Morphine and Clonidine Synergize to Ameliorate Low Back Pain in Mice

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 α2-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

Morphine and Clonidine Synergize to Ameliorate Low Back Pain in Mice

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) andα2-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

Peripheral Nerve Injury Is Associated with Chronic, Reversible Changes in Global DNA Methylation in the Mouse Prefrontal Cortex

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 sensitivityin 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

Overlapping Signatures of Chronic Pain in the DNA Methylation Landscape of Prefrontal Cortex and Peripheral T Cells

We tested the hypothesis that epigenetic mechanisms in the brain and the immune system are associated with chronic pain. Genome-wide DNA methylation assessed in 9 months post nerve-injury (SNI) and Sham rats, in the prefrontal cortex (PFC) as well as in T cells revealed a vast difference in the DNA methylation landscape in the brain between the groups and a remarkable overlap (72%) between differentially methylated probes in T cells and prefrontal cortex. DNA methylation states in the PFC showed robust correlation with pain score of animals in several genes involved in pain. Finally, only 11 differentially methylated probes in T cells were sufficient to distinguish SNI or Sham individual rats. This study supports the plausibility of DNA methylation involvement in chronic pain and demonstrates the potential feasibility of DNA methylation markers in T cells as noninvasive biomarkers of chronic pain susceptibility

The relationship between mesocerebral activity and sexual arousal in the snail, «Cornu aspersum»

The courtship behavior of the pulmonate snail Cornu aspersum comprises an intricate sequence of acts followed by dart shooting. This study aims at comparing mesocerebral electrical activity in ganglia removed from snails belonging to three stages of sexual arousal: Non-excited snails, pre dart shooters, and post dart shooters. The groups were compared using measurements of spontaneous mesocerebral activity and responses to simultaneous stimulation of six nerves. Dart shooters showed the highest spontaneous activity, followed by the pre dart shooters and finally, non-excited snails. Nerve stimulation increased activity only in non-excited snails. Cluster analysis failed to show a significant change in the number of active units before and after nerve stimulation. These results show that mesocerebral activity is correlated with the behavioral stages of courtship, and is influenced by input from the stimulated nerves, thus linking the ethology and physiology of mating in this species.Le comportement d'accouplement de l'escargot pulmonate, soit la Cornu aspersum, est composé d'un rituel établit suivi du lancement du dard. Cet étude vise à faire une étude comparative entre les différent niveaux d'activité électrique mésocérébrale perçus dans les ganglions extrait d'escargots ayant atteint l'un des trois niveaux d'excitation sexuelle, soit les escargots: non-excités, pré-lanceurs de dards et post-lanceur de dards. De ces échantillons, le niveau spontané d'activité mésocérébrale et l'effet de la stimulation simultanées de six nerfs ont été comparés. L'échantillon composé des post-lanceurs de dards ont démontré des niveaux spontané d'activité mésocérébrale les plus élevés parmi les trois; les échantillons composé de pré-lanceurs de dards et d'escargots non-excités ont démontrés des niveaux respectivement inférieurs à celle-ci. Alternativement, les stimulant nerveux augmentent uniquement l'activité mésocérébrale des escargots non-excités. Malgré ces indicatifs statistiquement significatif, l'analyse de groupement a échouer à la tâche d'identification d'un changement significatif d'unités actives avant et après la stimulation nerveuse. Ces résultats démontrent qu'il y a effectivement un corrélation entre l'activité mésocérébrale et les différents comportements d'accouplement associé a chacun des niveau d'excitation; en plus d'être affecté par l'influx sensoriel provenant des nerfs stimulés, ainsi liant l'ethologie et la physiologie au processus d'accouplement de l'espèce

The SPARC-null mouse model of low back pain: Mechanism, Treatment, and Translation to Humans

