Chronic pain is a major health problem affecting more than 1.5 billion people worldwide. Specifically, neuropathic pain and chronic post-surgical pain are debilitating clinical conditions with few efficacious treatments, warranting development of novel therapeutics. Starting with the hypothesis that dysregulated translation regulation pathways may underlie these pain states, we demonstrated that there is a major reorganization of translation machinery in the peripheral nervous system of rats and mice, including enhanced mTOR and ERK activity and increased phosphorylation of mTOR and ERK downstream targets in these persistent pain states. We also hypothesized that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the treatment of neuropathic and incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors. The AMP activated protein kinase (AMPK) activators, metformin, resveratrol and A769662, inhibited translation regulation signaling pathways in sensory neurons, eIF4F complex formation, nascent protein synthesis in injured nerves and sodium channel-dependent excitability of sensory neurons resulting in a resolution of neuropathic allodynia. We have further demonstrated that local injection of resveratrol, metformin or A769662 and topical application of resveratrol, a potent AMPK activator, into the hindpaw following plantar incision dose-relatedly reverses incision-mediated mechanical hypersensitivity as well as hyperalgesic priming induced by incision. In addition, co-treatment with systemic metformin and local resveratrol at individually sub-efficacious doses at the time of incision blocked acute hypersensitivity and hyperalgesic priming suggesting potential super-additive effects of combined AMPK activator use. These results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.

Persistent postsurgical pain (PPSP) is reported as recurrent and frequently disabling complication of many surgical procedures. The consequences for PPSP not only reduce the quality of life for patients but also financially tax the health care system, considering the volume of surgical procedures performed annually. Development of chronic pain has been proposed to involve a complex pathophysiology combined with pre-, intra-, and post-operative risk factors. There is no definite recommendation on which factor to assess (in which surgery) and what tools to utilize for conducting a study on PPSP, since many recognized risk factors for PPSP are contradictory. For a comprehensive overview of major PPSP risk factors for identification and possible prevention, we conducted a systematic review and meta-analysis of the published literature on the risk factors across six major surgical groups: breast surgery, chest/thoracic surgery, total hip arthroplasty/total knee arthroplasty (THA/TKA), gynecologic surgery, iliac crest bone harvest (ICBH), and groin hernia repair. Furthermore, to assess the generalizability of the meta-analysis results, we sought to conduct a retrospective, cross-sectional study examining the prevalence and major risk factors of PPSP after cystectomy for bladder cancer. The meta-analysis found that no single risk factor was associated with PPSP across all surgical groups. Age and previous surgery were found to be risk factors for PPSP in gynecologic surgery. For thoracic surgery, male sex and BMI were found as risk factors for PPSP. Surgical duration, presurgical chronic pain, and BMI were risk factors for groin hernia repair. The prevalence of PPSP in our cystectomy study was 22.1%. Female sex and presurgical chronic pain were risk factors significantly associated with PPSP after cystectomy. No risk factors were universally associated with PPSP. Persistent pain after each type of surgical procedure appear to have separate set risk factors among age, BMI, sex, previous surgery, and presurgical pain.

Chronic pain is an ever-present issue and some estimate its cost to society at $635 billion per year. Not only does chronic pain cause increased visits to medical personnel, it also complicates other medical conditions and lowers productivity in the workplace. One area of study includes Chronic Post Surgical Pain (CPSP) in children that have undergone spinal fusion surgery for Adolescent Idiopathic Scoliosis (AIS). Some of the major factors that may lead to CPSP include preoperative pain, psychosocial factors, age, intraoperative nerve injury, acute postoperative pain, and genetics. In order to explore the psychological factors, our lab has employed an Unpredictable Chronic Mild Stress (UCMS) paradigm, which models unforeseen life stressors and depression. Some sensory testing was conducted included Hot Plate and von Frey fiber testing. Previous studies from this lab have shown that adult male mice have hyperalgesia to thermal stimuli following a UCMS paradigm. To further explore this finding, a younger mice cohort of both sexes and a cohort that underwent Maternal Deprivation (MD) were added. Maternal Deprivation is a model of early-childhood stress and older female mice have been shown to have changes in thermal sensitivities as a result of early childhood stressors. Our lab found that stressed young females also exhibit a heightened sensitivity to thermal stimuli at 49°C compared to their male and control counter parts. These results indicate that the thermal sensitivity of young females can be affected by early childhood stress and depression.

