Pain is a multidimensional sensory and emotional experience that is important for our survival. Acute pain occurs in response to environmental stimuli and warns us of potential or actual tissue damage. In the event of actual tissue damage, pain serves to promote wound healing and repair. However, in some cases the pain outlasts the stimulus and becomes chronic. Once pain becomes chronic, it is no longer beneficial and, instead, becomes a disorder in and of itself.
Chronic pain is one of our nation’s most significant healthcare problems. Although our understanding of pain neurobiology has grown over the last several years, few new therapeutics have been developed. Thus, it is imperative that further research be conducted to better understand chronic pain; its causes, effects, and treatments.
There are three main objectives of our lab’s research in this area.
- To determine the factors that put some people, but not others, at risk for maladaptive chronic pain conditions. To achieve this objective, we study genetic, biological, and environmental factors associated with the initial onset of pain as well as its severity and duration. In addition, we are beginning to study factors associated with patient-centred outcomes, which may have the power to predict optimal management strategies for different individuals.
- To elucidate the mechanism(s) whereby genetic, biological, and environmental factors drive chronic pain. To achieve this objective, we integrate molecular genetics, animal models, and clinical epidemiologic measures in order to reveal pathogenic processes that are unique to as well as common across a particular condition or individual(s). This line of inquiry will provide novel targets for the development of individualized therapeutics for the management of chronic pain.
- To improve pharmacologic management of pain. To achieve this objective, we conduct pre-clinical studies to test the efficacy of new compounds and to optimize the efficacy of existing compounds in patient-relevant animal models.
Work by our group and others suggests that complex pain conditions are due, in large part, to diminished activity of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines), which results in elevated levels of cathecholamines and increased activity of β2/3-adrenergic receptors (β2/3ARs). β2- and β3ARs are uniquely positioned to promote peripheral and central sensitization by way of proinflammatory cytokines and nitric oxide. However, more work is necessary to understand the complex network of relationships that exists between peripheralm spinal, and central βARs and downstream signaling molecules and their relevance to persisitent pain.
The present studies employ a novel animal model or persistent pain produced by sustained COMT inhibition that closely mimics the persistent pain observed in FM, TMD, and related conditions to elucidate the role βArs play in driving prsistent pain. Specifically, we will 1) identify the subtype and location of βArs that contribute to persistent pain, 2) characterize the long-term consequences of sustained βAR activation on neurons and glia located in spinal and brain regions that relay pain information, 3) characterize the long-term consequences of sustained βAR activation on proinflammatory cytokines and NO, which represent validated markers of nociception, and 4) determine the ability of β2/3AR antagonistst to suppress the transmission of nociceptive information.
The outcome of these studies will provide new insights into mechanisms underlying maladaptive pain conditions, as well as contribute to the identification of previously unexploited targets (e.g., β2- and β3Ars) for development of effective therapies for patients with persistent pain conditions.
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.
Opioids are the most commonly prescribed analgesic for the treatment of clinical pain. However, significant individual variation exists in the degree of opioid analgesia and adverse side-effects (e.g., paradoxical hyperalgesia). This variation is influenced, in part, by allelic variations of the u1 opioid receptor (MOR-1). Recent work has revealed the existence of new exons within the human MOR-1 that contain polymorphisms associated with individual variability in pain sensitivity and MOR-1 agonist responses. Importantly, these polymorphisms are situated within a newly identified MOR-1 isoform that encodes a truncated version of the classical MOR-1 (MOR-1K). Stimulation of MOR-1K leads to excitatory signaling processes divergent from those of MOR-1. Preliminary studies in our lab reveal that MOR-1K transcript expression is enhances in mice exhibiting opioid hyperalgesia. These results suggest that MOR-1K may contribute to hyperalgesia versus analgesia. Additional studies to understand the functional characteristics of MOR-1K, and to determine its potential role in opioid hyperalgesia, are currently underway.
The management of post-operative dental pain is imperative to eliminate needless patient suffering, improve health-related quality of life, and reduce health care costs resulting from additional clinical visists. Post-surgical dental pain is typically treated with orally administered analgesics that block either inflammatory mediators (e.g., NSAIDs, corticosteroids) or central mechanisms of pain perception (e.g., opioids). Although extremely beneficial for managing pain, these orally delivered drugs require continuous self-medication by the patient, and hold potential for adverse systemic effects, which in severe circumstances may result in neurological and respiratory dysfunction, nausea, circulatory depression, addiction, and sleep disruption.
Sustained delivery of a local anesthetic may slow down drug uptake into systemic circulation, thereby improving dental pain management by prolonging drug effectiveness and reducing toxicity. In this approach, a local anesthetic such as Bupivacaine is embedded within a moldable polymeric matrix; when residing within a tooth socket, a sustained dosing regime is enabled. This formulation, presented as a moldable gel or putty, will allow oral surgeons to customize the analgesic to the specific size and shape of a patient’s cavity. As the cavity heals, the anesthetic is continuously released and the matrix dissolved.