Neurogastroenterol Motil (2004) 16, 447–454

Scorpion venom stimulates biliary/duodenal motility

and pancreatic exocrine secretion

J. W. C. CHEN, C. X. SHI, M. J. TENG, A. C. SCHLOITHE, J. TOOULI & G. T. P. SACCONE

Department of General and Digestive Surgery, Pancreatobiliary Research Group, Flinders Medical Centre, Flinders University,

SA, Australia

Abstract Scorpion envenomation causes severe upper

abdominal pain associated with nausea and vomiting.

Although scorpion venom (SV) stimulates pancreatic

and gastric secretion in animal models, its effects on

duodenal and biliary motility have not been reported.

The aim of this study was to determine the effects of

SV on sphincter of Oddi (SO), duodenal and gall

bladder motility and pancreatic amylase output.

Anaesthetized Australian possums (n ¼ 21) were

infused with SV via intravenous or closed intra-arter-

ial routes. Blood pressure, SO, duodenal and gall

bladder motility were continuously monitored for 4 h.

Trans-sphincteric flow (TSF), an indicator of bile duct

resistance, was measured concurrently. The amylase

output in pancreatic juice was also measured. SV

infusion resulted in profound transient increase in

blood pressure, SO motility and a significant decrease

in TSF. No significant differences were noted in SO

basal pressure changes. A transient increase in gall

bladder tone, duodenal contraction amplitude and

frequency, and amylase output were noted. Following

the peak in blood pressure, amylase output, SO, gall

bladder and duodenal motility were depressed. SV

induces a rapid but transient increase in biliary and

duodenal motility that is associated with stimulation

of pancreatic amylase output. These changes may

contribute to gastrointestinal symptoms associated

with early phases of envenomation.

Keywords duodenum, envenomation, gall bladder,

Oddi’s sphincter, pancreatic secretion, scorpion

venom.

INTRODUCTION

Scorpion envenomation causes profound systemic

changes occasionally resulting in deaths. Clinical

manifestations of scorpion evenomation include vom-

iting, abdominal pain, salivation, hypertension, tachy-

cardia, muscle rigidity, seizure and other symptoms.1–3

Most of these effects can be explained by direct

neurotoxicity scorpion venom (SV) has on cholinergic

and sympathetic nerves resulting in release of neuro-

transmitters causing intense stimulation of target

organs. The actions of SV on various muscles of the

body have been studied. They cause intense stimula-

tion of smooth muscles like in the ileum,4 uterus,5

arterial smooth muscle,6 vas deferens 7 and cardiac

muscle.8,9 SV from Brazilian scorpion (Tityus serrula-

tus) has shown to cause vomiting, abdominal pain and

acute pancreatitis. Tityus serrulatus venom induces

prolonged delayed gastric emptying for up to 48 h in

experimental animals 10 and stimulates gastric circular

smooth muscle.11,12 These effects combined with

stimulation of gastric secretion 13 could explain vom-

iting and abdominal pain associated with acute scor-

pion envenomation. However, there is no direct

evidence that the effects of delayed gastric emptying

were due to intense contraction of gastric muscle or

pyloric sphincter. SV has shown to cause ileal smooth

muscle contraction 4 and in contrast lower oesophageal

sphincter smooth muscle relaxation.14,15

Scorpion envenomation can result in acute pancre-

atitis.16,17 This was postulated to be due to stimulatory

effects of SV on sphincter of Oddi (SO) causing

obstruction coupled with stimulation of pancreatic

exocrine secretion.18 The effects of SV on duodenal,

gall bladder and SO motility in vivo have not been

studied.

The aims of this study were to characterize the

effects of T. serrulatus venom, on biliary gall bladder,

SO and duodenal motility as well as its effects on

pancreatic exocrine secretion.

