). The cut-off time was 30 s.

Groups of mice (n = 6/group) were given vinpocetine

(0.45, 0.9 or 1.8 mg/kg, sc, 0.2 ml, n = 6/group) or pi-

racetam (75, 150 or 300 mg/kg, sc, 0.2 ml) or saline

(control), 30 min prior to testing. The experimenter

was blind to the dose. Latency to lick a hind paw or

jump out of the apparatus was recorded for the control

and drug-treated groups.

Abdominal constriction assay

Separate groups of 6 mice each were given vinpocet-

ine (0.45, 0.9 or 1.8 mg/kg, ip, 0.2 ml), piracetam (75,

150 or 300 mg/kg, ip, 0.2 ml), indomethacin

(20 mg/kg, ip, 0.2 ml) or saline (0.2 ml, ip, control).

Unless otherwise indicated in the text, drugs or saline

were administered 30 min prior to an ip injection of

0.2 ml of 0.6% acetic acid [22]. Each mouse was then

placed in an individual clear plastic observational

chamber, and the total number of writhes experienced

by each mouse was counted for 30 min after acetic

acid administration by an observer who was not aware

of the animals’ treatment. Afterwards, animals were

sacrificed by CO2 exposure.

Further experiments were designed in an attempt to

elucidate the mechanisms by which vinpocetine or pi-

racetam exerts its anti-nociceptive effect. The dose of

1.8 mg/kg of vinpocetine or 300 mg/kg of piracetam

was then selected to be used in the subsequent experi-

ments.

Thus, we examined the effects of co-administration

of the �-1 adrenoceptor antagonists prazosin (2 mg/kg,

ip) and doxazosin (4 or 16 mg/kg, ip), �-2 adrenocep-

tor antagonist yohimbine (4 mg/kg, ip), �-adrenocep-

tor antagonist, propranolol (2 mg/kg, ip), muscarinic

acetylcholine receptor antagonist atropine (2 mg/kg

ip), non-selective opioid receptor antagonist naloxone

(5 mg/kg ip), GABA agonist baclofen (5 or 10 mg/kg)

�� 681

Antinociception by vinpocetine and piracetam��

and ATP-gated potassium channel blocker glibencla-

mide (5 mg/kg, ip) on antinociception caused by vin-

pocetine or piracetam. Drugs were administered

30 min prior to the abdominal constriction assay.

The effect of adrenergic neuron blockade with

guanethidine (16 mg/kg, ip) co-administered with ei-

ther vinpocetine or piracetam was also investigated.

The abdominal constriction assay was carried out

30 min after the administration of vinpocetine or pi-

racetam.

In addition, the effect of the non-selective adeno-

sine receptor antagonist theophylline (20 mg/kg ip) or

the nonsteroidal anti-inflammatory drug indometha-

cin (20 mg/kg, ip) was examined. Theophylline or

indomethacin was administered 30 min prior to vin-

pocetine or piracetam (60 min prior to the abdominal

constriction assay).

In further experiments, the effect of co-

administration of the centrally acting dopamine D2

receptor antagonists, sulpiride (10 or 20 mg/kg, ip)

and haloperidol (0.5, 1.5 or 3 mg/kg, ip) or D2 recep-

tor agonist bromocryptine (1.5 or 3 mg/kg, ip) on vin-

pocetine (1.8 mg/kg, ip) or piracetam (300 mg/kg, ip)

antinociception was examined. Lastly, the effect of

vinpocetine or piracetam on antinociception caused

by the tricyclic agent imipramine was studied.

Rota-rod test

Motor performance in mice was measured as the la-

tency to fall from an accelerating rota-rod located

over plates connected to an automatic counter (Ugo

Basile, Varese, Italy). Mice were trained to remain on

a rotating rod for 2 min as the rod rotated toward the

animal. After the 2-min training period, the mice were

administered vehicle (saline) or drugs (sc) and 30 min

later were placed on the rotating rod as it accelerated

from 4 to 40 rpm over 5 min and the time they could

remain on the accelerating rod was recorded [25]. The

cut-off time was 600 s. The time was measured from

the start of the acceleration period. The test was re-

peated 2 h after vehicle or drug injection. Six animals

were used per dose and for the controls.

