Evaluation of anti-inflammatory activity, effect on blood pressure
& gastric tolerability of antidepressants
Preeta Kaur Chugh, Bhupinder Singh Kalra, Nitin Kaushik & Uma Tekur
Department of Pharmacology, Maulana Azad Medical College, New Delhi, India
Received December 28, 2011
Background & objectives: Antidepressants are being used as analgesics for various pain related disorders
like neuropathic and non neuropathic pain. Although their analgesic activity is well recognized but
anti-inflammatory potential of antidepressants is still inconclusive. Since the antidepressants are used
for longer duration, it becomes important to elucidate effect of anti-depressants on blood pressure
and gastric mucosa. This study was undertaken to evaluate the anti-inflammatory potential of various
antidepressant drugs as well as their effect on blood pressure and gastric tolerability on chronic
administration in rats.
Methods: Rat paw oedema model was used for studying anti-inflammatory activity, single dose of test
drug (venlafaxine 20 and 40 mg/kg, amitryptline 25 mg/kg, fluoxetine 20 mg/kg) was administered
intraperitoneally 45 min prior to administration of 0.1 ml of 1 per cent carrageenan in sub-planter region.
Oedema induced in test group was compared with normal saline treated control group. For studying
effect on blood pressure and gastric tolerability, test drugs were administered for 14 days. Blood pressure
was recorded on days 0, 7 and 14 using tail cuff method. On day 14, 4 h after drug administration, rats
were sacrificed and stomach mucosa was examined for ulcerations.
Results: Pretreatment of rats with venlafaxine (40 mg/kg) resulted in a significant decrease in paw
oedema as compared to control (2.4 ± 0.15 to 1.1 ± 0.16 ml, P<0.01). Similarly, in the group pretreated
with fluoxetine, significant decrease in paw oedema was observed in comparison to control (P<0.05).
Significant change in mean blood pressure was seen in rats pretreated with venlafaxine 40 mg/kg (126.7
± 4.2 to 155.2 ± 9.7, P<0.05) and fluoxetine (143.5 ± 2.6 to 158.3 ± 1.2, P<0.05) on day 7. No significant
difference with regard to gastric tolerability was observed among groups.
Interpretation & conclusions: Our findings showed significant anti-inflammatory activity of venlafaxine
(40 mg/kg) and fluoxetine but these drugs were also associated with an increase in blood pressure. No
significant change in mean ulcer index was observed among groups.
Key words Anti-depressants - anti inflammatory - paw oedema - venlafaxine
of neuropathic and non neuropathic chronic pain1,2.
Several antidepressants are known to possess intrinsic
antinociceptive activity. Antidepressants by inhibiting
Antidepressants have been used for the treatment the uptake of monoamines lead to increased amount of
noradrenaline and serotonin in the synaptic cleft at both
spinal and supraspinal levels causing reinforcement
of descending pain inhibitory pathways1. There is a
Indian J Med Res 138, July 2013, pp 99-103
paucity of literature comparing antinociceptive/anti
inflammatory efficacy among the three different classes
of antidepressants namely tricyclic antidepressants
(TCA), selective serotonin reuptake inhibitors (SSRI)
and atypical antidepressants.
imipramine and cloimipramine have been shown to
have some anti-inflammatory activity3. Since this group
of drugs is to be used for longer durations, it becomes
important to elucidate effect of antidepressants on
blood pressure and gastric mucosa. Moreover, it has
been observed that patients of chronic pain disorder
are often associated with depression affecting their
day to day routine2. Antidepressants may benefit these
patients having depression along with inflammatory
In experimental models of inflammation, fluoxetine,
long period. Cardiovascular side effects from anti-
depressant drugs, including clinically significant
blood pressure changes may complicate long term
therapy. It has been suggested that though depression
is associated with a decrease in blood pressure, the use
of antidepressants increases the risk of hypertension4.
In a study, venlafaxine and imipramine were found
to be associated with small, but significant increase
in supine diastolic blood pressure during acute phase
therapy5. The effects on blood pressure may be due
to noradrenergic potentiation by the antidepressants6.
Chronic fluoxetine intake has been shown to cause a 2
per cent increase in supine systolic blood pressure in
Antidepressants often have to be taken for a
in whom the intake of other medications, especially
non steroidal anti inflammatory drugs (NSAIDs), is
seen for the treatment of different medical conditions.