OBJECTIVE: The overall goal of this study was to examine the relationship between preoperative, 1-year post-operative, and 2-year postoperative self-image in adolescents with idiopathic scoliosis undergoing spinal fusion surgery. In addition, a minor goal was to examine the relationship between pre-surgical mental health and post-surgical self-image and satisfaction. Additionally, spinal curvature and preoperative pain were explored in relation to the effect of pre-surgical mental health on post-surgical self-image. Analyses were performed in order to better understand the relationship of corrective surgery to self-image, and self-image's relationship to persistent postoperative pain, which has been recognized as a common clinically significant problem. METHODS: The Scoliosis Research Society Questionnaire-30 and Spinal Appearance Questionnaire were administered to 219 patients enrolled in the Prospective Pediatric Scoliosis study at pre-operative, 1-year post-operative, and 2-year post-operative time points. A subset (n=163) of these patients had complete data. The Scoliosis Research Society Questionnaire-30 includes pain and mental health subscales, which were examined preoperatively for the purpose of this study. Measurements of preoperative curve (Cobb) angle percentage correction were used in the analysis of this data, which were determined using operative notes. The Spinal Appearance Questionnaire (SAQ) includes self-image appearance and expectations subscales, which were examined at the preoperative, 1-year postoperative, and 2-year postoperative time points. RESULTS: There were significant improvements in self-image after surgical intervention in children with idiopathic scoliosis undergoing spinal fusion surgery. Cobb angle percentage correction, preoperative pain scores as determined by the SRS-30, and preoperative mental health scores as determined by the SRS-30 were not significant predictors of postoperative self-image as measured by the SAQ. There is little to no correlation between the preoperative measures and postoperative self-image. CONCLUSIONS: Prior studies have confirmed that pediatric persistent postsurgical pain is a significant health concern, and that presurgical mental health and self-image are factors that contribute to a pediatric patient's longitudinal experience with postsurgical pain. This study shows that there are clinically significant improvements in self-image after surgical intervention in patients with adolescent idiopathic scoliosis undergoing spinal fusion surgery. These findings suggest that preoperative pain, degree of spinal curvature correction, and preoperative mental health are not determinative of postoperative self-image in pediatric populations. Future studies should be conducted on more diverse populations, and take into account measures that may be predictors of poor postoperative self-image, specifically depression and anxiety. In summary it is important to explore the biological mechanisms pertaining to pediatric post-surgical chronic pain and their relation to differences in somatosensory phenotypes in this patient population.