Porsolt’s forced-swimming test

In this test, a commonly used tool for screening of po-

tential antidepressants, the floating time, which is

considered as the measure of despair, is decreased by

the administration of antidepressant drugs [32].

Briefly, each mouse was placed individually in a glass

cylinder (diameter 12 cm, height 24 cm) filled with

water to a height of 12 cm. Water temperature was

maintained at 24–25°C. The animal was forced to

swim for 6 min and the duration of immobility was

measured. The mouse was considered as immobile

when it stopped struggling and moved only to remain

floating in the water, keeping its head above water

[32].

In two separate sets of experiments, the floating

time was recorded after treatment with different doses

of vinpocetine (0.45–1.8 mg/kg, sc) or piracetam

(37.5–300 mg/kg, sc) and compared to that of imi-

pramine (15 mg/kg, sc). The control group received

saline. In the third set of experiments, the possible

modulation of the antidepressant effect of imipramine

(15 mg/kg, sc) by either vinpocetine (1.8 mg/kg, sc)

or piracetam (300 mg/kg, sc) or the possible effect of

combined vinpocetine (1.8 mg/kg, sc) and piracetam

(300 mg/kg, sc) administration was investigated.

Drugs

Vinpocetine (Vinporal, Amrya. Pharm. Ind., Cairo,

ARE), piracetam (Nootropil, Chemical Industries De-

velopment; CID, Cairo, ARE), guanethidine, propra-

nolol hydrochloride, yohimbine hydrochloride, na-

loxone hydrochloride (Sigma, St. Louis, USA), imi-

pramine hydrochloride, bromocryptine (Novartis

Pharma, Cairo, ARE), amitriptyline hydrochloride,

haloperidol, indomethacin (Kahira Pharm & Chem.

IND Co., Cairo, ARE), glibenclamide (Hoechst Ori-

ent, Cairo, ARE), atropine sulfate, baclofen (Misr

Pharm Co., Cairo, ARE), domperidone (Janssen-

Cilag, Switzerland), clozapine (APEX Pharma, Cairo,

ARE) were used. Analytical-grade glacial acetic acid

(Sigma, St. Louis, USA) was diluted with pyrogen-

free saline to provide a 0.6% solution for ip injection.

All drugs were dissolved in isotonic (0.9% NaCl) sa-

line solution immediately before use.

Statistical analyses

Data are expressed as the mean ± SE. Differences be-

tween vehicle control and treatment groups were

tested using one- and two-way ANOVA followed by

Duncan’s multiple comparison test. When there were

only two groups, a two-tailed Student’s t-test was

used. A probability value less than 0.05 was consid-

ered statistically significant.

682 ��

Results

Effect of vinpocetine or piracetam on thermal

nociception

The mean reaction time in the hot plate test was sig-

nificantly delayed at 30 min after the administration

of vinpocetine at doses of 0.9 mg/kg or 1.8 mg/kg,

compared with basal (pre-drug) values, denoting de-

creased nociception (p < 0.05, one way ANOVA). Pi-

racetam given at doses of 75–300 mg/kg failed to af-

fect the nociceptive response (Fig. 1).

Effect of vinpocetine or piracetam on visceral

nociception

Either vinpocetine (0.45, 0.9 or 1.8 mg/kg) or pi-

racetam (75, 150 or 300 mg/kg) inhibited the number

of writhes induced by ip acetic acid administration in

mice in a dose-dependent manner. The degree of inhi-

bition was 42.3, 53, 63.9% for vinpocetine at 0.45, 0.9

or 1.8 mg/kg (Fig. 2A) and 48.1, 51.3, 76.8% for pi-

racetam at 75, 150 or 300 mg/kg, respectively (Fig. 2B).

In comparison, the non-steroidal anti-inflammatory drug

indomethacin (20 mg/kg) decreased the number of ab-

dominal constrictions by 54.9%.