NSAIDs are known to cause gastric intolerance and
ulceration8. SSRIs have been shown to increase the
risk of upper gastrointestinal (GI) bleeding and more
so with the concurrent use of NSAIDs in a population
based case-control study9. However, animal studies
have not been conducted comparing the effect of
various antidepressants on gastric tolerability. Hence,
this study was designed to evaluate anti-inflammatory
activity of different classes of antidepressants along
with their effect on blood pressure and gastric
tolerability in a rat model.
Antidepressants are often taken by the elderly, and
Material & Methods
Pharmacology, Maulana Azad Medical College, New
This study was conducted in the department of
Delhi, India. The study protocol was approved by
institutional animal ethical committee.
used. Animals were procured from central animal house
and were housed in airconditioned environment. A gap
of one week was given for acclimatization of animals.
They were provided with normal rat food pellet diet
with water ad libitum. Rats were divided into 10 groups
with eight rats in each group. All animals received
drugs through intraperitoneal (ip) route in various
dosage (Table I). Drugs were dissolved in normal
saline. Prazosin, an alpha 1 adrenoceptor antagonist
was additionally added to drugs to elicit mechanism of
Wistar rats weighing 150-200 g body weight were
Anti-inflammatory activity: Paw oedema model: On
the morning of experiment, rats were weighed and
baseline paw volume was measured with the aid
of plethysmometer10. To ensure uniformity, lateral
malleolus of left hind limb was marked in all animals
so that the same length of paw is dipped in fluid each
time. This was followed by administration of drugs.
After 45 min of drugs administration, animals were
injected with 0.1 ml of 1 per cent carrageenan in sub-
planter region for inducing inflammation. Paw volume
was again measured after 3 h of sub-planter injection
of 1 per cent carrageenan. The paw volume and per
cent decrease in paw oedema was compared between
control group and drug-treated groups.
Effect on blood pressure: For measuring blood pressure
non invasive rat tail cuff-BP measuring device by Biopac
(India) was used. The animals were administered with
drugs (groups 1 to 6) once daily. The blood pressure
Table I. Dose and duration of antidepressants in various
groups of rats (n=8)
7Fluoxetine + Prazosin
8Imipramine + Prazosin
9Velnafaxine + Prazosin
10 Velnafaxine + Prazosin
0.1 ml/10 g
20 mg/kg +1 mg/kg
25 mg/kg + 1 mg/kg
20 mg/kg + 1 mg/kg
40 mg/kg + 1 mg/kg
100 INDIAN J MED RES, JUly 2013
CHUGH et al: ANTIDEPRESSANT’S ANTI-INFlAMMATORy ACTIVITy 101
was measured on days 0, 7 and 14. Digital readings
of blood pressure were obtained using computerized
Gastric tolerability: Animals who were being
administered drugs intraperitoneally once daily for
a period of 14 days to check out the effect on blood
pressure were used for evaluating gastric tolerability.
In the control group, rats received normal saline for 14
days. On day 14, 4 h after drug administration animals
were sacrificed. Each rat was subjected to midline
abdominal incision, abdomen was opened and stomach
was removed after ligating both oesophageal and
pylorus ends. Incision was given in the stomach along
greater curvature; mucosal surface was exposed and
washed with normal saline10. It was then stretched and
pinned on cork board. Mucosal surface was examined
for erosions and ulcerations. Severity of lesions was
recorded according to following scale11. 0=normal gray-
coloured mucosal surface. 0.5=pink to red colouration
of mucosal surface. 1=spot ulcer.1.5=haemorrhagic
streak. 2=number of ulcers less than five. 3=number
of ulcers more than five. 4=ulcers with bleeding. Ulcer
index was calculated by adding the total number of
ulcers plus the severity score. Ulcer index were recorded
and compared among drug-treated and control groups.
Statistical analysis: Results of paw oedema model,
blood pressure and ulcer index are expressed as mean
± standard error of mean. One way ANOVA followed
by post-hoc analysis with Dunnett test were applied for
paw oedema test. Student’s t test was used for blood
pressure comparisons among groups. Mann-Whitney
test was used for analysis of ulcer index outcomes.
planter injection of 0.1 ml of 1 per cent carrageenan.