To understand pain processing requires the assessment of an individual’s perception of pain with temporal stimulation over different periods. Offset analgesia (OA), a phenomenon widely studied, refers to a disproportionate decrease in pain experience following a small reduction in temperature during noxious thermal stimulation. OA leads to skin desensitization, causing brief pain inhibition at the stimulation site and leading to adaptation and a decrease in pain scores. To avoid sensitization and habituation during thermal pain procedures, previous studies have utilized protocols in which the thermal stimulation is applied to different areas of the skin (e.g., upper forearm versus lower forearm). The reliability of this thermal pain calibration procedure in producing a nonadaptive effect has been previously tested using pain rating scales. The utilization of neuroimaging to further elucidate these relationships has not been widely studied, but it is likely an important tool to investigate these constructs. Functional near-infrared spectroscopy (fNIRS) is a noninvasive optical imaging technique that measures changes in hemoglobin (Hb) concentrations within the brain using the characteristic absorption spectra of Hb in the near-infrared range. This thesis investigated whether adaptation exists across four conditions of the OA paradigm using fNIRS. Introducing fNIRS to define significant differences in brain metrics (e.g., activated regions of interest) in participants who have undergone surgery and are experiencing chronic pain as well as healthy, pain-free controls could have implications for more accurate measures of OA and more reliable pain treatment options. In this study, noxious thermal stimulation was given to 19 participants on the forearm of the nondominant hand through a commonly used three-temperature OA paradigm with offset, constant, and control trials. Each OA paradigm consisted of four conditions (A, B, C, and D) with a pseudorandom sequence design of three trials. OA was implemented with the participant while real-time fNIRS data were obtained on the subject’s prefrontal and somatosensory cortices, regions known to be involved in pain processing. Hemoglobin responses during the four OA trials were evaluated and compared within experimental conditions. Repeated measures ANOVA was used to analyze the significant differences among conditions. Results showed no significant differences among the four OA trials. The findings of this thesis study indicated that brain response from the prefrontal and somatosensory cortices is not affected within the four OA trials. The consistent brain activation across multiple trials of stimulation suggests an absence of adaptive responses. In line with previous findings, these results imply the reliability of such thermal pain calibration procedures by fNIRS brain imaging. Further investigation with a larger sample size is likely for the verification of the findings from this study. / 2026-02-14T00:00:00Z

Background: Thousands of Canadians undergo cardiac surgery each year with the aim of relieving symptoms (e.g., angina) and improving health-related-quality-of-life (HRQoL). Despite the demonstrated symptom-related benefits of these surgeries, evidence suggests that the development of chronic post-surgical pain (CPSP) is a major clinical problem. To date, several perioperative factors have been examined for their potential to confer risk for CPSP. Purpose: The purpose of the study was to explore the association between preoperative moderate to severe anxiety and depressive symptoms; moderate to severe acute postoperative pain; and cumulative opioid dose consumption with the development of CPSP at six months and 12 months after cardiac surgery. Method: Design. This thesis was a prospective observational cohort sub-study of adults undergoing cardiac surgery in a tertiary care hospital setting (n=735), recruited from Hamilton Health Sciences, Canada over a five year period. Measures. The independent variables included state anxiety, depressive symptoms, acute postoperative pain intensity, and opioid dose consumption. At baseline, the Spielberger State-Trait Anxiety Inventory (STAI) assessed state anxiety and the Hospital Anxiety and Depression Scale (HADS) assessed depressive symptoms. The Brief Pain Inventory-Short Form (BPI-SF) assessed acute postoperative pain intensity on postoperative days three (in-hospital) and 30 (at home via telephone). All instruments have established reliability and validity in cardiac surgery