Investigation of the mechanism of visceral

antinociception by vinpocetine or piracetam

Figures 3–5 show the effect of the �-2 adrenoceptor

antagonist yohimbine (4 mg/kg) and �-1 adrenoceptor

antagonists prazosin (2 mg/kg) and doxazosin

(16 mg/kg) on the nociceptive responses. The admini-

stration of prazosin or doxazosin caused a marked re-

duction in the number of abdominal constrictions.

The administration of yohimbine or prazosin at the

above-mentioned doses significantly enhanced the

antinociceptive action of vinpocetine or piracetam in

the abdominal constriction assay. When administered

at 16 mg/kg, doxazosin given alone or combined with

either vinpocetine or piracetam markedly inhibited

the abdominal constrictions by 94.8–90.2% (Fig. 4).

To delineate whether there is any synergism between

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doxazosin and either nootropic, doxazosin was ad-

ministered at a lower dose of 4 mg/kg. Figure 5 shows

that doxazosin at the dose of 4 mg/kg was able to en-

hance the piracetam-induced antinociception.

The effect of vinpocetine was markedly potentiated

by co-administration of the beta-adrenergic antagonist

propranolol or muscarinic receptor antagonist atro-

pine, with 99.5% inhibition of the abdominal constric-

tion response. Propranolol or atropine also enhanced

the piracetam effect (Fig. 6). Antinociception caused

by vinpocetine or piracetam was, in addition, en-

hanced by co-administration of the adrenergic neuron

blocking agent guanethidine. Guanethidine by itself

elicited a significant reduction in the number of ab-

dominal constrictions as compared to the control

group (Fig. 7).

Potentiation of antinociception caused by vinpocet-

ine or piracetam was also observed when the non-

specific opioid receptor antagonist naloxone was ad-

ministered along with the nootropics. Naloxone ad-

ministered alone increased the writhing response (Fig.

8A). The potassium channel blocker gibenclamide ad-

ministered ip 30 min prior to testing inhibited

abodominal constrictions but did not affect antino-

ciception by vinpocetine or piracetam (Fig. 8B). The

non-steroidal anti-inflammatory drug indomethacin

given 30 min prior to vinpocetine or piracetam in-

creased the antinociceptive response (Fig. 9). The vin-

pocetine- or piracetam-induced antinociception was,

however, inhibited by pretreatment with the non-

selective adenosine receptor antagonists theophylline

administered at the dose of 20 mg/kg (Fig. 9).

The antinociception induced by the nootropic drugs

vinpocetine and piracetam was also examined in the

presence of the dopamine D2 receptor antagonists,

sulpiride and haloperidol or the dopamine D2 receptor

agonist bromocryptine. As shown in Figure 10, the

antinociception caused by vinpocetine was reduced

by sulpiride; while that of piracetam was enhanced by

sulpiride. The administration of either vinpocetine or

piracetam with haloperidol at 1.5 or 3 mg/kg, almost

abolished the writhing response. However, haloperi-

dol administered at 1.5 or 3 mg/kg by itself inhibited

the writhing response by 93.1 and 98.4%, respec-

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tively, vs. the saline-treated control group (Fig. 10).

Thus, the effect of a lower dose of haloperidol

(0.5 mg/kg, ip) was examined. Figure 11 shows that

the piracetam effect was enhanced by a lower dose

(0.5 mg/kg) of the dopamine D2 receptor antagonist

haloperidol. On the other hand, the administration of

the D2 receptor agonist bromocryptine (1.5 or 3 mg/kg)

reduced the number of abdominal constrictions in

a dose-dependent manner by 30.1 and 61.3%, respec-

tively (Fig. 12). A marked and significant antino-

ciception was still observed when either nootropic

was co-administered with bromocryptine (Fig. 12).

Figure 13A shows that marked potentiation of

antinociception occurred upon a co-administration of

vinpocetine and GABA agonist baclofen (5 or 10 mg/kg).

In contrast, piracetam antagonized antinociception

caused by the low (5 mg/kg), but not the high

(10 mg/kg) dose of baclofen (Fig. 13A).