Mean paw oedema in the control rats was 2.4±0.15
ml (Table II). Venlafaxine (40 mg/kg) and fluoxetine
showed significant reduction (P<0.05) in paw oedema
compared to control group. However, in the groups
treated with amitryptyline and venlafaxine 20 mg/kg,
no significant decrease in oedema was observed as
compared to control group (Table II). Pretreatment of
rats with prazosin alone resulted in mean paw oedema
of 2.7±0.20 ml. Addition of prazosin to fluoxetine,
venlafaxine (20 and 40 mg/kg) and amitryptline groups
did not influence oedema significantly in comparison
Marked paw oedema was produced in rats with sub-
III). Mean BP was 126.7±4.2 mmHg on day 0 in group
administered with venlafaxine (40 mg/kg), on day 7
recorded mean BP was 155.2±9.7 mmHg. The change
in mean BP was significant (P<0.05). Mean BP on
day 14 (145.7±7.5 mmHg) was significantly different
as compared to mean BP of day 7 (P<0.05).Similarly,
in the group administered with fluoxetine, significant
change in mean BP (143.5±2.6 to 158.3±1.2 mmHg)
was observed on day 7 (P<0.05) and day 14 (P<0.05).
In groups administered with venlafaxine (20 mg/kg)
and amitryptline, no significant difference in mean BP
Mean BP was recorded on days 0, 7 and 14 (Table
amitryptline (0.25±0.09) and two doses of venlafaxine
(0.56±0.2, 0.37±0.08) did not show significant
difference in mean ulcer index as compared to control
Mean ulcer index in control rats was 0.18±0.09.
pretreated with fluxoteine (0.37±0.08),
Table II. Effect of various drugs on paw oedema in rats
GroupDrugs Paw oedema
Mean paw oedema (ml)
Values are mean±SEM (n=8), P *<0.05, **<0.01 compared to
Control (normal saline)
Velnafaxine 20 mg
Velnafaxine 40 mg
Table III. Effect of drug treatment on mean blood pressure
Drugs Day 0
Amitryptline 136.0 ± 4.8
Fluoxetine143.5 ± 2.6
Values are mean ± SEM (n=8), *P<0.05 compared to day 0,
+P<0.05 compared to day 7
Day 7 Day 14
145.7 ± 7.5+
126.7 ± 4.2155.2 ± 9.7*
148.7 ± 1.8146.9 ± 2.1147.5 ± 1.3
144.5 ± 8.4
158.3 ± 1.2*
141.7 ± 5.7
153.3 ± 0.8+
chronic treatment often lasts several months. The
observation that these classes of drugs have anti-
inflammatory potential might led to important clinical
implication. Moreover, it has been observed that
patients with chronic inflammatory disorders have
high prevalence of depression12-14. Earlier studies have
demonstrated analgesic activity of antidepressants
but there is scanty information on anti-inflammatory
activity of various groups of antidepressants.
Antidepressants are prescribed worldwide and
activity of fluoxetine and venlafaxine 40 mg/kg was
observed in rat paw oedema model but this activity was
blunted, when prazosin was added to venlafaxine and
fluoxetine. Addition of prazosin resulting in loss of anti-
inflammatory activity of fluoxetine and venlafaxine
is indicative of probable role of noradrenergic/
serotonergic pathway in inflammation.
In our study, a significant anti-inflammatory
release of tumour necrosis factor-α (TNF-α) from
lipopolysaccharide (lPS)-treated monocytes and
anti-oedema effect of fluoxetine was partially
suppressed by the opioid antagonist naloxone15,16.
Other hypothesis was brought up that serotonin/
noradrenaline transporters are expressed in peripheral
leucocytes and amines released from these cells have
immunomodulatory role on interacting with receptors
present on immune cells17-19. In our study, a significant
anti-inflammatory activity of venlafaxine at a dose of
40 mg/kg and fluoxetine was observed but amitryptline
did not show significant anti-inflammatory potential
which is in contrast to earlier published studies20-22.
This could be due to low dose of amitryptline used in
Fluoxetine dose-dependently inhibited the
in blood pressure with venlafaxine 40mg/kg and
fluoxetine when administered for 14 days, which
is in concordance with earlier published studies4,5.