Address for correspondence

Dr John W C Chen, Department of General and DigestiveSurgery, Flinders Medical Centre, Bedford Park, SA 5042,Australia.Tel: 618-8204-5511; fax: 618-8204-5843;e-mail: [email protected]: 12 August 2003Accepted for publication: 27 January 2004

Neurogastroenterol Motil (2004) 16, 447–454 doi: 10.1111/j.1365-2982.2004.00566.x

� 2004 Blackwell Publishing Ltd 447

METHODS

Animal preparation

Twenty-one Australian Brush-tailed possums (Tri-

chosurus vulpecular) of either sex (1.5–3.5 kg) were

prepared as previously described.19–21 Briefly, anaes-

thesia was induced with a combination of intramus-

cular ketamine (20 mg kg)1 Ketalar; Park Davis,

Caringbah, NSW, Australia) and xylazine (10 mg kg)1

Rompun; Bayer, Botany, NSW, Australia) IM. The left

and right femoral veins were cannulated and anaesthe-

sia maintained for the duration of the experiment with

a constant infusion of sodium pentobarbitone (nembu-

tal 15–20 mg kg)1 h)1; Boehringer Ingelheim Pty. Ltd,

Artarmon, NSW, Australia) into the left vein. The right

femoral vein was used for infusion of SV or vehicle.

The left femoral artery was cannulated and connected

to a pressure transducer (Transpac� IV; Abbot Ireland,

Silgo, Ireland) for blood pressure monitoring. A trach-

eostomy was performed and the animal ventilated with

a small animal ventilator (Phillips and Bird Inc.,

Richmond, VA, USA). In experimental groups subjec-

ted to closed intra-arterial infusion to the biliary tree,

pancreas and duodenum, the splenic artery was can-

nulated retrogradely and the tip of the catheter placed

at the origin of the hepatic artery.

Sphincter of Oddi, duodenal and gall bladdermotility and trans-sphincteric flow measurement

At laparotomy, a small choledochotomy was made in

the common bile duct distal to the entry of the cystic

duct. A single lumen side-hole polyethylene manome-

try catheter (OD 1 mm, ID 0.6 mm) and a polyethylene

bile diversion tube (OD 1.2 mm, ID 0.8 mm) were

inserted (Fig. 1).19 The distal end of this catheter was

placed in the distal duodenum to divert bile from

proximal bile duct. The manometry catheter, to meas-

ure SO motility, was connected to a minimally com-

pliant pneumohydraulic pump (Arndorfer Medical

Specialties Inc., Greendale, WI, USA) and a pressure

transducer. To collect pancreatic exocrine secretion, the

pancreatic duct proximal to the SO was incised and one

end of a polyethylene catheter (OD 1.2 mm, ID 0.8 mm)

was inserted and secured with a 6/0 silk suture. An

inflow catheter was inserted into the common bile duct

with the manometry catheter to measure trans-sphinc-

teric flow (TSF), as previously reported.19–21 Briefly, a

polyethylene inflow catheter (OD 1.2 mm, ID 0.8 mm)

was positioned in the common bile duct proximal to the

manometry catheter, secured with a ligature and con-

nected to a saline-filled reservoir suspended from a force

transducer (FT03; Grass Instruments, Quincy, MA,

USA) acting as an electromagnetic balance. As TSF

proceeds, the weight of the reservoir decreases and the

rate of change (slope) represents TSF. Aliquots of saline

(1 mL) were delivered into the reservoir at regular

intervals to maintain a relatively constant inflow

pressure. Cessation of TSF was indicated an upward

slope as complete obstruction at the SO resulted in

transfer of the manometry catheter perfusate into the

saline reservoir via the inflow catheter.

Gall bladder motility

The gall bladder was aspirated to empty the bile. The

fundus of the gall bladder was incised and a saline-

filled balloon connected to a pressure transducer is

then inserted as shown in Fig. 1 and secured with a

4/0 silk purse string.

Duodenal activity

A strain gauge is then attached to the serosal surface of

the duodenum 2 cm distal to the SO junction for

continuous monitoring of duodenal activity. All trans-

ducers were connected to a MacLab� (AO Instruments,

Castle Hill, NSW, Australia) recording system.

Dose of scorpion (T. serrulatus) venom

Previous study had demonstrated that each manual

extraction of SV from this species yield between 100 and

1000 mcg of venom. Hence, doses of 100–500 mcg kg)1

were used in this study. This is equivalent to each

manual extraction of venom from this species. The

serum concentration following scorpion sting varies

between 1 and 40 mcg L)1 in one study.22 However, the

concentration could be higher than measured as the

duration between inoculation of the venom and samp-

ling of sera was not documented in this particular study.