Persistent low back pain (LBP) is the most common form of chronic illness in Canadians age 60 and under, affecting 15% of the population. In addition to being a major health problem, it also has serious economic consequences. Current diagnostic and therapeutic approaches to chronic back pain are limited by our narrow understanding of the underlying biological mechanisms. As a consequence, treatment is not always effective and individuals may suffer for years without relief. LBP is often associated with signs of degeneration in the intervertebral discs. LBP encompasses a wide spectrum of pain disorders including axial pain in the back region and radiating pain down one or both legs. This thesis investigates the mechanisms and treatment of axial and radiating pain associated with disc degeneration (DD) in a transgenic mouse model and in human subjects. SPARC-null mice show anatomical signs of disc degeneration and behavioral signs of pain and are thus a valid model of LBP due to DD.Our results show that loss of lumbar disc height correlates with radiating pain in mice. In addition, we show that axial pain and radiating pain have different pharmacological profiles, suggesting the involvement of different mechanisms. Furthermore, we explore the use of opioid-adrenergic combination therapy to improve therapeutic outcome in our model. Finally, we propose an epigenetic mechanism governing SPARC expression, disc degeneration, and back pain in aging wild-type mice and in human subjects with LBP.The results shown in this thesis will serve to increase our understanding of the mechanisms of pain due to DD. This mechanism-based approach is key in improving therapeutic options for the millions of patients suffering from chronic low back pain.La douleur persistante du bas du dos (lombalgie) est la forme la plus commune des maladies chroniques chez les Canadiens de 60 ans et moins, touchant 15% de la population. En plus d'être un problème majeur de santé, la lombalgie a également de graves conséquences économiques. Les approches actuelles de diagnostic et de traitement de la lombalgie chronique sont limitées par notre compréhension limitée des mécanismes biologiques sous-jacents et la prise en charge n'est pas toujours efficace. Ainsi, les patients peuvent souffrir pendant de très longues périodes de temps sans soulagement. La lombalgie est souvent associée avec des signes de dégénérescence des disques intervertébraux. Elle englobe un large éventail de désordres douleureux et peut être sub-divisée en douleur axiale (dans la région du dos) et/ou douleur radiculaire (le long d'une jambe ou deux). Cette thèse étudie les mécanismes et le traitement des douleurs axiales et radiculaires associées à la dégénérescence des disques (DD) dans un modèle murin transgénique et chez des sujets humains. Les souris SPARC-nul montrent simultanément des signes anatomiques de dégénérescence des disques intervertébraux et des signes comportementaux de douleur. Ces souris représentent donc un modèle valide de lombalgie due à la dégénérescence des disques.Nos résultats prouvent que la perte de hauteur des disques lombaires corrèle avec le développement de douleur radiculaire chez la souris. En outre, les douleurs axiales et radiculaires présentent des profils pharmacologiques différents, suggèrant l'implication de mécanismes différents. Dans notre modèle, nous explorons également l'utilisation d'une thérapie combinant des traitements opiacés et adrénergiques pour améliorer des résultats thérapeutiques. Finalement, nous proposons un mécanisme épigénétique régissant l'expression de SPARC, la dégénérescence des disques, et la lombalgie chez des souris sauvages agées et des sujets humains. Nous croyons que les résultats présentés dans cette thèse serviront à améliorer notre connaissance des mécanismes de la douleur lièe à la dégénérescence des disques intervertébraux. Une telle approche mécanistique permettra d'augmenter les options thérapeutiques pour des millions de patients souffrant de douleur lombo-sacrée chronique.

Nonpharmacological Interventions in Targeting Pain-Related Brain Plasticity

Chronic pain is a highly prevalent and debilitating condition that is frequently associated with multiple comorbid psychiatric conditions and functional, biochemical, and anatomical alterations in various brain centers. Due to its widespread and diverse manifestations, chronic pain is often resistant to classical pharmacological treatment paradigms, prompting the search for alternative treatment approaches that are safe and efficacious. The current review will focus on the following themes: attentional and cognitive interventions, the role of global environmental factors, and the effects of exercise and physical rehabilitation in both chronic pain patients and preclinical pain models. The manuscript will discuss not only the analgesic efficacy of these therapies, but also their ability to reverse pain-related brain neuroplasticity. Finally, we will discuss the potential mechanisms of action for each of the interventions