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The Effect of
Damage to the spinal cord often results in neuropathic pain.
This pain is experienced as a stabbing, burning shooting ortingling sensation. Allodynia (hypersensitivity to non-noxious
Inhibitor Meloxicam on
stimuli) and hyperalgesia (hypersensitivity to noxious stimuli)may also develop. The pain may be experienced at the level of
Neuropathic Pain following
injury (pain experienced at the site of injury as well as two
Spinal Cord Injury
segments above and below) or below the site of injury (at least3 segments below the injury). Pain at the level of injury couldresult from either a central trauma or disease of the peripheral
nervous system (Siddall et al.
, 1997; Finnerup et al.
Finnerup et al.
’s study (2004) demonstrated that abnormal
behaviors observed in animals and human models of at levelNP have been correlated with hyper excitability and abnormal
Daniel Resnick M.D., Gurwattan Miranpuri Ph.D.,
background activity in the dorsal horn at or near the site of
injury. The present study focused on below level pain. Below
level pain only occurs from damage to the central nervoussystem (Siddall et al.
, 1997; Finnerup et al.
, 2004). One of the
Department of Neurological Surgery
main characteristics of below level pain is the dysfunction of
School of Medicine and Public Health
the spinothalamic tract—a bundle of fibers leading from thespine to the thalamus that plays a central role in conducting
central pain. (Finnerup et al.
Neuropathic pain is a common complication following from
Several studies have shown that NP has an effect on the
spinal cord injury. However, few adequate treatments are
quality of life of patients with this pain. The presence and
available to alleviate this pain. The COX-2 gene has been
severity of NP often negatively affect physical and emotional
shown to play a role in NP development. Therefore, we
well being, sleep, the patients’ ability to participate in
hypothesize that COX-2 inhibitor Meloxicam would inhibit
employment and to a lesser extent socialization. (Jensen,
the development of NP. To test the hypothesis, rats received
Chodroff & Dworkin, 2007). For these reasons, studying NP
spinal cord injuries through the contusion method. The
and potential treatments to alleviate it are important.
animals then received either a high or low concentration ofMeloxicam or saline intrathecally for 7 days. NP development
was measured using the thermal hyperalgesia pain test.
Many factors contribute to the development and maintenance
Functional recovery and gene expression were also measured.
of NP. The initial damage to major tissues and structures
At this point in the study, we have shown that administration
contributes to the degeneration and reorganization of the NS.
of Meloxicam promotes functional recovery at least 7 days
Various aspects of the inflammatory response have been
post injury. This suggests that COX-2 may play a role in the
shown to promote regeneration and degeneration. Changes
inhibitory environment of the SCI site and the potential of
resulting from specific trauma (such as ischemia or hypoxia)
Meloxicam to as a promoter of axonal regeneration.
may play a role in hypersensitivity to pain responses.
Elevation of excitatory amino acids (EAAs) near the site of
injury may also result in hyper excitability of nociceptivepathways (N. B. Finnerup et al., 2004; Lu and Richardson,
Approximately 40-75% of patients with spinal cord injuries
1991; Leon et al., 2000; DeLeo & Yezierski). This study
(SCIs) experience chronic neuropathic pain (NP) disorders
focused on the nociceptive pathway of cyclooxygenase.
(Barrett, 2003; Siddall, 2003; Finnerup 2001). Despite thefrequency of these disorders, few optimally effective
treatments are available. Because similar symptoms develop in
One pathway that is believed to be involved in the
various NP disorders, treatment development largely focuses
development of NP is the COX pathway. The COX pathway
on pain mechanisms. COX-2 has been identified as a major
leads to the formation of eicosanoids including prostaglandin
gene involved in pain development. Several non selective
E2 (PGE2) (Hara , Kong, Sharp & Weinstein, 1998).
COX inhibitors have been shown to reduce NP. However,
Enhanced eicosanoids has been observed in various
often result in intestinal ulcerations. Due to the selectivity of
pathological processes in the CNS such as SCI (Mitsuhashi et
Meloxicam for COX-2 inhibition, we hypothesize that it will
, 2004.). Tissue damage in addition to oxidative stress
be an effective treatment against NP.
activates phospholipase A2. This hydrolyzes membrane
phospholipids into arachidonic acid. Cyclooxygenase
were utilized in this study because of the lack of in vitro and
synthesizes prostaglandin (PGs), fatty acid derivatives, from
computer based models. The rats weigh between 275 and 325
arachidonic acid (Phillis, Horrocks, & Farooqui, 2006). PGs
g at the time of surgery. Animal care was performed in
have been shown to play a major role in pain (Steinmeyer
compliance with the published National Institutes of Health
guidelines. The Institutional Animal Care and Use Committeeapproved all animal procedures.
Cyclooxygenase has two isoforms: COX-1 and COX 2. COX1 is expressed constitutively. It is responsible for the
Spinal Cord Injury
homeostasis of prostaglandins (PGs) and found in various
Animals were anesthetized using inhalation anesthetic
tissues (Smith, Marnett & DeWitt, 1991; Reddy &
(Isoflurane 5% for induction and 1. 5% for maintenance along
with oxygen and nitrous oxide in a 1:1 mixture). A T9 and L1laminectomy were performed on a warming pad. Each animal
COX-2, nearly undetectable in most mammalian organisms, is
received a contusion spinal cord injury (cSCI) using the New
an immediate early gene (activated transiently and rapidly in
York University Impactor (Gruner, 1992) by dropping a 10g
response to a wide variety of cellular stimuli) expressed
weighted rod from 12. 5 mm above the exposed area through
mainly in the CNS and activated immune cells (Reddy et al.
