Aveneu Park, Starling, Australia

Effect of the Study 6 Materials and Method


of topiramate and gabapentin on neuropathic pain induced in rats by sciatic
nerve ligation


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Submitted by:

Obaidallah alharbi



Supervision  by

Dr. Hossam El
sisi and Dr. Ibrahim Awwad

College of Pharmacy

Qassim University

DEC 2017


This is to certify that this graduation
project report entitled “Effect
of topiramate and gabapentin on neuropathic pain
induced in rats by sciatic nerve ligation” is submitted to the College of Pharmacy, Qassim University in partial
fulfilment of the requirements for the degree of Doctor of Pharmacy (Pharm.D)
by Abdullatif Obaidallah alharbi under the supervision of Dr.Hossam Elsisi &
Dr.Ibrahim Awwad. I hereby confirm that the work submitted in this project is
my own. I have not violated the college’s policy on plagiarism.





Dr.Ibrahim Awwad



Abdullatif Alharbi



of contents


   4List of Figures and Tables                                                 
   4List of Abbreviations                                                         
   4Abstract                                                                                            5Keywords                                                                              
5Introduction and Review of literature                                  6Aims of the Study                                                                            6        Materials and Method                                                           7        Results                                                                                   10      



 References                                                                                               13          








I would like to thank my supervisors
Dr.Hossam Elsisi and Dr.Ibrahim Awwad for their tremendous help, support and
time that they had spent with me in the lab and outside lab from the first day
of graduation project. Also, I would like to thank Dr.Sultan Sajid for his help
in lab. Last but not least, I would like to thank my friend Waleed Alharbi for
his help and support.


Figures and Tables

                                                                                          Page Number

Figure  1                                                                        

2                                                                                 10

Table 1                                                                                     

Table 2                                                                                      

Table 3                                                                                      

Figure 3                                                            



Abbreviations :

 (IASP) the International Association for the
Study of  Pain , (GBP) Gabapentin ,(TPM) Topiramate , (TPM) Thiopental,(CBZ)
carbamazepine .





To study the effect of
topiramate and gabapentin on neuropathic pain induced in rats by sciatic nerve

To compare the effect of topiramate and gabapentin on neuropathic pain
induced in rats by sciatic nerve ligation


The hypothesis of this study is that topiramate and gabapentin is effective to treatment neuropathic


Study design: Experimental study

Sampling: rats

Equipments  : Analgesia

Drugs: Gabapentin ,Topiramate ,Thiopental.

Results :

Both Gababentin and Topiramate produce
analgesic effect on the rat .


neuropathic pain,
Antiepileptic drugs, Gabapentin, Topiramate.



Introduction and
review of literature:


Neuropathic pain have a tendency to be
chronic and may be present for months or years. the
International Association for the Study of 
Pain (IASP) defined neuropathic pain as “pain initiated or caused by a
primary lesion or dysfunction in the nervous system”(1). Neuropathic pain is
caused by nerve damage, and is often followed by changes in either the
peripheral or the central nervous system (CNS)(2).

Ibuprofen or paracetamol maybe not effective
in neuropathic pain, while drugs that are sometimes used to treatment
depression or epilepsy can be very effective in some people with neuropathic
pain. Antiepileptic
medications are used for treat epilepsy, but are recently used extensively for
treating neuropathic pain.
Antiepileptic drugs that currently used to neuropathic pain are : topiramate,
clonazepam, gabapentin ,CBZ, lamotrigine, levetiracetam, lacosamide, phenytoin,
pregabalin, and valproate (3)

Different antiepileptic drugs will have
different mechanisms of action, not all of which are likely to be well
understood, especially in terms of how a particular drug produces pain relief
in any particular individual with any particular chronic pain condition(4) Antiepileptics in general are thought to reduce the ability of the

neuron to ?re at high frequency(7).Topiramate has been shown to enhance the action of GABA
receptors, block activity-dependent voltage-gated sodium channels, inhibit
L-type voltage-gated calcium channels, presynaptically reduce glutamate release
and post-synaptically block
kainate/?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA) receptors(5)
. On the other hand gabapentin acts by binding to calcium channels and by
modulating calcium in?ux(6).

Aims of the Study:                             

Aims of the research is to study and to compare the effects of topiramate
and gabapentin on neuropathic pain induced in rats by sciatic nerve ligation.




and Methods:



Albino-rats weighing 200-350gm were used in this study. They
were maintained in cages with free access to food and water and kept
on a 12-h light/dark schedule.


Gabapentin (GBP) 60mg/kg (10).

Topiramate (TPM) 40mg/kg (11).

Thiopental (TPM) 40mg/kg .

          All the above drugs were
dissolved in distilled water just before intraperitoneal injection.



Induction of chronic neuropathic pain in

this method neuropathic pain is induced in experimental animals by unilateral
ligation of the sciatic nerve in the thigh under general anesthesia with 40
mg/kg thiopental (8). The right sciatic nerve is exposed and isolated at
the mid thigh and one third to one half of the nerve is ligated tightly with
5-0 silk suture. Within few
hours after the operation and for several months thereafter, the rats develop a
guarding behavior of the ipsilateral hind paw and lick it. The cause of this
behavior is development of hyperalgesia. The plantar surface of the foot became
highly sensitive to non-noxious and noxious stimuli and a sharp decrease in the
reaction time measured by analgesia meter in response to thermal stimulation is
noticed (9).

     Sham operated rat model: Animals of this group were subjected to all procedures of sciatic
nerve ligation. The nerve was dissected and isolated at the midthigh then left
without ligation to evaluate the effect of surgical intervention on the
reaction time.


Measurement of the reaction time

The reaction time which indicate the tolerability of the animals to
thermal pain (10), is measured using Analgesia Meter 11TC Model 390
Paw Stimulator “figure 1” {Woodland hills, C.A., U.S.A} 

Figure (1):
Analgesia Meter.

          This instrument allows the user to apply
heat stimulation (infra red) to the experimental animals (with intensity and
brightness of 50%) without any physical contact between the test subject and
the heat source.



Experiment model:

      After 10
days of Induction of chronic neuropathic pain the animals were divided into
three groups. The number
of animals in each group were 4 (n=4).

For the first group ; treated with normal saline as a
control group and we noted the reaction time of animals on the hot plate at 30,60,90
minutes after drug administration. For the second group ; treated with
Gabapentin (GBP) 60 mg/kg. and we noted the reaction time of animals on the hot plate at 30,60,90
minutes after drug administration. For the third group ; treated with
Topiramate (TPM). 40mg/kg and we noted the reaction time of animals on the hot plate
at 30,60,90 minutes after drug administration.


Statistical analysis:















Results :

Induction of chronic
neuropathic pain test

We initially started by Induction of chronic neuropathic pain in rats
,so to ensure that we measured the postoperative reaction time. the results of
postoperative reaction time was decrease As explained in Figure 2 .


               Figure 2


hot- plate analgesia test

In the hot- plate analgesia test showed the average latency of the
control group was between 11.17 and 11.4 
sec ( Table 1 ). And The animals treated with Gabapentin (60 mg/kg) increased the latency reaction on 30,60  and 90 min (p


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