Chronic pain affects millions of people worldwide and is a serious socioeconomic problem. Unfortunately, pain mechanisms are poorly understood, often resulting in inadequate treatment outcomes where the vast majority of individuals suffer for years with little relief. Fortunately, in the last decade, we have witnessed an increased enthusiasm in the field of pain research; a trend that is very encouraging for the millions of pain sufferers worldwide.
My PhD work has focused on a very prevalent condition: chronic low back pain. The main emphasis was on the mechanisms of back pain in a mouse model and we were fortunate enough to translate our findings to humans. Interestingly, we were also the first group to report the link between DNA methylation and pain; a field that is currently advancing very rapidly since it provides a molecular mechanism of environment-gene interactions. In addition to our back pain studies, we have also carried out research examining the brain changes that occur after peripheral nerve injury, with particular emphasis on reversible methylation changes in the prefrontal cortex. Our findings provide the molecular link between peripheral nerve injury and changes in the brain, thus helping us account for the co-morbidities associated with pain. These formative years at the Alan Edwards Center for Research on Pain (AECRP) have given me a solid training in the field of pain research.
I began my postdoctoral training at Stanford University in 2013, where I chose to study another debilitating chronic pain condition, Complex Regional Pain Syndrome (CRPS). Using a previously-validated mouse model of CRPS, we could show that pain-associated comorbidities are paralleled by dendritic architectural changes in various brain regions. In parallel, I developed a novel interest in the autoimmune mechanisms of CRPS, an area that remains largely unexplored. We believe this line of investigation to be paradigm shifting; indeed, approaching CRPS as an autoimmune disease opens entirely new experimental pathways to identifying specific supporting mechanisms and provides opportunities for novel therapeutic development.
In addition to laboratory research, I am passionate about science outreach in general and pain outreach in particular. I believe it is our responsibility as scientists to disseminate our knowledge to the layperson, particularly since chronic pain is a widespread condition with significant socioeconomic impact. To that end, I am an avid participant in pain awareness efforts through public lectures and social media involvement.
Honors & Awards
Graduate Fellowship, The Network for Oral and Bone Health Research (2009)
Graduate Fellowship, Armenian International Women's Association (2009)
Hugh E Burke graduate fellowship, McGill University (2010)
Trainee Research Grant, Canadian Pain Society (2010)
Award for best poster presentation (McGill Pain day), Quebec Pain Research Network (2010)
Award for best oral presentation (Philip Bromage Research Day), Anesthesia Dept., McGill University (2011)
Doctoral Fellowship, Louise and Alan Edwards Foundation (2011)
National poster competition silver award, Canadian Institute of Health Research (2011)
Medstar award for Research Excellence, Faculty of Medicine, McGill University (2012)
Kresimir Krnjevic award for Best Published Manuscript., Anesthesia Dept., McGill University (2012)
Doctor of Philosophy, McGill University (2013)
Master of Science, McGill University (2008)
Bachelor of Science, American University Of Beirut (2004)
David Clark, Postdoctoral Faculty Sponsor
Community and International Work
Co-founder of Thwacke
Science Media Consultant
Opportunities for Student Involvement
New Concepts in Complex Regional Pain Syndrome.
2016; 32 (1): 41-49
Despite the severe pain and disability associated with complex regional pain syndrome (CRPS), the lack of understanding of the pathophysiological mechanisms supporting this enigmatic condition prevents the rational design of new therapies, a situation that is frustrating to both the physician and the patient. The review highlights some of the mechanisms thought to be involved in the pathophysiology of CRPS in preclinical models and CRPS patients, with the ultimate goal that understanding these mechanisms will lead to the design of efficacious, mechanism-based treatments available to the clinic.