1996). COX 2 can be induced by inflammatory stimuli (Smithet al.
, 1991), cerebral ischemia (Nogawa, Zhang, Ross &
Iadecola, 1997), N-methyl-D-aspartate (an EAA), receptor-
Following cSCI, rats underwent placement of a mini-osmotic
dependent synaptic activity (Nagaoka et al.
pump (n=40) filled with either a high (300_g/kg/day) or low
synaptic brain activity. COX 2 can be found in motor neurons
(150_g/kg/day) concentration of Meloxicam (high and low
of lamina IX, glial cells and white matter (Beiche et al.
concentrations) to be delivered at a rate of 1_L/hr over 7 days.
The tubing was inserted intrathecally (along the spinal cord) at
Current Treatments and COX Inhibitors
L1 to end just bellow the injury site at T8/T9. The pump was
There are currently several COX-2 inhibitors sold
placed subcutaneously (under the skin). Control rats (n=20)
commercially for various arthritic symptoms (celecoxib,
underwent placement of mini-osmotic pump in a similar
rofecoxib, valdecoxib). However these drugs are not effective
fashion to the Meloxicam treatment group and received saline
in treating NP (Everts, Wahrborg & Hedner, 2000). There are
some COX-2 inhibitors that have been shown to inhibit NP to
Following the placement of the pumps, the incisions and skins
an extent (Bingham et al., 2005). Non-steroidal anti-
were closed with sutures. The intrathecal pump and catheters
inflammatory drugs (NSAIDs) have been used in the past as
non selective COX inhibitors. These drugs however result ingastric/intestinal ulceration (Francischi et al., 2002). This
appears to be due to COX-1 inhibition. Selective COX-2
Rats were individually videotaped for approximately 4
inhibitors prevent this side effect (Bambardier, 2002).
minutes in an unfilled wading pool on post impaction days 2,7, 14, 21, 28, 35, 42 and 49. Behavior was scored using the
Meloxicam, a NSAID, is a strong inhibitor of COX
Basso, Beattie and Brensnahan (BBB) locomotor rating scale
(Engelhardt et al.
, 1995) with selectivity for COX-2
(Basso et al.
, 1995)—a 21-point scale of increasing numbers
(Engelhardt, Bogel, Schnitzeler, & Utzmann, 1996). It is an
indicating greater improvement in hind limb function. Scores
effective NSAID with a good gastro-intestinal tolerability
were based primarily on the level of complexity of specific
(Turck, Busch, Heinze, Narjes, 1997).
locomotive behaviors: coordination, stance, joint extensionand stepping behavior.
Due to the effectiveness of Meloxicam as a COX inhibitor andtherapeutic potential with minimal side effects, we propose to
Thermal Hyperalgesia Pain Test
determine the effect of Meloxicam on NP following spinalcord injury. We hypothesized that Meloxicam would inhibit
Thermal hyperalgesia, or hypersensitivity to thermal stimulus,
the COX-2 gene expression and that this would block the
is one behavioral sign of chronic NP. This test assessed the
production of PGs which would inhibit the development of
withdrawal latency of the hind paw from a thermal noxious
stimulus. An animal was placed inside a plastic box on araised glass surface. A movable focused beam of radiant heat
was placed under the animal’s paw and a timer started. Thebeam turns off as soon as the animal moved its paw. Thelatency for the animal (in seconds) to withdraw its paw was
recorded. This test was administered on days 28, 35, 42 and 49
Male Sprague-Dawley rats were used for this study. Animals
post injury. In animals experiencing thermal hyperalgesia
(TH), the withdrawal latency typically decreased to a mean of
The animals receiving Meloxicam were also expected to show
a down regulation or lower expression of the COX-2 genecompared to the control rats while the controls were expected
to show an up regulation of COX-2 gene. This would confirm
On day 49 post injury, the spinal cords were harvested and
that Meloxicam does inhibit COX-2 expression that SCI
sectioned into rostal, epicenter and caudal sections. These
induces up regulation of COX-2 and that up regulation of
samples were used for real-time polymerase chain reaction
COX-2 is related to the development of neuropathic pain.
(RT-PCR) to analyze alteration in COX-2 gene expression inhigh dose, low dose and control animals.
I would like to thank Dr. Daniel Resnick for allowing theopportunity to conduct research in his lab and Dr. Gurwattan
Miranpuri for his guidance and advice. I would also like tothank all the members of the Spinal Cord Injury and Repair
BBB score means for the treatment groups were compared in
lab for their contribution to this project development. Lastly, I
Figure 1. The mean BBB score of animals receiving the high
would like to thank Dr. Janet Branchaw and IBS-SRP. This
dose of Meloxicam, 6.7, was higher than the mean BBB scores
of animals receiving low concentration of meloxicam, 4.2, and
University of Wisconsin-Madison Graduate School
Functional Recovery of Rats following SCI
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Campbell IB, Chessell IP, Clayton N, Collins SD,Davey PT, Goodland H, Gray N, Haslam C, Hatcher
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JP, Hunter AJ, Lucas F, Murkitt G, Naylor A, Pickup
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