Exercise is often prescribed for patients with chronic pain, but there is little objective evidence supporting this recommendation. Therefore, we tested the effect of moderate aerobic exercise on the sensory hypersensitivity produced in an animal model of neuropathic pain. Male rats that underwent unilateral ligation of the L5 and L6 spinal nerves (SNL) were divided into exercise-trained or sedentary groups. Exercise training was performed using a treadmill, beginning 7 days after surgery, and continued 5 days a week for 5 weeks. Animals were exercised 30 min/day, at a speed of 14-16 m/min. Sensory testing was performed 23 hours after exercise training. Typical thermal and tactile hypersensitivity developed within 1 week after surgery. Treadmill training reversed thermal and tactile hypersensitivity in injured animals within 4 weeks, but had no effect on sham-operated or non-operated animals. One week after the cessation of exercise training, tactile hypersensitivity returned.The effects of exercise training on SNL-induced sensory hypersensitivity were reversed by the opioid receptor antagonist naloxone. Naloxone or naloxone methiodide reversed the effects of exercise when administered intracerebroventricularly (i.c.v.). Immunohistochemistry revealed increased immunostaining for B-endorphin and met-enkephalin in the periaquaductal grey (PAG) and rostral ventromedial medulla (RVM) regions of exercise-trained animals compared to sedentary animals. An ELISA immunoassay revealed a 31% increase in PAG B-endorphin content in exercise-trained SNL animals. More BDNF was also present in the brain's of exercise-trained animals compared to sedentary, specifically in the ventromedial hypothalamus, hippocampus, and outer rim of the PAG. Administering a BDNF sequestering agent reversed B-endorphin increases in the PAG of exercise-trained animals. Exercise-trained SNL animals treated with 25 ug BDNF sequestering agent (i.c.v.) had lower tactile thresholds compared to the exercise-trained vehicle group.These results support the recommendation of moderate aerobic exercise for patients suffering from neuropathic pain, and suggest that exercise-induced pain reversal results from the upregulation of endogenous opioids in the brainstem. Additionally, increased BDNF with exercise training may play a role in exercise-induced reversal of neuropathic pain by increasing the expression of endogenous opioids, but this needs to be verified further.

Patients suffering from central neuropathic pain have thermal sensory deficits within the painful area. Prior research proposed that the loss of thermal sensation in regions of central neuropathic pain may reflect similar central nervous system interaction between warm and cold sensory inputs that underlie the Thermal Grill Illusion (TGI) in which burning pain is felt while reduced warm/cold sensations are reported. This work presents a portable and reliable device that was used to systematically evaluate the characteristics of the TGI in healthy individuals. The results suggest that the spatial distribution of the warm and cool stimuli significantly affected the quality of perceived TGI. Additionally, simultaneous tactile and thermal stimulation was shown to be significantly less painful than thermal stimulation alone. A high correlation was also seen in the subject‘s TG intensity scores and their cold pain threshold. These results are useful for future TGI studies for central neuropathic pain.

Patients suffering from central neuropathic pain have thermal sensory deficits within the painful area. Prior research proposed that the loss of thermal sensation in regions of central neuropathic pain may reflect similar central nervous system interaction between warm and cold sensory inputs that underlie the Thermal Grill Illusion (TGI) in which burning pain is felt while reduced warm/cold sensations are reported. This work presents a portable and reliable device that was used to systematically evaluate the characteristics of the TGI in healthy individuals. The results suggest that the spatial distribution of the warm and cool stimuli significantly affected the quality of perceived TGI. Additionally, simultaneous tactile and thermal stimulation was shown to be significantly less painful than thermal stimulation alone. A high correlation was also seen in the subject‘s TG intensity scores and their cold pain threshold. These results are useful for future TGI studies for central neuropathic pain.