patients (e.g., STAI Cronbach’s alpha (α) =0.82; HADS α=0.81; BPI-SF α=0.87). Medical records were reviewed and total dose of opioids consumed up to three days postoperatively, were collected via analgesic chart audit and converted into milligrams of parenteral morphine equivalent dose using standard dosage tables. Dependent variable. The primary outcome of CPSP was assessed dichotomously (i.e., yes/no) at six months and 12 months after cardiac surgery. If present, CPSP was assessed via the BPI-SF. At baseline, data was collected on pre-specified model covariates (e.g., age, sex). Data Analyses. Logistic regression was used to model the primary outcome with the presence of CPSP at six months and 12 months, while adjusting for model covariates. Secondary linear regression models were constructed to examine the effect of the independent variables on the severity of CPSP with statistical significance set at p-values <0.05. Results: The incidence of CPSP was 8.7% at six months and 4.1% at 12 months after cardiac surgery. Baseline demographics (i.e., age, sex) and medical status (i.e., diabetes mellitus) were significantly associated with the presence of CPSP. Moderate to severe preoperative anxiety was not significantly associated with CPSP at six months (adjusted OR 0.629, 95% CI [0.300, 1.322], p=0.222) or 12 months (adjusted OR 0.743, 95% CI [0.242, 2.285], p=0.604). Moderate to severe preoperative depressive symptom was not significantly associated with CPSP at six months (adjusted OR 0.676, 95% CI [0.152, 3.005], p=0.607) or 12 months (adjusted OR 3.216, 95% CI [0.835, 12.382], p=0.089). Acute postoperative pain rated as pain ‘right now’ on day three was significantly associated with CPSP at six months (adjusted OR 2.263, 95% CI [1.255, 4.081], p=0.007) and 12 months (adjusted OR 2.749, 95% CI [1.174, 6.441], p=0.020). Acute postoperative pain ‘right now’ on day 30 was significantly associated with CPSP at six months (adjusted OR 2.913, 95% CI [1.304, 6.505], p=0.009). Cumulative opioid dose consumed was significantly associated with the development of CPSP at six months (adjusted OR 1.001, 95% CI [1.000, 1.002], p=0.003) and 12 months (adjusted OR 1.001, 95% CI [1.000, 1.001], p=0.033) after cardiac surgery. Significance: The findings demonstrate that acute postoperative pain ‘right now’ and cumulative opioid dose consumed are risk factors for CPSP after cardiac surgery. These findings offer targets for nursing staff to identify potentially at-risk patients, implement evidence-based pain management strategies, as well as contribute to nursing-led research designed to target CPSP after cardiac surgery. / Dissertation / Doctor of Philosophy (PhD)

With chronic post surgical pain affecting up to one third of patients undergoing surgeries and the price of treatment being astoundingly high there has been a transition in research to investigate and identify risk factors. Through identification of risk factors new preventative measures can be taken to ensure better surgical outcomes. The role that psychosocial factors can play in the development of chronic post surgical pain has long been recognized yet its mechanisms are still unknown. We aim to investigate how environment can play a direct role in pain perception and sensitivity. We used a Chronic Mild Stress (CMS) paradigm to induce depression in 10 adult male mice, we used 10 control mice who were left in standard opti cages, and 10 enriched mice who were placed in large enrichment cages. CMS mice were exposed to a series of stressors and all mice underwent spared nerve injury surgery. During spared nerve injury the common peroneal and tibial branches of the sciatic nerve were severed while the sural branch was left intact. Overall well-being and pain threshold of mice were tested via Von Frey, Hot Plate, Heat Place Preference, Dynamic Weight Bearing, Hole Board, and Social Interaction. It was found that CMS mice experienced thermal hyperalgesia yet normal thermal threshold sensation. CMS mice also spent less time interacting with novel mice in social interaction, and less amount of time exploring the center of the hole board arena than control or enriched mice. While Von Frey results did not change over the course of the experiment, dynamic weight bearing results indicated spared nerve injury surgery was successful and produced chronic pain. Results indicate that environment plays a role in thermal pain perception and CMS affected overall well being of mice as CMS mice exhibited more timid and anxious behavior.

