Download BRIEF RESUME OF THE INTENDED WORK: Need for the study

BRIEF RESUME OF THE INTENDED WORK:
Need for the study:
Pain is an unpleasant sensory and emotional experience associated with actual or
potential tissue damage. It is a symptom of many diseases requiring treatment with
analgesics and is a common phenomenon in all vertebrate animals similar to that felt by
man.1,2
Pain on longer duration leads to symptoms of depression and anxiety. Despite
recent advances in our understanding of chronic pain mechanisms and normal
nociceptive transmission, the management of chronic pain is far from complete with
currently available therapeutic regimens. Although many effective treatments are
available, a number of adverse effects that interfere with quality of life may be associated
with treatment, and a significant number of patients obtain no relief from these
treatments. 3
In the recent past antidepressants have been shown to possess analgesic activity in
different kinds of animal pain models like diabetic neuropathy, post herpetic neuralgia,
acute and chronic inflammatory pain etc. Now they have been frequently used in chronic
backache, diabetic neuropathy, post herpetic neuralgia, cancer pain and phantom limb.
4,
5, 6
Analgesic effect of these drugs has been attributed to increase in noradrenaline
and/or serotonin concentration in the extracellular spaces via inhibition of re-uptake by
blocking their transporters. The blockade of neurotransmitter re-uptake is not the only
mechanism involved, there are other additional central and peripheral mechanisms that
contribute to their antinociceptive effect. One among them is modulation of potassium
channels. 4
A mechanism-based treatment approach may prove to be successful in effective
treatment of neuropathic pain, but requires more detailed insights into the persistence of
cellular and molecular pain mechanisms which renders pain unremitting. 7
Hence purpose of this study is to look into the possible antinociceptive
mechanisms of antidepressants concerned with modification by voltage gated potassium
channels. As there is lack of literature regarding effect of peripheral administration of
potassium channel modulators on antinociceptive effect of antidepressants, the present
study may shed more light on their role.
An insight into the various analgesic mechanisms of antidepressants may prove
beneficial in the development of drug combinations which have synergistic or additive
effect in relieving pain. One can also prove the possible drug interactions of these drug
combinations when indicated in the same disease condition.
REVIEW OF LITERATURE :
Studies have demonstrated that the opening of some of potassium channels
play an important role in the antinociception induced by agonists of many G-proteincoupled receptors (alpha2-adrenoceptors, opioid, GABAB, muscarinic M2, adenosine A1,
serotonin 5-HT1A and cannabinoid receptors), as well as by other antinociceptive drugs
like nonsteroidal antiinflammatory drugs [NSAIDs], tricyclic antidepressants etc. 4,8
In a meta analysis done by Dharmshaktu et al. (2011) concluded the efficacy of
antidepressants as analgesics in both neuropathic and non-neuropathic pain and also
suggested that they have diverse mechanisms independent of their antidepressant effects.
6
Valiollah et al. (2011) in an animal model involving formalin test showed that
Glibenclamide (ATP sensitive potassium channel blocker) could suppress the
antinociceptive effect of Amitriptyline and Fluvoxamine either partially or completely. 4
A comparative study done in diabetic neuropathy animal models by Talha et
al. (2008) concluded that Sertraline is superior to Amitriptyline in diabetic neuropathy as
Sertraline had both hypoglycemic and analgesic effect. 9
Gilron et al. (2006) clinically evaluated that the analgesic effect of TCA in
neuropathic pain may be attributed to noradrenaline and serotonin reuptake blockade,
NMDA receptor antagonism and sodium channel blockade. 10
A study by Calso E. (2005) showed that most potent drugs that are currently
used to manage neuropathic pain, amitriptyline and other TCAs block voltage gated
sodium channels in addition to having several other mechanisms of action. 11
Galeotti N. et al. (2001) studied the effect of central administration of ATP
dependent potassium channel blocker, Gliquidone a sulfonylurea, which reversed the
antinociception induced by Amitriptyline and Clomipramine in mouse hot plate test. 12
In another study by the same investigator (1997) intracerebroventricular
administration of antisense oligodeoxyribonucleotide in an animal which is an inactivator
of Kv1.1 gene coding ATP sensitive potassium channel resulted in inhibition of Baclofen
and Morphine analgesia in hot plate method. 13
Objectives of study:
1) To study the possible effect of ATP sensitive potassium channel opener
(Nicorandil) and blocker (Repaglinide) on the antinociceptive action of
antidepressants.
2) To give suggestions towards more rationalized use of above drugs concurrently if
essential.
MATERIALS AND METHODS:
Source of data:
Albino rats of either sex of average weight 180-220g which are inbred in central
animal house of S. S. INSTITUTE OF MEDICAL SCIENCES AND RESEARCH CENTRE,
Davangere will be used. Animals will be randomly housed at an ambient temperature and
humidity, with a 12 hour light and 12 hour dark cycle. The animals will have free access
to food and water. In order to minimize circadian rhythm influence, all experiments are
conducted between 08:00 and 16:00 h, in a noise-free room with controlled lighting.
Drugs and Chemicals :

