3 research outputs found
The attenuation of pain behaviour and serum interleukin-6 concentration by nimesulide in a rat model of neuropathic pain Author's personal copy
No full texta b s t r a c t Background: Evidence for a role of immune system in hyperalgesic pain states is increasing. Recent work in neuroimmunology suggests that the immune system does more than simply perform its well known functions of recognizing and removing invading pathogens and tumors. Interest in neuroinflammation and neuroimmune activation has grown rapidly in recent years with the recognition of the role of central nervous system inflammatiom and immune responses in the aetiology of pain states. Among various theories, the role of inflammatory responses of the injured nerve has recently received attention. Cytokines are heterogenous group of polypeptides that activate the immune system and mediate inflammatory responses, acting on a variety of tissue, including the peripheral and central nervous system. Interleukin-6 (IL-6) a pro-inflammatory cytokine, is potentially important in pain aetiology, have pronociceptive actions. Neuropathic pain may be due to a primary insult to the peripheral or central nervous system. Substances released during inflammation from immune cells play an important role in the development and maintenance of chronic pain. Nimesulide, a highly selective cox-2 inhibitor, effectively reduces hyperalgesia due to peripherally administration of inflammatory agents like formalin. The safety of nimesulide was reported for some conditions in which other NSAIDs are contraindicated. Here we have determined the effect of nimesulide on pain behaviour and serum IL-6 level in chronic constriction injury (CCI) model of neuropathic pain. Methods: Experiments were carried out on male Wistar rats, (weight 150-200 g, n = 8). Rats were divided into 3 different groups: 1-CCI + saline 0.9% 2-Sham + saline 0.9% (control) 3-CCI + drug. Nimesulide (1.25, 2.5, 5 mg/kg, i.p.) was injected 1h before surgery and continued daily to day 14 post-ligation. 42 • C water for thermal hyperalgesia, von Frey filaments for mechanical allodynia, acetone test for cool allodynia and 10 • C water for cold hyperalgesia were respectively used as pain behavioural tests. Behavioural tests were recorded before surgery and on postoperative days 1, 3, 5, 7, 10, 14 and the serum concentration of IL-6 was determined at the day 14. Results: The results of this study showed a decrease in hyperalgesia and allodynia following nimesulide administration. Conclusions: It appears that nimesulide was able to reduce pain behaviour due to nerve inflammation and a parallel decrease in the serum IL-6 concentration was observed. Implications: The immune system is an important mediator in the cascade of events that ultimately results in hyperalgesia. Cytokines contribute to the patheogenesis of neuropathic pain, therefore drugs that inhibit cytokine release from immune cells may reduce inflammatory pain states
The attenuation of pain behaviour and serum interleukin-6 concentration by nimesulide in a rat model of neuropathic pain
No full textAbstract
Background
Evidence for a role of immune system in hyperalgesic pain states is increasing. Recent work in neuroimmunology suggests that the immune system does more than simply perform its well known functions of recognizing and removing invading pathogens and tumors. Interest in neuroinflammation and neuroimmune activation has grown rapidly in recent years with the recognition of the role of central nervous system inflammatiom and immune responses in the aetiology of pain states. Among various theories, the role of inflammatory responses of the injured nerve has recently received attention. Cytokines are heterogenous group of polypeptides that activate the immune system and mediate inflammatory responses, acting on a variety of tissue, including the peripheral and central nervous system. Interleukin-6 (IL-6) a pro-inflammatory cytokine, is potentially important in pain aetiology, have pronociceptive actions. Neuropathic pain may be due to a primary insult to the peripheral or central nervous system. Substances released during inflammation from immune cells play an important role in the development and maintenance of chronic pain. Nimesulide, a highly selective cox-2 inhibitor, effectively reduces hyperalgesia due to peripherally administration of inflammatory agents like formalin. The safety of nimesulide was reported for some conditions in which other NSAIDs are contraindicated. Here we have determined the effect of nimesulide on pain behaviour and serum IL-6 level in chronic constriction injury (CCI) model of neuropathic pain.
Methods
Experiments were carried out on male Wistar rats, (weight 150–200 g, n = 8). Rats were divided into 3 different groups: 1-CCI + saline 0.9% 2Sham + saline 0.9% (control) 3CCI + drug. Nimesulide (1.25, 2.5, 5 mg/kg, i.p.) was injected 1h before surgery and continued daily to day 14 post-ligation. 42 °C water for thermal hyperalgesia, von Frey filaments for mechanical allodynia, acetone test for cool allodynia and 10 °C water for cold hyperalgesia were respectively used as pain behavioural tests. Behavioural tests were recorded before surgery and on postoperative days 1, 3, 5, 7, 10, 14 and the serum concentration of IL-6 was determined at the day 14.
Results
The results of this study showed a decrease in hyperalgesia and allodynia following nimesulide administration.
Conclusions
It appears that nimesulide was able to reduce pain behaviour due to nerve inflammation and a parallel decrease in the serum IL-6 concentration was observed.
Implications
The immune system is an important mediator in the cascade of events that ultimately results in hyperalgesia. Cytokines contribute to the patheogenesis of neuropathic pain, therefore drugs that inhibit cytokine release from immune cells may reduce inflammatory pain states.
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Germline determinants of outcome and risk in colorectal cancer
No full textGenome-wide association studies (GWAS) have identified germline single nucleotide
polymorphisms (SNPs) that are associated with colorectal cancer (CRC) susceptibility.
This thesis applies the same approach to the identification of germline determinants of
prognosis in CRC, attempts to verify potential susceptibility loci, and examines the
relationship between SNPs and some forms of non-SNP based germline variation.
The GWAS for prognosis used 931 patients enrolled in the VICTOR trial in the
discovery phase, screening 309,200 autosomal SNPs for an association with disease-free
survival (DFS). Following the application of selection filters based on statistical
significance levels and performance of the genotyping, 40 SNPs were identified to be
examined in further cohorts. The verification phase consisted of 1338 patients in the
PETACC 3 trial and three population based cohorts: 899 patients from Scotland, 599
patients from Denmark, and 962 patients from Finland.
The SNPs that came closest to genome-wide significance in stage 2 and 3 CRC was
rs7556894, 15kb from Actin-related protein 2 (ARP2) on chromosome 2, part of the
ARP2/3 complex essential for cell shape and motility, with p=8.96e-07. The impact on
prognosis of rs7556894 was estimated as HR=1.52 (95% CI 1.17-1.96).
Because of the failure to reach genome-wide significance (p<1e-07), two further
approaches to the discovery phase are presented: the meta-analysis of two discovery
cohorts to increase event rate and subject numbers and a GWAS for predictive markers
for the benefit of adjuvant 5-FU chemotherapy. Formal verification of either approach
was not undertaken as part of this thesis.
Further loci were subjected to specific analyses of association with prognosis or CRC
susceptibility: rs6983267 and the previously identified CRC susceptibility loci to a survival
analysis, and not found to be associated; rs6687758, previously identified as a potential
CRC risk locus to a susceptibility verification, confirming a significant association with
HR=1.15, 95% CI 1.10-1.21, p=5.04e-08; and a variety of hypothesis driven potential
risk loci to a screen for an association with CRC susceptibility, none was found but the
LD relationship between tagSNPs and insertion/deletion polymorphisms appears to be
the same as for ‘normal’ SNPs.
Overall, the data presented in this thesis quantify further the contribution of germline
variation to CRC susceptibility, exclude a major effect of such variation on prognosis, and
verify rs6687758 as a further low-penetrance CRC susceptibility locus
