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The Effect of
Neuropathic Pain
Damage to the spinal cord often results in neuropathic pain.
Cyclooxygenase 2
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., 2004).
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 Abstract
central pain. (Finnerup et al., 2004).
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 Etiology
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 Introduction
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 Cyclooxygenase
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 al., 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 & Drug Administration
Iadecola, 1997), N-methyl-D-aspartate (an EAA), receptor- Following cSCI, rats underwent placement of a mini-osmotic dependent synaptic activity (Nagaoka et al.,1993), and 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., 1998).
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 Behavioral Assessment
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 Gene Expression
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 Behavioral Assessment
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
1. Barrett H, McClelland JM, Rutkowski SB, Siddall PJ.
Pain characteristics in patients admitted to hospital with complications after spinal cord injury. Arch Phys BBB Score
2. Basso, D.M., Beattie, M.S., Bresnahan, J.C. (1995). A sensitive and reliable locomotor rating scale for openfield testing in rats. J Neurotrauma. 12, 1-21.
Day Post Injury
Figure 1. Comparison of functional recovery measured by BBB scores
3. Beiche F, Klein T, Nusing R, Neuhuber W, Goppelt- between treatment groups. Both the low and high doses of Meloxicam had Struebe M. Localization of cyclooxygenase-2 and much higher scores post-injury than saline.
prostaglandin E2 receptor EP3 in the rat lumbarspinal cord. J Neuroimmunol. 1998; 89(1-2):26-34.
4. Bingham S, Beswick PJ, Bountra C, Brown T, The present study demonstrated that Meloxicam Campbell IB, Chessell IP, Clayton N, Collins SD,Davey PT, Goodland H, Gray N, Haslam C, Hatcher administration promotes functional recovery at least 7 days JP, Hunter AJ, Lucas F, Murkitt G, Naylor A, Pickup post injury. This suggests that COX-2 plays a role in the E, Sargent B, Summerfield SG, Stevens A, Stratton growth inhibiting environment that develops after SCI and that SC, Wiseman J. The cyclooxygenase-2 inhibitor Meloxicam may be a potential promoter of axonal [ 2 - ( 4 - e t h o x y p h e n y l ) - 3 - [ 4 - (methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine] iseffective in animal models of neuropathic pain and The predicted outcome of the study was that rats receiving central sensitization. J Pharmacol Exp Ther. 2005 Meloxicam would display a decrease in NP behavior. Animals receiving the high dose of Meloxicam were expected to havewithdrawal latency times at or near the baseline times by day 5. Bombardier C. An evidence-based evaluation of the 49 post-injury. Animals receiving the low dose were expected gastrointestinal safety of coxibs. Am J Cardiol. 2000; to have higher latency times than the control rats, but not as high as the high dose. The control rats were expected to havelatency times below the baseline.
6. Camu F, Shi L, Vanlersberghe C. The role of COX-2 inhibitors in pain modulation. Drugs. 2003;63 Suppl1:1-7.
7. Engelhardt G, Bogel R, Schnitzeler C, Utzmann R.
19. Nogawa S, Zhang F, Ross ME, Iadecola C. Cyclo- oxygenase-2 gene expression in neurons contributes metabolism. Part 1. In vitro findings. Biochem.
to ischemic brain damage. J Neurosci. 1997 Apr 8. Everts B, Wahrborg P, Hedner T. COX-2-Specific inhibitors--the emergence of a new class of analgesic prostaglandin production following mast cell activation and anti-inflammatory drugs. Clin Rheumatol. 2000; is mediated by proximal secretory phospholipase A2 9. Finnerup NB and Jensen TS. Spinal Cord injury pain- mechanisms and treatment. European journal of 21. Siddall PJ McClelland MJ Rutowski SB Cousins MJ. A longitudional study of the prevalence andcharacteristics of pain in the first 5 years following 10. Fimnerup NB, Johannesen IL, Sindrup SH, Bach FW, spinal cord injury. Pain. 2003; 103:249—257.
Jensen TS. Pain and dysesthesia in patients withspinal cord injury: a postal survey. Spinal Cord 2001; 22. Siddall PJ, Taylor DA and Cousins MJ. Classifcation of pain following spinal cord injury. Spinal Cord.
1997;35, 69-75 11. Finnerup NB, Sindrup SH, Jensen TS. Chronic neuropathic pain: mechanisms, drug targets and 23. Smith WL, Marnett LJ, DeWitt DL. Prostaglandin and thromboxane biosynthesis. Pharmacol Ther.
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hypoalgesia in a rat paw model of inflammation. Br JPharmacol. 2002;137(6):837-44.
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