View details for DOI 10.1016/j.hcl.2015.08.003
View details for PubMedID 26611388
Novel cytogenic and neurovascular niches due to blood-brain barrier compromise in the chronic pain brain
The mechanisms by which painful injuries are linked to the multitude of pain-related comorbidities and neuroplastic changes in the brain remain poorly understood. Here we propose a model that relies on epi-neuronal communication through the vascular system to effect various brain structures. Specifically, we hypothesize that the differential vulnerability of the blood-brain barrier (BBB) in different brain regions is associated with region-specific neuroplastic and neurovascular changes that are in turn associated with particular pain-related comorbidities.We will present our hypothesis by focusing on two main points: (A) chronic pain (CP) is associated with differential BBB compromise. (B) Circulating mediators leaking through the BBB create cytogenic and neovascular niches associated with pain-related co-morbidities.Pre-clinically, our hypothesis can be tested by observing, in parallel, BBB compromise, (neo)vascularization, neurogenesis, and their co-localization in animal pain models using imaging, microscopy, biochemical and other tools. Furthermore, the BBB can be experimentally damaged in specific brain regions, and the consequences of those lesions studied on nociception and associated comorbidities. Recently developed imaging techniques allow the analysis of blood brain barrier integrity in patients providing a route for translation of the laboratory findings. Though perhaps more limited, post-mortem examination of brains with available pain histories constitutes a second approach to addressing this hypothesis.Understanding changes in BBB permeability in chronic pain conditions has clear implications both for understanding the pathogenesis of chronic pain and for the design of novel treatments to prevent chronic pain and its consequences. More broadly, this hypothesis may help us to understand how peripheral injuries impact the brain via mechanisms other than commonly studied efferent sensory pathways.
View details for DOI 10.1186/s12990-015-0066-6
View details for Web of Science ID 000362540900001
View details for PubMedID 26453186
Sex differences in a Murine Model of Complex Regional Pain Syndrome
NEUROBIOLOGY OF LEARNING AND MEMORY
2015; 123: 100-109
Complex Regional Pain Syndrome (CRPS) is a major cause of chronic pain after surgery or trauma to the limbs. Despite evidence showing that the prevalence and severity of many forms of chronic pain, including CRPS, differ between males and females, laboratory studies on sex-related differences in animal models of CRPS are not available, and the impact of sex on the transition from acute to chronic CRPS pain and disability are unexplored. Here we make use of a tibia fracture/cast mouse model that recapitulates the nociceptive, functional, vascular, trophic, inflammatory and immune aspects of CRPS. Our aim is to describe the chronic time course of nociceptive, motor and memory changes associated with fracture/cast in male and female mice, in addition to exploring their underlying spinal mechanisms. Our behavioral data shows that, compared to males, female mice display lower nociceptive thresholds following fracture in the absence of any differences in ongoing or spontaneous pain. Furthermore, female mice show exaggerated signs of motor dysfunction, deficits in fear memory, and latent sensitization that manifests long after the normalization of nociceptive thresholds. Our biochemical data show differences in the spinal cord levels of the glutamate receptor NR2b, suggesting sex differences in mechanisms of central sensitization that could account for differences in duration and severity of CRPS symptoms between the two groups.
View details for DOI 10.1016/j.nlm.2015.06.004
View details for Web of Science ID 000359510900013
- The role of the extracellular matrix in chronic pain following injury PAIN 2015; 156 (3): 366-370
Differential Efficacy of Ketamine in the Acute versus Chronic Stages of Complex Regional Pain Syndrome in Mice.
2015; 123 (6): 1435-47
Complex regional pain syndrome (CRPS) is a painful, disabling, and often chronic condition, where many patients transition from an acute phase with prominent peripheral neurogenic inflammation to a chronic phase with evident central nervous system changes. Ketamine is a centrally acting agent believed to work through blockade of N-methyl-D- aspartate receptors and is being increasingly used for the treatment of refractory CRPS, although the basis for the drug's effects and efficacy at different stages of the syndrome remains unclear.The authors used a mouse model of CRPS (n = 8 to 12/group) involving tibia fracture/cast immobilization to test the efficacy of ketamine (2 mg kg day; 7 days) or vehicle infusion during acute (3 weeks after fracture) and chronic (7 weeks after fracture) stages.Acute-phase fracture mice displayed increased limb temperature, edema, and nociceptive sensitization that were not reduced by ketamine. Fracture mice treated with ketamine during the chronic phase showed reduced nociceptive sensitization that persisted beyond completion of the infusion. During this chronic phase, ketamine also reduced latent nociceptive sensitization and improved motor function at 18 weeks after fracture. No side effects of the infusions were identified. These behavioral changes were associated with altered spinal astrocyte activation and expression of pain-related proteins including N-methyl-D-aspartate receptor 2b, Ca/calmodulin-dependent protein kinase II, and brain-derived neurotrophic factor.Collectively, these results demonstrate that ketamine is efficacious in the chronic, but not acute, stage of CRPS, suggesting that the centrally acting drug is relatively ineffective in early CRPS when peripheral mechanisms are more critical for supporting nociceptive sensitization.
