Elevated Levels of PGE2-Metabolite in Cerebrospinal Fluid and Cox-2 Gene Polymorphisms in Patients with Chronic, Post Cholecystectomy Pain and Visceral Hyperalgesia Compared to Healthy Controls. A Hypothesis-Generating Pilot Study.

Abstract

Chronic, abdominal pain remains a problem in a subset of patients after cholecystectomy. The cause is often obscure but central sensitization may be an important component and could theoretically be mediated by spinal PGE2, which is regulated by several cytokines. The aim of the study was to examine cerebrospinal fluid (CSF) of participants with post cholecystectomy syndrome and healthy volunteers for signs of PGE2 and cytokine mediated central sensitization. In phase 1 of the study, 83 subjects were included for DNA analysis, eight of these subjects with post cholecystectomy syndrome. We examined the SNPs rs5275, rs16944 and rs1800795 from the Cox-2, IL-1β and IL-6 genes respectively. In phase 2 of the study, we examined concentrations of PGE2-metabolite (PGEM), IL-1β and IL-6 in CSF and plasma from 6 patients with post cholecystectomy syndrome and visceral hyperalgesia and 11 pain free volunteers. We found a significant difference in distribution of the rs5275 SNP of the Cox-2 enzyme (CT-genotype=88% in pain group, 45% in pain free group, TT-genotype=0 in pain group, 41% in pain free group, p=0.05) but not in the other SNPs. PGEM, but not IL-6, was significantly elevated in CSF of the pain group (3.6 pg/mL, sd=1.9 vs 2.1 pg/mL, p=0.03), IL-1β was undetectable. We found elevated PGEM levels in CSF of patients with post cholecystectomy syndrome and visceral hyperalgesia, suggesting a central, possibly inflammatory component to the pain, and overrepresentation of the CT-genotype in the rs5275 SNP in the Cox2 gene, suggesting overexpression of Cox2 as a possible cause for elevated PGEM levels.