Increase in blood pressure with venlafaxine is
documented but data for association of fluoxetine
with increase in BP are lacking. In a meta-analysis
with 3744 patients, dose-dependent increase in
supine diastolic blood pressure with venlafaxine
was observed5. One study documents increase in
blood pressure with intracerebral administration of
fluoxetine mainly attributed to increase in sympathetic
tone and vasopressin release23. In two studies, low
rate of sustained hypertension with fluoxetine was
In our study, we observed significant increase
observed24,25. Whether hypertension is a class effect
of antidepressants or is associated with all classes of
antidepressants is still not clear.
ulceration with any of the test drugs used in our study
whereas literature shows increased propensity of
gastric ulcerations with selective serotonin reuptake
inhibitors as these block the uptake of serotonin into
platelets, leading to an impairment in the platelet
haemostatic response26. Also, concurrent use of
NSAIDs, anticoagulants, and antiplatelet agents with
SSRIs leads to increase risk of GI bleeding6. In a
nested case control study, risk of gastric bleeding with
venlafaxine was found to be significantly higher than
matched controls27. These findings were in contrast to
our observations; which could be attributed to short
duration (14 days) of drug administration.
We did not observe increased risk of gastric
fluoxetine showed potent anti-inflammatory activity in
rats. This effect was associated with an increase in blood
pressure on chronic therapy but did not have adverse
gastric tolerability when administered as monotherapy.
limitations of our study were that ED50 was not
elucidated of various test drugs and gastric tolerability
was not studied in combination with NSAIDs.
In conclusion, venlafaxine in high dose and
Cadila ltd for providing venlafaxine, fluoxetine and amitriptyline
pure powders for our research project.
Authors acknowledge Sun Pharmaceutical ltd, Cipla &
drugs for chronic non-cancer pain. Am Fam Physician 2005;
71 : 483-90.
1. aizels M, McCarberg B Antidepressants and antiepileptic
McQuay HJ, Tramèr M, Nye BA, Carroll D, Wiffen PJ, Moore
RA. A systematic review of antidepressants in neuropathic
pain. Pain 1996; 68 : 217-27.
Abdel-Salam OM, Nofal SM, El-Shenawy SM. Evaluation of
the anti-inflammatory and anti-nociceptive effects of different
antidepressants in the rat. Pharmacol Res 2003; 48 : 157-65.
licht CM, de Geus EJ, Seldenrijk A, van Hout HP, Zitman
FG, van Dyck, et al. Depression is associated with decreased
blood pressure, but antidepressant use increases the risk for
hypertension. Hypertension 2009; 53 : 631-8.
Thase ME. Effects of venlafaxine on blood pressure: a meta-
analysis of original data from 3744 depressed patients. J Clin
Psychiatry 1998; 59 : 502-8.
Sawynok J, Esser MJ, Reid AR. Antidepressants as analgesics:
an overview of central and peripheral mechanisms of action.
J Psychiatry Neurosci 2001; 26 : 21-9.
102 INDIAN J MED RES, JUly 2013
R Download full-text
EG, Bigger JT Jr. Cardiovascular effects of fluoxetine in
depressed patients with heart disease. Am J Psychiatry 1998;
155 : 660-5.
Armstrong CP, Blower Al. Non-steroidal anti-inflammatory
drugs and life threatening complications of peptic ulceration.
Gut 1987; 28 : 527-32.
de Abajo FJ, Rodríguez lA, Montero D. Association
between selective serotonin reuptake inhibitors and upper
gastrointestinal bleeding: population based case control study.
BMJ 1999; 319 : 1106-9.
Sharma JN, Samud AM, Asmauei MZ. Comparison between
plethysmometer and micrometer methods to measure acute
paw oedema for screening anti-inflammatory activity in mice.
Inflammopharmacology 2004; 12 : 89-94.
Kunchandy J, Khanna S, Kulkarni SK. Effect of alpha 2
agonists clonidine, guanfacine and B-HT 920 on gastric acid
secretion and ulcers in rats. Arch Int Pharmacodyn Ther
1984; 275 : 123-38.
Hurwitz El, Morgenstern H. Cross-sectional associations of
asthma, hay fever, and other allergies with major depression
and low-back pain among adults aged 20-39 years in the
United States. Am J Epidemiol 1999; 150 : 1107-16.