View details for DOI 10.1097/ALN.0000000000000889
View details for PubMedID 26492479
An epigenetic hypothesis for the genomic memory of pain.
Frontiers in Cellular Neuroscience
2015; 9 (88)
View details for DOI 10.3389/fncel.2015.00088
Brain Neuroplastic Changes Accompany Anxiety and Memory Deficits in a Model of Complex Regional Pain Syndrome
2014; 121 (4): 852-865
View details for Web of Science ID 000342741000020
Peripheral Nerve Injury Is Associated with Chronic, Reversible Changes in Global DNA Methylation in the Mouse Prefrontal Cortex
2013; 8 (1)
Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with abnormal behavior and pathological gene expression in the central nervous system. DNA methylation might also be involved in mediating the pathologies associated with chronic pain in the brain. We therefore tested a) whether alterations in DNA methylation are found in the brain long after chronic neuropathic pain is induced in the periphery using the spared nerve injury modal and b) whether these injury-associated changes are reversible by interventions that reverse the pathologies associated with chronic pain. Six months following peripheral nerve injury, abnormal sensory thresholds and increased anxiety were accompanied by decreased global methylation in the PFC and the amygdala but not in the visual cortex or the thalamus. Environmental enrichment attenuated nerve injury-induced hypersensitivity and reversed the changes in global PFC methylation. Furthermore, global PFC methylation correlated with mechanical and thermal sensitivity in neuropathic mice. In summary, induction of chronic pain by peripheral nerve injury is associated with epigenetic changes in the brain. These changes are detected long after the original injury, at a long distance from the site of injury and are reversible with environmental manipulation. Changes in brain structure and cortical function that are associated with chronic pain conditions may therefore be mediated by epigenetic mechanisms.
View details for DOI 10.1371/journal.pone.0055259
View details for Web of Science ID 000315211500068
View details for PubMedID 23383129
- Peripheral nerve injury is accompanied by chronic transcriptome-wide changes in the mouse prefrontal cortex molecular pain 2013; 9 (21)
Acute and chronic phases of complex regional pain syndrome in mice are accompanied by distinct transcriptional changes in the spinal cord
2013; 9 (40)
View details for DOI 10.1186/1744-8069-9-40
Lumbar intervertebral disc degeneration associated with axial and radiating low back pain in ageing SPARC-null mice
2012; 153 (6): 1167-1179
Chronic low back pain (LBP) is a complex, multifactorial disorder with unclear underlying mechanisms. In humans and rodents, decreased expression of secreted protein acidic rich in cysteine (SPARC) is associated with intervertebral disc (IVD) degeneration and signs of LBP. The current study investigates the hypothesis that IVD degeneration is a risk factor for chronic LBP. SPARC-null and age-matched control mice ranging from 6 to 78 weeks of age were evaluated in this study. X-ray and histologic analysis revealed reduced IVD height, increased wedging, and signs of degeneration (bulging and herniation). Cutaneous sensitivity to cold, heat, and mechanical stimuli were used as measures of referred (low back and tail) and radiating pain (hind paw). Region specificity was assessed by measuring icilin- and capsaicin-evoked behaviour after subcutaneous injection into the hind paw or upper lip. Axial discomfort was measured by the tail suspension and grip force assays. Motor impairment was determined by the accelerating rotarod. Physical function was evaluated by voluntary activity after axial strain or during ambulation with forced lateral flexion. SPARC-null mice developed (1) region-specific, age-dependent hypersensitivity to cold, icilin, and capsaicin (hind paw only), (2) axial discomfort, (3) motor impairment, and (4) reduced physical function. Morphine (6 mg/kg, i.p.) reduced cutaneous sensitivity and alleviated axial discomfort in SPARC-null mice. Ageing SPARC-null mice mirror many aspects of the complex and challenging nature of LBP in humans and incorporate both anatomic and functional components of the disease. The current study supports the hypothesis that IVD degeneration is a risk factor for chronic LBP.
View details for DOI 10.1016/j.pain.2012.01.027
View details for Web of Science ID 000304249100011
View details for PubMedID 22414871
Morphine and clonidine synergize to ameliorate low back pain in mice.
Pain research and treatment
2012; 2012: 150842-?