Experimental design

The possums were divided into four groups (Table 1).

These included the control group (n ¼ 6), which

received vehicle (0.01% bovine serum albumin; Sigma

Chemical Co., St Louis, MO, USA) infusion into the

hepatic artery, a second group (n ¼ 5) with close intra-

arterial infusion received SV (T. serrulatus, Sigma

Chemical Co.) at 500 mcg kg)1 over 1 h using a syringe

pump. The intra-arterial route was used to achieve a

higher concentration of the SV in the region of the

pancreas and biliary tree. The third (n ¼ 5) and fourth

(n ¼ 5) groups received intravenous infusion of SV at

448 � 2004 Blackwell Publishing Ltd

J. W. C. Chen et al. Neurogastroenterology and Motility

100 and 500 mcg kg)1, respectively. All parameters

measured were monitored for 4 h after initial period of

stabilization (30 min), after which, the animals were

killed by sodium pentobarbitone (Lethabarb�, Virbac

Pty. Ltd., NSW, Australia).

Data analysis

The effects of SV on SO basal pressure and phasic

amplitude (mmHg) and frequency of contraction (con-

tractions per minute) were evaluated. Integrated SO

motility as represented by mean amplitude under the

curve (mmHg) was measured for 2 min every half

hourly.

The change in TSF (lL min)1) was determined by the

difference between the mean flow rate (over 2 min)

every half and the flow rate before SV infusion

(baseline).

Duodenal motility was measured as contractions

frequency and amplitude (mV). The magnitude of

strain registered is proportionate to voltage output.

Motion artefacts from ventilation (when present) rep-

resent changes of less than 0.15 mV and were not

included in the analysis. The duodenal frequencies

were measured as mean contraction per minute over a

period of 2 min. As SV causes a burst of duodenal

activity about 30–60 min after commencing infusion,

the period of maximal activity was evaluated. Duode-

nal motility was expressed as change from baseline in

frequency and amplitude. Gall bladder motility was

manifested as tonic contraction and is expressed as

change from baseline pressure.

Figure 1 Schematic representation of the animal preparation used in this study showing bile diversion tube, sphincter of Oddi (SO)manometry catheter, duodenal strain gauge (for duodenal motility), duodenal decompression tube, and saline-filled balloon formeasurement of gall bladder motility. A catheter was also inserted into the pancreatic duct with the outlet set at 1 cm below theduodenum for pancreatic juice collection. An inflow catheter was also inserted into common bile duct to measure trans-sphinctericflow. All parameters were recorded using MacLab� computer recording system.

Table 1 Experimental groups

Groups Route of infusion n

Control (vehicle) Intra-arterial 6Scorpion venom

500 mcg kg)1 Intra-arterial 5100 mcg kg)1 Intravenous 5500 mcg kg)1 Intravenous 5


Volume 16, Number 4, August 2004 Pancreatobiliary effects of scorpion venom

Pancreatic juice amylase output

After a 30-min stabilization period, pancreatic juice

was collected half hourly, the secretion rate deter-

mined gravimetrically. The pancreatic juice amylase

activity was measured using enzymatic colorimetric

spectroanalysis (Boehringer Mannheim, Meylan,

France and Sigma) in a centrifugal analyser (Cobas�

Bios; F.Hoffmann-La Roche, Basle, Switzerland). Plas-

ma amylase and lipase levels were expressed as a

percentage of the baseline levels.

Statistical analysis

The statistical analysis of the data utilized SSPS

software. Changes in blood pressure, motility param-

eters, TSF and pancreatic amylase output were ana-

lysed using Mann–Whitney test. A P value of <0.05 was

regarded as significant. All data are expressed as

mean ± SEM unless otherwise stated. This study was

approved by the Animal Welfare Committee of the

Flinders University.

RESULTS

Low- or high-dose SV infusion by either intravenous or

intra-arterial routes cause a profound increase in blood

pressure, gall bladder, duodenal and SO motility

(Fig. 2). Pancreatic exocrine amylase secretion was also

increased. Although salivation was noted in all ani-

mals subjected to SV infusion, this was not quantified.