Spinal cord injury (SCI) results in a number of devastating consequences, including loss of motor function, paralysis, and neuropathic pain. Concomitant peripheral tissue injury below the lesion site can result in uncontrollable nociception that sensitizes spinal neurons and promotes chronic pain. Additionally, drugs like morphine, though critical for pain management, elicit pro-inflammatory effects that exacerbate chronic pain symptoms. Currently, there is a lack of effective therapeutic mechanisms to promote regeneration at the lesion site, and a limited understanding of regulatory mechanisms that can be utilized to therapeutically manipulate spinal cord plasticity. MicroRNAs (miRNAs) constitute novel targets for therapeutic intervention to both promote repair and regeneration, and mitigate maladaptive plasticity that leads to neuropathic pain. Microarray and qRT-PCR comparisons of contused and sham rat spinal cords at 4 and 14 days following SCI indicated that a total of 35 miRNAs were dysregulated, with miR1, miR124, and miR129 exhibiting significant down-regulation after SCI, and both miR21 and miR146a being transiently induced. Localized expression of miRNAs and cellular markers indicated that changes in miRNA regulation favor the emergence of neural stem cell niches and reversion of surviving neurons to a pre-neuronal phenotype. Additionally, both uncontrollable nociception and morphine administration resulted in further dysregulation of SCI-sensitive miRNAs, along with their mRNA targets. Morphine administration significantly induced expression of both miR21 and IL6R expression, indicating that morphine-induced miRNA dysregulation is involved in the promotion of neuroinflammation that drives increased pain-sensitivity. Similarly, uncontrollable nociception significantly modulates expression of miR124, miR129, and miR146a, which inhibit cell cycle proteins and microglial activation, and dysregulation of these miRNAs, along with BDNF and IGF-1, likely contributes towards promotion of hypersensitivity in spinal neurons that underlies neuropathic pain. Consequently, SCI- sensitive miRNAs may constitute therapeutic targets for modulation of neuroinflammation and microglial activation in order to mitigate secondary injury, promote regeneration, and prevent maladaptive plasticity that drives neuropathic pain and exacerbation of chronic pain symptoms by morphine administration.

To date, most studies investigating the neural signature of pain in humans have focused on the brain, and those studies concerned with more caudal areas (such as the spinal cord (SC) or brainstem) have used only experimental models of pain. The objectives of this study were 1) to determine the neural activity in the human brainstem and SC that is caused by a noxious mechanical stimulus and 2) to compare the neural response to noxious stimuli in healthy controls and a patient population diagnosed with peripheral neuropathic pain. The SC and brainstem contain important synaptic points in several major pain pathways, and comparing the neural response between a control and patient population in these areas provides a more complete picture of healthy and pathological pain processing. Functional MRI studies of the SC and brainstem were carried out in healthy control subjects and patients diagnosed with carpal tunnel syndrome (CTS) in a 3T Siemens Magnetom Trio. Subjects reported the point at which the pressure (in mmHg, applied to the wrist at the location of the median nerve) corresponded to a pain level of 2, 4, and 6 on a numerical 11 point pain scale. Spatially normalized group results superimposed on anatomical templates in the axial orientation were visually identified using several stereotaxic atlases. We observed consistent signal intensity change in areas implicated in the transmission and modulation of pain in both control and CTS groups. Both groups showed a similar decrease in signal change with increasing pain, as results at pain level 2 are predominantly positive signal change and at pain level 6 are typically negative. This may indicate a reduction in the tonic inhibition of painful sensations. Differences between groups were readily visible in regions anatomically consistent with the dorsal horn (DH) of the cervical SC, rostral ventromedial medulla (RVM), dorsolateral pontine tegmentum (DLPT), and midbrain periaqudectal gray (PAG). The anatomical variation in signal change between groups may represent, for the first time, a visualization of the functional difference between healthy and pathological pain processing in the SC and brainstem using spinal fMRI. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-08-03 14:46:01.7

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Antigen induced activation of Th1 cells in the peripheral blood leads to elevated production of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that have been directly linked to disease induction and neuropathic pain. It was hypothesized that following antigenic induction, cytokines gain access to the spinal cord and participate in direct cellular interaction with dorsal horn neurons. Using an animal model of MS, we show that TNF-α gene and protein expression in the dorsal root ganglia (DRG) and spinal cord tissue is increased in the active group. In addition, our findings show TNF-α mRNA expression in the dorsal root entry point. Therefore, our results support the hypothesis that antigen induced DRG derived TNF-α can transport to the spinal cord via the dorsal roots and is involved in the underlying pathogenesis of MS induced neuropathic pain.

Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, resulting in significant challenges in its management. In addition to its complex pathophysiology, the clinical management of MS-induced NPP is further complicated by the lack of clinical therapeutics trials specific to this population. The primary aim of the work underlying this thesis was to contribute to the evidence-based management of individuals with MS-induced NPP through the completion of two clinical therapeutics trials in this population. A secondary aim was to describe pain variability in this patient population through the development and validation of a pain variability algorithm tool. Resulting from this work, we demonstrated that nabilone – a synthetic oral cannabinoid – represents an effective, well-tolerated and novel treatment for MS-induced NPP. Additionally, we show that the SSRI paroxetine was poorly tolerated in our patient population, with a correspondingly high attrition rate. As a result, we were unable to determine any treatment effect in this trial due to insufficient recruitment due to drop-out. Lastly, we were able to define and describe pain instability in this cohort, noting that approximately 30% of individuals with MS-induced NPP experiencing highly variable daily pain. The results of these projects provide novel information for this patient population. Patients currently living with the daily burden of MS-induced NPP would benefit from additional trials ensuing from this, and other, research in order to initiate a momentum for much-needed clinical research in this complicated patient cohort.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Antigen induced activation of Th1 cells in the peripheral blood leads to elevated production of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that have been directly linked to disease induction and neuropathic pain. It was hypothesized that following antigenic induction, cytokines gain access to the spinal cord and participate in direct cellular interaction with dorsal horn neurons. Using an animal model of MS, we show that TNF-α gene and protein expression in the dorsal root ganglia (DRG) and spinal cord tissue is increased in the active group. In addition, our findings show TNF-α mRNA expression in the dorsal root entry point. Therefore, our results support the hypothesis that antigen induced DRG derived TNF-α can transport to the spinal cord via the dorsal roots and is involved in the underlying pathogenesis of MS induced neuropathic pain.

Neuropathic pain (NPP) is a chronic syndrome suffered by patients with multiple sclerosis (MS), for which there is no cure. Underlying cellular mechanisms involved in its pathogenesis are multifaceted, resulting in significant challenges in its management. In addition to its complex pathophysiology, the clinical management of MS-induced NPP is further complicated by the lack of clinical therapeutics trials specific to this population. The primary aim of the work underlying this thesis was to contribute to the evidence-based management of individuals with MS-induced NPP through the completion of two clinical therapeutics trials in this population. A secondary aim was to describe pain variability in this patient population through the development and validation of a pain variability algorithm tool. Resulting from this work, we demonstrated that nabilone – a synthetic oral cannabinoid – represents an effective, well-tolerated and novel treatment for MS-induced NPP. Additionally, we show that the SSRI paroxetine was poorly tolerated in our patient population, with a correspondingly high attrition rate. As a result, we were unable to determine any treatment effect in this trial due to insufficient recruitment due to drop-out. Lastly, we were able to define and describe pain instability in this cohort, noting that approximately 30% of individuals with MS-induced NPP experiencing highly variable daily pain. The results of these projects provide novel information for this patient population. Patients currently living with the daily burden of MS-induced NPP would benefit from additional trials ensuing from this, and other, research in order to initiate a momentum for much-needed clinical research in this complicated patient cohort.

Neuropathic pain (NP) after spinal cord injury (SCI) can significantly and negatively affect a person’s quality of life and is often refractory to currently available treatments. In order to advance the field and find effective therapeutic avenues; signs, symptoms, and biomarkers in humans should be identified and related to specific pain-generating mechanisms. The present work utilizes quantitative sensory testing (QST) and magnetic resonance spectroscopy (MRS) to evaluate the relationship between the functional integrity of the dorsal column-medial lemniscus pathway (DCML), the spinothalamic tract (STT), and metabolic markers of neuronal loss and glial activation in the thalamus of persons with/without NP after SCI. This work was based on the hypothesis that the presence/severity of NP after SCI is dependent both on function of ascending somatosensory pathways and changes in neuronal and glial markers in the thalamus. The results indicate that NP is associated with a decreased afferent DCML input to the thalamus resulting in a loss of inhibitory neurons and that residual function from STT afferents may contribute to thalamic glial activation and NP. Based on this work, in combination with previous studies in animals and humans, it can be proposed that NP after SCI partly results from the combination of residual STT function and loss of neuronal inhibition leading to neuronal hyperexcitability in the spinal cord and the thalamus. Thus, the presence of NP in chronic SCI is dependent on several underlying mechanisms which may be measured in human subjects with methods such as QST and MRS. Clinical implications and recommendations for further research are enclosed.