Amitriptyline [10mg/kg, intra peritoneal] 4

Fluoxetine [10mg/kg, intra peritoneal] 4

Maprotiline [10mg/kg, intra peritoneal] 4

Nicorandil [5mg/kg, intra peritoneal] 14

Repaglinide [1mg/kg, intra peritoneal] 15

Normal saline [5 ml/kg, intra peritoneal]
Method of collection of data (including sampling procedure, if any)
A total of 108(n=108) animals will be divided into 18 groups of 6 (n=6) animals each
and will be subjected to the following tests,
1. Tail flick test (Radiant heat method)
2. Hot plate test (Hot plate method)
The animals will be divided into following groups in each of the above mentioned tests.
Group 1 : Amitriptyline + Normal saline
Group 2 : Amitriptyline + Nicorandil
Group 3 : Amitriptyline + Repaglinide
Group 4 : Fluoxetine + Normal saline
Group 5 : Fluoxetine + Nicorandil
Group 6 : Fluoxetine + Repaglinide
Group 7 : Maprotiline + Normal saline
Group 8 : Maprotiline + Nicorandil
Group 9 : Maprotiline + Repaglinide
All animal groups before administering the drugs will be subjected to both tail
flick and hot plate methods to know the baseline latencies and mean latency of each
group is calculated.
The tests will be repeated at 30, 60 and 120 minutes after the administration of test
drugs in both methods.16
Inclusion Criteria :
 Albino rats of either sex weighing between 180-220 g.
 Healthy rats with normal behavior and activity.
Exclusion Criteria:
 Rats <180 g or >220 g.
 Pregnant female rats or those who have delivered.
 Animals previously used in other experiments.
Methods:
1) Tail Flick test: This method involves use of an Analgesiometer in which distal
third of rat’s tail is exposed to heated nichrome wire and the reaction time of the
animal is recorded. Reaction time is defined as “Time interval between exposure
to radiant heat and the tail flick”. Cut off time of 6sec is taken to avoid damage to
the rat’s tail. 16
2) Eddy’s Hot Plate: Animals are placed on electrically heated surface maintained
at 55˚C-56˚C & the time until either licking or jumping occurs is recorded by a
stop watch. 16 Cut off time of 10sec is taken to avoid damage to the rat paw.17
Statistical analysis: Data analysis will be done by one way analysis of variance
(ANOVA) followed by Tukey’s post-hoc test for group wise analysis.
Does the study require any investigations or interventions to be conducted on
patients or other humans or animals? If so describe briefly?
Yes, the study involves using of rats and requires intraperitoneal administration of
Amitriptyline, Fluoxetine, Maprotiline, Nicorandil, Repaglinide and Normal saline.
Analgesic activity is assessed by subjecting rats to Tail flick and Hot plate methods
using Tail flick Analgesiometer and Eddy’s hot plate respectively.
Has ethical clearance been obtained from your institution?
Yes.
LIST OF REFERENCES:
1. Baumann TJ. Pain management. In: Dipiro JT, editor. Pharmacotherapy – A
pathophysiologic approach. 6th ed. Newyork: McGraw HILL; 2005 . p. 1089-90.
2. Merskey H, Bogduk N. Task force on taxonomy of the IASP. Classification of
chronic pain - Descriptions of chronic pain syndromes and definitions of pain terms.
2nd ed. Seattle: IASP Press; 1994 .p. 209-14.
3. Jeon Y, Ga SD, Jung-gu, Daegu. Cell based therapy for the management of chronic
pain. Korean J Anesthesiol 2011; 60(1): 3–7.
4. Hajhashemi V, Amin B. Effect of glibenclamide on antinociceptive effects of
antidepressants of different classes. Clinics. 2011; 66(2):321-25.
5.
Sawynok J, Esser MJ, Reid AR. Antidepressants as analgesics - an overview of
central and peripheral mechanisms of action. J Psychiatry Neurosci 2001; 26(1):21-9.
6. Dharmshaktu P, Tayal V, Kalra BS. Efficacy of antidepressants as analgesics - A
Review. J Clin Pharmacol 2011; 1-11.
7. Berger VJ, Knaepen L, Janssen SPM, Jaken RJP, Marcus MAE, Joosten EAJ, et al.
Cellular and molecular insights into neuropathy-induced pain hypersensitivity for
mechanism-based treatment approaches. Brain Res 2011; 67(1-2):282-310.
8. Ocana M, Cendan CM, Cobos EJ, Entrena JM, Baeyens JM. Potassium channels and
pain - present realities and future opportunities. Eur J Pharmacol 2004; 500(1-3):20319.
9. Jawaid T, Shakya AK, Kamal M, Hussain S. Amitriptyline and Sertraline in diabetic
neuropathy - A comparative view. Int J Health Res 2008; 1(2):73-8.
10. Gilron IC, Watson PN, Cahill CM, Moulin DE. Neuropathic pain - a practical guide
for the clinician. Can Med Assoc J 2006; 175(3):265-75.
11. Kalso E. Sodium channel blockers in neuropathic pain. Curr Pharm Des 2005;
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amitriptyline and clomipramine analgesia. Neuropharmacology. 2001; 40:75–84.
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smoke on concentration of nicorandil in plasma of rats. J Pharma Sci 1992;
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15. Fuhlendorff, Jannie, Rorsman, Patrik, Kofod, Hans et al. Stimulation of Insulin
Release by Repaglinide and Glibenclamide Involves Both Common and Distinct
Processes. Diabetes 1998; 47(3):345-51.
16. Schleyerbach R, Weithmann KU, Barlett RR. H. Analgesic, anti-inflammatory and
anti-pyretic activity. In: Vogel HG, Vogel WH, Scholkens BA, Sandow J, Muller G,
Vogel WF, editors. Drug discovery and Evaluation: Pharmacological assays. 2nd ed.
New York: Springer; 2002 .p.694-6.
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of diabetes and progression of neuropathic pain. J Res Pharm Sci 2010; 5(1):41–7.