Blood pressure

Scorpion venom causes a dose-dependent increase in

blood pressure (Fig. 3A). Intravenous SV causes a

greater increase than both intra-arterial and lower

intravenous dose (P < 0.01). The blood pressure peaked

DU

O-S

G(m

v)G

B(m

mH

g)F

LOW

(UL)

BD

-(m

mH

g)B

P(m

mH

g)

1 h

Figure 2 A typical multi channel recording showing blood pressure (BP), sphincter of Oddi (SO) pressure, trans-sphincteric flow(FLOW), gall bladder pressure (GB) and duodenal tension (DUO-SG) response to intravenous infusion of scorpion venom. The 1-hinfusion period is indicated by horizontal bar and the commencement of the infusion by the vertical arrow. The peak activityoccurs at 30–60 min during the infusion. Note the slowing of trans-sphincteric flow with peak SO activity.



between 30 and 60 min of the onset of infusion then

declined to baseline levels by about 2 h after cessation

of the infusion.

Sphincter of Oddi motility and trans-sphinctericflow

Scorpion venom infusion caused a profound increase in

SO phasic contraction amplitude and frequency, with

maximal effects noted between 30 and 60 min follow-

ing the onset of SV infusion. (Fig. 3B) The SO ampli-

tude declined after 2 h and remained low for the

duration of the experiment. However, the frequency of

contractions increased as shown in Fig. 4. There was,

however, no significant change in basal pressures. The

integrated SO motility was also increased with SV

infusion (P < 0.01, Fig. 3C). This change in integrated

motility corresponds to a significant slowing of TSF

rate (Fig. 3D) with subsequent recovery and increase in

flow rate as the phasic amplitude declines for the

remainder of the experiment. The high dose intra-

arterial SV infusion produced the greatest increase in

SO motility and the most significant decrease in TSF

(Fig. 3E).

**

**

**

*

*

+ #

–40

–20

0

20

40

60

80

100

120

0 30 60 90 120 150 180 210 240

Time (min)

BP

Cha

nge

from

Bas

elin

e (

mm

Hg)

ControlSV500 IASV100 IVSV500 IV

SO amplitude change

–20

–10

0

10

20

30

40

50

0 60 120 180 240

Time (min)

Cha

nge

in A

mpl

itude

from

Bas

elin

e (m

mH

g)

*

SO frequency

0

2

4

6

8

10

12

0 60 120 180 240

Time (min)

Con

trac

tions

/min

*

–4

–2

0

2

4

6

8

10

0 60 120 180 240

Time (min)

Inte

gate

d S

O m

otili

ty c

hang

e (m

mH

g)

*

*

*

Flow change from baseline

–10

–8

–6

–4

–2

0

2

4

6

0 60 120 180 240

Time (min)

Tran

s-sp

hinc

teric

Flo

w C

hang

e(u

l/min

)

*

*

*

A

B C

D E

Figure 3 Scorpion venom induces a dra-matic increase in systemic blood pressure(*P < 0.02, **P < 0.01). (A) Intravenous(i.v.) high-dose scorpion venom resulted inthe highest increase in blood pressurewhich was significantly higher than intra-arterial (i.a.) (+P < 0.05) or intravenous lowdose (P < 0.01). (B) Significant increase insphincter of Oddi (SO) amplitude is notedwith all doses of scorpion venom irre-spective of route of administration. Theamplitude declined following cessation ofthe infusion (*P < 0.05). (C) Significantincrease in sphincter of Oddi (SO) fre-quency is noted with all doses of scorpionvenom irrespective of route of adminis-tration. The frequency continues toincrease subsequent to initial risefollowing cessation of the infusion(*P < 0.05). (D) Scorpion venom infusionproduces dramatic increase in sphincter ofOddi (SO) motility from baseline(*P < 0.01). A dose-related increase in SOmotility was noted with the doses ofscorpion venom and routes of administra-tion tested. (E) Scorpion venom infusiondecreased trans-sphincteric flow. High-dose scorpion infusion results in maximaldecrease of trans-sphincteric flow(*P < 0.01). In control group, there is aminor increase in flow with time.