When we examined the effect of vinpocetine or pi-

racetam on the imipramine-induced inhibition of the

writhing response, we observed that either nootropic en-

hanced antinociception caused by imipramine (Fig. 13B).

Effect of vinpocetine or piracetam in rota-rod test

Vinpocetine (0.45, 0.9 or 1.8 mg/kg) or piracetam (75,

150 or 300 mg/kg) did not produce any significant

changes on the rota-rod performances of the mice.

Both controls and either vinpocetine- or piracetam-

treated mice remained on accelerating rotating rod

during the acceleration period (5 min) and for 5 min

thereafter (data not shown).

Effect of vinpocetine or piracetam in Porsolt’s

forced-swimming test

The floating time, was reduced by 19.9 and 20.8% af-

ter treatment with low doses of vinpocetine

(0.45 mg/kg) or piracetam (37.5 mg/kg), respectively,

but was markedly reduced by 63.4% after treatment

with imipramine (15 mg/kg) (Fig. 14A, B). The co-

administration of either vinpocetine (1.8 mg/kg) or pi-

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racetam (300 mg/kg) with imipramine (15 mg/kg) had

no significant effect on the antidepressant effect of

imipramine (Fig. 14C). Meanwhile, a decrease in im-

mobility time by 31.8% was noted in mice treated

with a combination of vinpocetine (1.8 mg/kg) and pi-

racetam (300 mg/kg), suggesting an additive antide-

pressant effect of either nootropic (Fig. 14C).

Discussion

The present study provides evidence that the

nootropic drugs vinpocetine and piracetam exert

pain-modulating effects. In the hot-plate test of ther-

mal pain, vinpocetine showed antinociceptive effect.

Vinpocetine is capable of blocking NaV1.8 sodium

channel activity, which is likely to be responsible for

the analgesic properties of the drug [44]. In this model

of supraspinal analgesia, piracetam failed to alter no-

ciception. In another study, nefiracetam, a new mem-

ber of the piracetam group of cognition enhancers, re-

versed the thermal hyperalgesia in mouse models of

neuropathic pain [33]. It should be noted, however,

that members of the 2-oxopyrrolidine group though

structurally close to piracetam differ markedly in their

pharmacological properties and clinical effects.

On the other hand, either vinpocetine or piracetam

clearly inhibited the abdominal constrictions induced

in mice by injection of dilute acetic acid into the peri-

toneal cavity, a model of visceral inflammatory pain,

brought about by the release of prostaglandins [2].

Vinpocetine and piracetam did not impair motor per-

formance in the rota-rod test, thus ruling out the con-

founding influence of a possible sedative effect. The

inhibition of adrenergic, cholinergic and opioidergic

systems appears to facilitate vinpocetine- or pi-

racetam-induced antinociception.

The induction of pain behaviors in animals relies

upon a stimulus applied to a nociceptive neuron and

the activation of a pain pathway and reflexes. Several

drugs induce analgesia or antinociception by interfer-

ing with the neuronal pathways involved in the receipt

and transmission of nociceptive information from the

periphery to higher centers in the central nervous sys-

tem. In this context, the spinal cholinergic system and

muscarinic receptors are important for modulation of

nociception. Spinal muscarinic agonists, such as car-

bachol and the cholinesterase inhibitor neostigmine,

induce a potent analgesia in the rat; spinal M1 and/or

M3 receptor subtypes [26] likely mediate these ef-

fects. Activation of spinal muscarinic receptors inhib-

its dorsal horn neurons through inhibition of the gluta-

matergic synaptic input [23] and potentiation of syn-

aptic GABA release in the spinal cord [43]. Also,

M1-muscarinic agonists increased the pain threshold

in the mouse acetic acid writhing test and in rat paw

pressure test [1]. In contrast, atropine, a cholinergic

muscarinic antagonist, has been reported to produce

analgesia when administered at low doses of 1–100 µg/kg,

while hyperalgesia was observed with 5 mg/kg of the

agent. The analgesia caused by very low doses of at-

ropine was attributed to amplification of cholinergic

transmission by a selective blockade of presynaptic

muscarinic autoreceptors [15]. In the present study,

atropine administered ip at 2 mg/kg increased the

number of writhes in the abdominal constriction as-

say, yet amplified the antinociceptive action of vinpo-

cetine or piracetam.