In this thesis, rodent models of chronic pain were used to explore analgesic mechanisms that may potentially be engaged in spinal and peripheral compartments by systemically-administered amitriptyline, a tricyclic antidepressant. The first project (Chapter 2) identified the roles of spinal adenosine A1 and serotonin 5-HT7 receptors, as well as of peripheral adenosine A1 receptors, in the acute antinociceptive effects of amitriptyline in mice. The second project (Chapter 3) examined the potential utility of amitriptyline as a preventive analgesic against persistent post-surgical pain, and involved perioperative administration of amitriptyline after peripheral nerve injury in rats. Changes in post-injury behavioural outcomes, as well as spinal noradrenergic sprouting, were assessed. Overall, spinal serotonergic pathways linked to adenosine A1 receptors, as well as peripheral adenosine A1 receptors, appear to be important in antinociception by amitriptyline. Preventive analgesia by this drug does not appear to result from anatomical changes in spinal noradrenergic pathways.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Monoamines appear to play an important modulatory role on pain descending pathways and are involved in the antinociceptive mechanism of several drugs commonly used for the management of pain. In this study, we assessed the involvement of monoamine oxidase B (MAO-B), a key enzyme implicated in monoamine metabolism, on models of postsurgical and neuropathic pain in mice. For this purpose, we evaluated the effects of the selective and irreversible MAO-B inhibitor selegiline on mechanical sensitivity and ex vivo MAO-B activity in different central nervous system regions in mice submitted to incisional and partial sciatic nerve ligation (PSNL) pain models. Mice subjected to plantar incision showed a significant decrease in mechanical threshold when compared with sham-operated mice, characterizing the development of mechanical allodynia. Selegiline, at a dose sufficient to inhibit selectively the MAO-B activity (10 mg/kg), showed an anti-allodynic effect from 0.5 until 6 h after incision. The MAO-B activity was not altered in incision submitted mice when compared with sham-operated animals in any analyzed structure. Likewise, PSNL submitted mice also developed mechanical allodynia, which was reversed by selegiline (10 mg/kg) from 2 until 6 h after treatment. In addition, a significant increase on striatal MAO-B activity was observed in mice subjected to PSNL when compared with sham-operated animals, which was reversed by selegiline treatment. Taken together, our results showed that selegiline presented an antinociceptive effect on mice models of both acute and chronic pain, suggesting a potential involvement of MAO-B on pain mechanisms. / As monoaminas possuem uma função modulatória importante nas vias descendentes do controle da dor e estão envolvidas no mecanismo antinociceptivo de diversos fármacos comumente utilizados no tratamento de síndromes dolorosas. Nesse estudo, nós avaliamos a participação da monoamina oxidase B (MAO-B), uma enzima chave envolvida no metabolismo das monoaminas, em modelos de dor pós-operatória e neuropática em camundongos. Para esse propósito, foram avaliados os efeitos da selegilina, um inibidor seletivo e irreversível da MAO-B, na sensibilidade mecânica e na atividade ex vivo da MAO-B em diferentes regiões do sistema nervoso central (córtex cerebral, estriado e medula espinhal) de camundongos submetidos à incisão plantar ou à ligação parcial do nervo ciático (PSNL). Os camundongos que foram submetidos à incisão plantar apresentaram uma diminuição significativa no limiar mecânico quando comparados aos animais falso-operados, caracterizando o desenvolvimento de alodínia mecânica. Tanto o pré quanto o pós-tratamento com selegilina, em uma dose capaz de inibir seletivamente a atividade da MAO-B (10 mg/kg, p.o.), apresentaram efeito anti-alodínico a partir de 0,5 até 6 h após o tratamento. A atividade da MAO-B, medida 4 h após o procedimento cirúrgico, não foi alterada nos camundongos submetidos à incisão quando comparada com a atividade dos animais falso-operados em nenhuma das estruturas analisadas. Os camundongos submetidos à PSNL também desenvolveram alodínia mecânica, a qual foi revertida pela selegilina (10 mg/kg, p.o.) de 2 até 6 h após o tratamento. Além disso, os camundongos submetidos à PSNL apresentaram um aumento significativo na atividade da MAO-B no estriado 4 h após o tratamento, o qual foi revertido pela selegilina. Foi observado também que a selegilina, em uma dose sem efeito antinociceptivo (1 mg/kg, p.o.) em ambos os modelos de dor utilizados, não foi capaz de inibir a atividade da MAO-B. Nossos resultados mostram que a selegilina apresentou um efeito antinociceptivo tanto em um modelo de dor aguda quanto em um modelo de dor crônica, sugerindo um possível envolvimento da MAO-B nos mecanismos da dor.

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