Gall bladder and duodenal motility

Scorpion venom infusion caused a dramatic increase in

gall bladder tone (Fig. 4A). This effect is dose-related

lasting for about 60 min. Intra-arterial infusion caused a

greater increase in peak gall bladder tone than intraven-

ous infusion (P < 0.02). Under baseline conditions,

duodenal motility was usually quiescent; however, SV

infusion induced duodenal contraction, with bursts of

activity evident at 30–60 min after onset of infusion.

These bursts of activity consisted of increased contrac-

tion amplitude and frequency (Fig. 4B,C). As seen with

gall bladder motility, greater responses were observed

when SV was infused via the intra-arterial compared

with the intravenous route (P < 0.05).

Pancreatic amylase output

Scorpion venom stimulated pancreatic amylase output

(Fig. 5) and this was dose dependent (P < 0.01). Amy-

lase secretion was significantly elevated even at a

lower dose of SV when compared with control

(P < 0.05). The rate of amylase secretion declined soon

after cessation of SV infusion as seen with several other

parameters measured.

DISCUSSION

Scorpion envenomation is serious and often associated

with life-threatening complications such as hyperten-

sive crisis, cardiac dysrhythmia23 or acute pancreati-

tis.16,17 This study evaluated direct effects of SV

through intravenous and intra-arterial route demon-

strating that the effects of scorpion envenoma-

tion occur very early (within 15–30 min) and cause

profound transient hyperstimulation followed by a

prolonged period of depression of motility, secretion

as well as blood pressure. Although the hyperten-

sive effects of SV is well documented,23 its stimulatory

effects on SO, gall bladder and duodenal motility in

vivo have not been demonstrated previously.

Several subtypes of SV have been identified and

some have been used in the experimental setting to

deplete neurotransmitter and hence �eliminate� neur-

0

1

2

3

4

5

6

7

8

9

10

Duo

dena

l fre

quen

cy (

cont

ract

ions

per

min

ute)

ControlSV100D IV

0

5

10

15

20

25

30

35

Duo

dena

l pha

sic

ampl

itude

(m

mH

g)

SV500D IVSV500D IA

–3

–2

–1

0

1

2

3

4

5

6

Groups

GB

pre

ssur

e (m

mH

g)

**

**

*

*

**

*

*

#

##

A

B C

Figure 4 Scorpion venom infusion produ-ces dramatic increase in gall bladdermotility. (A) Gall bladder motility, asreflected by gall bladder pressure,increased following scorpion venom infu-sion, reaching a maximum 30–60 minafter commencement of the infusion. Thehigh dose of scorpion venom administeredby the intra-arterial route produced thegreatest increase in gall bladder pressure(***P < 0.02), followed by the intravenousinfusion of high and low dose (**P < 0.02,*P < 0.01 respectively). In the controlgroup, gall bladder pressure declined overthe same period. Scorpion venom stimu-lates duodenal contraction frequency andamplitude. (B) The maximal increase induodenal motility occurred 30–60 minafter the commencement of the scorpionvenom infusion (*P < 0.01). (C) Intra-arterial administration produced thegreatest increase in amplitude, followedby the high and low doses administeredintravenously (P < 0.01, ##P < 0.05,respectively). In control groups, theduodenum is inactive prior to theadministration of scorpion venom.



onal influence on parameters studied.14 SV’s action

appears to cause depletion of neurotransmitter from

nerve endings resulting in profound stimulation of

target organs. This stimulatory response is then fol-

lowed by a period of �exhaustion� of the organ con-

cerned.

The mechanisms of action of SV are complex and

incompletely understood. The current data suggest

that the toxins (and other components) in the venom

depolarize nerve endings to release neurotransmitters

and also have prejunctional effects.24,25 As the regula-

tion of biliary and duodenal motility and also pancre-

atic exocrine secretion involves muscarinic receptors,

we attempted to determine whether muscarinic recep-

tors are involved in the observed responses. However,

we found that treatment with atropine, at concentra-

tions which definitely blocked muscarinic receptors

based on functional tests, significantly increase blood

pressure. Furthermore, the combination of atropine

treatment with SV infusion resulted in cardiovascular

collapse. Therefore, we have not been able to pursue

this question.