The sympathetic nervous system has also been im-

plicated in the modulation of nociceptive transmis-

sion. Certain pain conditions involve the sympathetic

nervous system, e.g., visceral pain due to abdominal

and pelvic cancers; ischemic pain from peripheral

vascular disease, arterial spasm or frostbite and oth-

ers. Sympathetcomy or intravenous regional sympa-

thetic block with guanethidine can be carried out to

reduce pain [35]. Afferent nociceptive fibers from the

viscera accompany sympathetic nerves to enter the

spinal cord at the dorsal horn. Transmission of pain

impulses through the spinal cord can be inhibited by

descending reflexes that originate in the noradrener-

gic neurons of the mesencephalic periductal gray mat-

ter, and the pontine locus ceruleus, thereby altering

ascending transmission mediating visceral sensation

[4]. Behavioral, neurophysiological and clinical evi-

dence shows that most forms of gastrointestinal pain

are mediated by activity in visceral afferent fibers

running in sympathetic nerves [5]. Sympathetic block

interrupts these pathways and also the efferent

viscero-visceral reflexes so that ischemia and spasm

are relieved [9]. Voltage-gated sodium channels

(Nav1.7) have been found predominantly in sensory

and sympathetic neurons [42]. Sympathectomy pro-

duced in rats by administering 6-hydroxydopamine

reduced spontaneous activity of sacral spinal cord

neurons and attenuated visceral nociceptive responses

due to colorectal distension [19]. Duarte et al. [7] ob-

served a significant inhibition of writhing in the acetic

688 ��

acid abdominal constriction assay with the adrenergic

neuron blocker guanethidine (27% at 30 mg/kg, sc).

In the present study, a 30% reduction in the nocicep-

tive response was observed with 16 mg/kg of ip

guanethidine. The latter is taken up into adrenergic

neurons, where it binds to the storage vesicles and

prevents release of the neurotransmitter in response to

a neuronal impulse, which results in generalized de-

crease in sympathetic tone. In the present study,

guanethidine potentiated antinociception when co-

administered with either nootropic. A decrease in

writhing response was also observed after a non-

selective beta-adrenoceptor antagonist propranolol.

The latter enhanced antinociception elicited by pi-

racetam, whereas its administration with vinpocetine

almost abolished the writhing response. Based upon

these results, it might be suggested that a decrease in

sympathetic tone facilitates antinociception caused by

vinpocetine or piracetam.

Descending brainstem systems influence nocicep-

tive stimuli spinally while other systems modulate no-

ciceptive input supraspinally. The administration of

�-2 adrenoceptor agonists produces anti-nociception

in rodents by inhibiting synaptic transmission in the

spinal cord dorsal horn and there is an evidence of de-

scending noradrenergic system, the stimulation of

which results in the activation of spinal �-2-adrenergic

receptors and antinociception [37]. Visceral nocicep-

tion induced by ip administered 2% solution of acetic

acid was reduced dose-dependently by prazosin, an

�-1-adrenoceptor antagonist and clonidine, an �-2-

adrenoceptor agonist [21]. Results of the present

study indicated that visceral nociception was mark-

edly inhibited by the administration of �-1 antago-

nists. The administration of �-1 or �-2 antagonists

amplified the vinpocetine or piracetam antinocicep-

tion. Piracetam exerts GABAB antagonistic effect

[13]. There is evidence to suggest that spinally pro-

jecting noradrenergic A7 neurons in the dorsolateral

pontine tegmentum may be under tonic inhibitory

control by GABA neurons [29]. Removal of inhibi-

tory GABAB mechanisms by piracetam might thus fa-

cilitate a descending noradrenergic pathway so as to

alter nociception. This hypothesis, however, cannot

explain the potentiating effect of �-1 or �-2 antago-

nists on vinpocetine antinociception.