Kozora E, Ellison MC, West S. Depression, fatigue, and pain
in systemic lupus erythematosus (SlE): relationship to the
American College of Rheumatology SlE neuropsychological
battery. Arthritis Rheum 2006; 55 : 628-35.
Zielinski TA, Brown ES, Nejtek VA, Khan DA, Moore JJ,
Rush AJ. Depression in asthma: Prevalence and clinical
implications. Prim Care Companion J Clin Psychiatry 2000;
2 : 153-8.
Roumestan C, Michel A, Bichon F, Portet K, Detoc M,
Henriquet C, et al. Anti-inflammatory properties of desipramine
and fluoxetine. Respir Res 2007; 8 : 35.
Abdel-Salam OM, Baiuomy AR, Arbid MS. Studies on the
anti-inflammatory effect of fluoxetine in the rat. Pharmacol
Res 2004; 49 : 119-31.
Faraj BA, Olkowski Zl, Jackson RT. Expression of a high-
affinity serotonin transporter in human lymphocytes. Int J
Immunopharmacol 1994; 16 : 561-7.
Marino F, Cosentino M, Bombelli R, Ferrari M, lecchini S,
Frigo G. Endogenous catecholamine synthesis, metabolism
7. oose SP, Glassman AH, Attia E, Woodring S, Giardina
Reprint requests: Dr Bhupinder Singh Kalra, Assistant Professor, Department of Pharmacology,
Maulana Azad Medical College, New Delhi 110 002, India
storage, and uptake in human peripheral blood mononuclear
cells. Exp Hematol 1999; 27 : 489-95.
Elenkov IJ, Wilder Rl, Chrousos GP, Vizi ES. The sympathetic
nerve-an integrative interface between two supersystems:
the brain and the immune system. Pharmacol Rev 2000;
52 : 595-638.
Abdelmawla AH, langley RW, Szabadi E, Bradshaw
CM.Comparison of the effects of venlafaxine, desipramine,
and paroxetine on noradrenaline- and methoxamine-evoked
constriction of the dorsal hand vein. Br J Clin Pharmacol
1999; 48 : 345-54.
Hajhashemi V, Sadeghi H, Minaiyan M, Movahedian A,
Talebi A. The role of central mechanisms in the anti-
inflammatory effect of amitriptyline on carrageenan-induced
paw edema in rats. Clinics (Sao Paulo) 2010; 65 : 1183-7.
Vismari l, Alves GJ, Palermo-Neto J. Amitriptyline and
acute inflammation: a study using intravital microscopy and
the carrageenan-induced paw edema model. Pharmacology
2010; 86 : 231-9.
lazartigues E, Brefel-Courbon C, Bagheri H, Costes S,
Gharib C, Tran MA, et al. Fluoxetine-induced pressor response
in freely moving rats: a role for vasopressin and sympathetic
tone. Fundam Clin Pharmacol 2000; 14 : 443-51.
Amsterdam JD, Garcia-Espana F, Fawcett J, Quitkin
FM, Reimherr FW, Rosenbaum JF, et al. Blood pressure
changes during short-term fluoxetine treatment. J Clin
Psychopharmacol 1999; 19 : 9-14.
Volkers AC, Tulen JH, van den Broek WW, Bruyn JA, Passchier
J, Pepplinkhuizen l. Effects of imipramine, fluvoxamine and
depressive mood on autonomic cardiac functioning in major
depressive disorder. Pharmacopsychiatry 2004; 37 : 18-25.
Andrade C, Sandarsh S, Chethan KB, Nagesh KS. Serotonin
reuptake inhibitor antidepressants and abnormal bleeding: a
review for clinicians and a reconsideration of mechanisms.
J Clin Psychiatry 2010; 71 : 1565-75.
de Abajo FJ, García-Rodríguez lA. Risk of upper
gastrointestinal tract bleeding associated with selective
serotonin reuptake inhibitors and venlafaxine therapy:
interaction with nonsteroidal anti-inflammatory drugs and
effect of acid-suppressing agents. Arch Gen Psychiatry 2008;
65 : 795-803.
CHUGH et al: ANTIDEPRESSANT’S ANTI-INFlAMMATORy ACTIVITy 103