Chronic low back pain (LBP) is a debilitating condition associated with signs of axial and radiating pain. In humans with chronic LBP, opioids are often prescribed with varying outcomes and a multitude of side effects. Combination therapies, in which multiple pharmacological agents synergize to ameliorate pain without similar potentiation of adverse reactions, may be useful in improving therapeutic outcome in these patients. The SPARC-null mouse model of low back pain due to disc degeneration was used to assess the effects of opioid (morphine) and ?(2)-adrenergic agonist (clonidine) coadministration on measures of axial and radiating pain. The results indicate that systemic morphine and clonidine, coadministered at a fixed dose of 100?:?1 (morphine?:?clonidine), show a synergistic interaction in reversing signs of axial LBP, in addition to improving the therapeutic window for radiating LBP. Furthermore, these improvements were observed in the absence of synergy in assays of motor function which are indicative of side effects such as sedation and motor incoordination. These data show that the addition of low-dose systemic clonidine improves therapeutic outcome in measures of both axial and radiating pain. Combination therapy could be of enormous benefit to patients suffering from chronic LBP.
View details for DOI 10.1155/2012/150842
View details for PubMedID 22577543
DNA methylation of SPARC and chronic low back pain
The extracellular matrix protein SPARC (Secreted Protein, Acidic, Rich in Cysteine) has been linked to degeneration of the intervertebral discs and chronic low back pain (LBP). In humans, SPARC protein expression is decreased as a function of age and disc degeneration. In mice, inactivation of the SPARC gene results in the development of accelerated age-dependent disc degeneration concurrent with age-dependent behavioral signs of chronic LBP.DNA methylation is the covalent modification of DNA by addition of methyl moieties to cytosines in DNA. DNA methylation plays an important role in programming of gene expression, including in the dynamic regulation of changes in gene expression in response to aging and environmental signals. We tested the hypothesis that DNA methylation down-regulates SPARC expression in chronic LBP in pre-clinical models and in patients with chronic LBP.Our data shows that aging mice develop anatomical and behavioral signs of disc degeneration and back pain, decreased SPARC expression and increased methylation of the SPARC promoter. In parallel, we show that human subjects with back pain exhibit signs of disc degeneration and increased methylation of the SPARC promoter. Methylation of either the human or mouse SPARC promoter silences its activity in transient transfection assays.This study provides the first evidence that DNA methylation of a single gene plays a role in chronic pain in humans and animal models. This has important implications for understanding the mechanisms involved in chronic pain and for pain therapy.
View details for DOI 10.1186/1744-8069-7-65
View details for Web of Science ID 000295594100001
View details for PubMedID 21867537
Behavioral Signs of Chronic Back Pain in the SPARC-Null Mouse
2011; 36 (2): 95-102
Secreted Protein, Acidic, and Rich in Cysteine (SPARC)-null mice were examined for behavioral signs of chronic low back and/or radicular pain.to assess SPARC-null mice as an animal model of chronic low back and/or radicular pain caused by degenerative disc disease.degeneration of intervertebral discs is a major cause of chronic low back and adicular pain in humans. Inactivation of the SPARC gene in mice results in premature intervertebral disc degeneration. The effect of disc degeneration on behavioral measures of chronic pain has not been evaluated in this model.cohorts of young and old (3 and 6-12 months, respectively) SPARC-null and wild-type control mice were screened for behavioral indices of low back and/or radiating pain. Sensitivity to mechanical, cold and heat stimuli, locomotor impairment, and movement-evoked hypersensitivity were determined. Animals were challenged with 3 analgesic agents with different mechanisms: morphine, dexamethasone, and gabapentin.SPARC-null mice showed signs of movement-evoked discomfort as early as 3 months of age. Hypersensitivity to cold stimuli on both the lower back and hindpaws developed with increasing age. SPARC-null mice had normal sensitivity to tactile and heat stimuli, and locomotor skills were not impaired. The hypersensitivity to cold was reversed by morphine, but not by dexamethasone or gabapentin.SPARC-null mice display behavioral signs consistent with chronic low back and radicular pain that we attribute to intervertebral disc degeneration. We hypothesize that the SPARC-null mouse is useful as a model of chronic back pain due to degenerative disc disease.
View details for DOI 10.1097/BRS.0b013e3181cd9d75
View details for Web of Science ID 000286177900011
View details for PubMedID 20714283