Unexpected also was the finding that the visceral

antinociceptive effects of vinpocetine or piracetam

were enhanced by co-administration the opioid recep-

tor antagonist naloxone. The latter increased the no-

ciceptive behavior in the abdominal constriction assay

when administered alone and was thus expected to re-

duce antinociception by the two nootropic drugs.

Voltage-gated potassium channels can also contribute

to the sensitization of primary afferents observed in

gastrointestinal pain states [6]. The possible involve-

ment of ATP-gated potassium channels in the media-

tion of antinociception induced by vinpocetine or pi-

racetam is ruled out, in view of the inability of gliben-

clamide, an ATP-sensitive potassium channels

blocker to reduce their antinociceptive effect.

Adenosine is an inhibitory neuromodulator that can

increase nociceptive thresholds in response to noxious

stimulation [34] and blockade of adenosine receptors

by theophylline, a non-selective adenosine receptor

antagonist at A1 and A2 was shown to induce hyperal-

gesia [30]. The antinociceptive effects of vinpocetine

or piracetam were reversed by prior administration of

the adenosine receptor blocker theophylline. There-

fore, it is suggested that an adenosine sensitive

mechanism is likely to be responsible for the visceral

antinociceptive properties of both nootropic drugs.

Baclofen, a prototypical agonist of GABAB recep-

tors, alters nociception at the level of the spinal cord

by acting on GABAB receptors located on primary af-

ferent terminals and is known to produce analgesia in

man and animals [18]. In the present work, baclofen

markedly inhibited the nociceptive response in the ab-

dominal constriction assay. The drug potentiated

antinociception elicited by vinpocetine. In contrast,

piracetam antagonized antinociception caused by the

low dose (5 mg/kg), though not the high dose

(10 mg/kg) of baclofen. The prevention of baclofen

antinociception is in accordance with other studies.

Piracetam (and also aniracetam) antagonized GABA-

ergic antinociception caused by baclofen [13].

Dopamine D2 receptors are involved in nociceptive

and analgesic mechanisms [12, 38] and there is evi-

dence to suggest that dopamine may acts tonically in

the cortex to inhibit nociception [3]. In the present

study, haloperidol itself dose-dependently inhibited

the nociceptive behavior. In contrast, sulpiride, a highly

selective D2-dopamine receptor antagonist, increased

the nociceptive response. It is likely that different

pharmacological receptor binding profiles of the two

antagonists might be associated with different effects

on visceral nociception. Haloperidol is a partially se-

lective dopamine D2 receptor antagonist [24]. The in-

volvement of other dopamine receptors as well is

likely to account for the antinociceptive effect of ha-

�� 689


loperidol seen in the present study. Haloperidol at

0.5 mg/kg potentiated antinociception caused by pi-

racetam. On the other hand, sulpiride reduced antino-

ciception caused by vinpocetine, but enhanced that of

piracetam. Blockade of D2 receptors thus potentiates

piracetam antinociception, but might reduce vinpocet-

ine antinociception. These results suggest alteration

of dopaminergic neurotransmission by modifying the

D2-receptors which can alter antinociception induced

by the two nootropic drugs.

Antidepressant drugs such as clomipramine or imi-

pramine can also modulate visceral nociception [14].

Data from the present study indicate that vinpocetine

or piracetam are likely to enhance visceral antino-

ciception caused by imipramine. Interestingly, when

examined in the forced-swimming test in mice,

a commonly used tool for screening of potential anti-

depressants [32], low doses of vinpocetine and also

piracetam displayed antidepressant-like activity.

In summary, vinpocetine, but not piracetam re-

duced thermal nociception. The two nootropics, how-

ever, displayed marked antinociceptive effect on vis-

ceral pain caused by ip injection of acetic acid in

mice. This effect depended on the activation of adeno-

sine receptors. Cholinergic muscarinic blockade with

atropine, adrenorecptor blockade or opioid antago-

nism with naloxone potentiated vinpocetine or

piracetam-induced antinociception. An interaction at

the level of dopamine D2 receptors by the two

nootropic agents is also suggested.

Acknowledgment:

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Vinpocetine and piracetam exert antinociceptive effect in visceral