The action of SV on SO function and acute pancre-

atitis has received little attention. The single published

study that investigated the effects of SV on SO activity

noted that scorpion toxin stimulated SO contractile

activity resulting in a decrease in TSF.26 The authors

also noted a stimulatory effect on pancreatic exocrine

secretion.

They postulated that acute pancreatitis associated

with scorpion envenomation could be caused by

stimulation of SO activity resulting in pancreatic duct

obstruction in conjunction with a stimulated exocrine

pancreas. The results of the current in vivo study

indicate that SV is associated with a transient stimu-

lation of SO motility and an increase in bile duct

resistance. Although SO dysfunction may play a role in

causation of various forms of acute pancreatitis,27 this

mechanism has not been shown to be the basis of

SV-induced acute pancreatitis. We have previously

demonstrated in an in vivo model that stimulation of

SO motility with a cholinergic agonist, carbachol, can

induce not only sphincteric obstruction but can also

result in acute pancreatitis.19 However, complete bile

duct obstruction was achieved and this lasted for a

period of 5 h. In contrast, during the current study,

there was only a transient decrease in TSF. This

difference in the magnitude and duration of these

effects may be related to the concentration of circula-

ting agonists. In this study, we demonstrated that

following the initial period of stimulated activity, there

was �exhaustion� or depression of SO activity with an

associated increase in TSF. These responses are not

consistent with pancreatic duct obstruction as the

major mechanism responsible for the induction of

acute pancreatitis.

In addition to biliary and pancreatic responses, SV

also stimulated salivary secretion in this model,

although this parameter was not quantified. The

increased biliary and duodenal motility coupled with

increased stimulation of the exocrine pancreas may

explain why upper abdominal pain with nausea and

vomiting are frequent and early symptoms of scorpion

envenomation in the presence or absence of acute

pancreatitis.1,23 From this study, it is evident that

profound physiological changes accompany scorpion

envenomation including an early period of intense

stimulation (hypertensive crisis) followed by a long

period of depressed motility activity and blood pres-

sure. This response profile has prompted some authors

to suggest that treatment should include vasodilator

support early followed by inotropic support in the later

period of envenomation.2

In a previous study, the concentration of venom in

victims� sera is directly proportional to the severity of

clinical manifestations. This observation is similar to

the dose-related increase in SO and GB motility as well

as pancreatic exocrine secretion prior to the period of

�exhaustion�.22 This study of SV levels in human

victims� sera and our findings of dose-related effects

on the parameters measured suggest that the degree of

toxicity related to scorpion envenomation is dose

related. Larger scorpion (hence the size of inoculation)

envenomation in children has been shown to correlate

Pancreatic amylase secretion

1

10

100

1000

10 000

100 000

0 1 2 3 4 5 6 7 8Time (h)

Am

ylas

e (%

of c

ontr

ol) Control

SV500 IA

SV100 IV

SV500 IV

Figure 5 Scorpion venom increased pancreatic amylasesecretion. Administration of scorpion venom at low and highdoses, via either the intravenous or intra-arterial routes, sig-nificantly increased pancreatic amylase secretion comparedwith control (*P < 0.05, **P < 0.01). Infusion of the high doseof scorpion venom by either route then produced the greatesteffects (+P < 0.05).



with increased clinical severity of envenomation, indi-

cating a dose-related effect of scorpion envenomation.1

In conclusion, we have demonstrated for the first

time that intravenous or close intra-arterial infusion of

SV results in transient profound effects on biliary and

duodenal motility. These effects occur early following

infusion and may explain the upper gastrointestinal

symptoms that accompany scorpion envenomation.

ACKNOWLEDGMENTS

The study was supported by the Royal Australasian

College of Surgeons and the National Health and

Research Council of Australia. Permission for the use

of the Australian Brush tailed possum in this study was

granted by the South Australian National Parks and

Wildlife Service. The technical assistance of Mr Aaron

Citti is acknowledged.

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Neurogastroenterol Motil (2004) 16, 447–454