Ineffective treatment of common complex persistent pain conditions (CPPCs) such as fibromyalgia (FM), irritable bowel syndrome (IBS), vulvar vestibulitis syndrome (VVS), and episodic migraine (EM) constitutes a significant healthcare problem. These complex cinditions tend to co-occur and are characterized by a report of pain greater than would be expected based on a standard physical evaluation. The pathophysiology of CPPCs is largely unknown and conventional therapeutics possess limited efficacy and adverse side-effects. Thus, further research is imperative to better understand the mechanisms underlying FM, IBS, VVS, and EM. Identification of biological mediators that contribute to these conditions will lead to more accurate subdiagnoses and rational treatment strategies.
Emerging evidence indicates that polymorphic variations in genes coding for key regulators of pain-relevant pathways can produce a phenotype vulnerable to CPPCs. These genes and their corresponding proteins can be classified into one of three major clusters. Cluster 1 consists of those that influence the transmission of pain via peripheral afferents or central nervous system (CNS) pain processing systems (e.g., opioid, catecholamine, and ion channel pathways). Cluster 2 consists of those that mediate inflammatory responses to tissue injury and physiological stress (e.g., prostaglandin, glucocorticoid, and cytokine pathways). Cluster 3 consists of those that influence psychological state (e.g., catecholamine and serotonergic pathways). We hypothesize that common functional polymorphisms in these genes represent areas of genetic vulnerability, that when coupled with environmental triggers, will contribute to altered protein expression levels, enhances pain perception, and psychological dysfunction in individuals with CPPCs.
To test this hypothesis, the present studies will: 1) examine candidate gene polymorphisms in FM, IBS, VVS, and EM cases and pain free controls, using the Pain Research Panel that contains over 3,000 candidate single nucleotide polymorphisms (SNPs) in 360 genes, 2) measure expression of proteins encoded by candidate genes in FM, IBS, VVS, and cases and pain free controls by using a custom protein expression microarray, and 3) measure cell regulatory pathways in FM, IBS, VVS, and EM cases and pain free controls using FACTORIAL biosensor technology developed to assess the activity of multiple transcription factors simultaneously, generating a profile that represents a stable and sustained cell signaling signature. Secondary analyses will be conducted to explore the relationship between genotype, protein expression, regulatory processes, and clinical phenotype.
Elucidating the relationship between genotype, protein expression, regulatory processes, and clinical phenotype will provide new insights into mechanisms underlying maladaptive CPPCs. The outcome of these studies will contribute to the identification of unique genetic and molecular markers for the diagnosis of clinical pain conditions, as well as provide novel targets for the development of effective individualized therapeutics for CPPCs.