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Allegri M.,University of Parma | Allegri M.,SIMPAR Group Study in Multidisciplinary Pain Research | Ornaghi M.,University of Milan Bicocca | Ferland C.E.,SIMPAR Group Study in Multidisciplinary Pain Research | And 18 more authors.
Pain Research and Management | Year: 2017

Background. Intraperitoneal nebulization of ropivacaine reduces postoperative pain andmorphine consumption after laparoscopic surgery. The aim of this multicenter double-blind randomized controlled trial was to assess the efficacy of different doses and dose-related absorption of ropivacaine when nebulized in the peritoneal cavity during laparoscopic cholecystectomy. Methods. Patients were randomized to receive 50, 100, or 150mg of ropivacaine 1% by peritoneal nebulization through a nebulizer.Morphine consumption, pain intensity in the abdomen, wound and shoulder, time to unassisted ambulation, discharge time, and adverse effects were collected during the first 48 hours after surgery. The pharmacokinetics of ropivacaine was evaluated using high performance liquid chromatography. Results. Nebulization of 50mg of ropivacaine had the same effect of 100 or 150mg in terms of postoperative morphine consumption, shoulder pain, postoperative nausea and vomiting, activity resumption, and hospital discharge timing (>0.05). Plasma concentrations did not reach toxic levels in any patient, and no significant differences were observed between groups (P > 0.05). Conclusions. There is no enhancement in analgesic efficacy with higher doses of nebulized ropivacaine during laparoscopic cholecystectomy. When administered with a microvibration-based aerosol humidification system, the pharmacokinetics of ropivacaine is constant and maintains an adequate safety profile for each dosage tested. Copyright © 2017 Massimo Allegri et al.


Laferriere A.,Alan Edwards Center for Research on Pain | Abaji R.,Alan Edwards Center for Research on Pain | Ragavendran J.V.,Alan Edwards Center for Research on Pain | Coderre T.J.,Alan Edwards Center for Research on Pain | Coderre T.J.,McGill University
Anesthesia and Analgesia | Year: 2014

BACKGROUND: Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle, and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. METHODS: Mechanical allodynia was induced in the hindpaws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (postocclusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats. RESULTS: Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared with vehicle in CPIP rats (N = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5- to 10-fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (N = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors were not reproduced by the same treatment of the contralateral hindpaw (N = 28). Topical combinations produced antiallodynic effects lasting up to 6 hours (N = 15) and were significantly enhanced by low-dose systemic pregabalin in early, but not late, CPIP rats (N = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed postocclusive reactive hyperemia in CPIP rats (N = 61) and to increase formazan production in postischemic tissues (skin and muscle) (N = 56). CONCLUSIONS: The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS. Copyright © 2014 International Anesthesia Research Society.


Krock E.,Orthopeadic Research Laboratory | Krock E.,Alan Edwards Center for Research on Pain | Krock E.,McGill Scoliosis and Spine Research Group | Currie J.B.,Orthopeadic Research Laboratory | And 12 more authors.
Journal of Biological Chemistry | Year: 2016

Nerve growth factor (NGF) contributes to the development of chronic pain associated with degenerative connective tissue pathologies, such as intervertebral disc degeneration and osteoarthritis. However, surprisingly little is known about the regulation of NGF in these conditions. Toll-like receptors (TLR) are pattern recognition receptors classically associated with innate immunity but more recently were found to be activated by endogenous alarmins such as fragmented extracellular matrix proteins found in degenerating discs or cartilage. In this study we investigated if TLR activation regulates NGF and which signaling mechanisms control this response in intervertebral discs. TLR2 agonists, TLR4 agonists, or IL-1β (control) treatment increased NGF, brain-derived neurotrophic factor (BDNF), and IL-1β gene expression in human disc cells isolated from healthy, pain-free organ donors. However, only TLR2 activation or IL-1β treatment increased NGF protein secretion. TLR2 activation increased p38, ERK1/2, and p65 activity and increased p65 translocation to the cell nucleus. JNK activity was not affected by TLR2 activation. Inhibition of NF-κB, and to a lesser extent p38, but not ERK1/2 activity, blocked TLR2-driven NGF up-regulation at both the transcript and protein levels. These results provide a novel mechanism of NGF regulation in the intervertebral disc and potentially other pathogenic connective tissues. TLR2 and NF-κB signaling are known to increase cytokines and proteases, which accelerate matrix degradation. Therefore, TLR2 or NF-κB inhibition may both attenuate chronic pain and slow the degenerative progress in vivo.


Villemure C.,U.S. National Institutes of Health | Ceko M.,U.S. National Institutes of Health | Cotton V.A.,Alan Edwards Center for Research on Pain | Bushnell M.C.,U.S. National Institutes of Health
Cerebral cortex (New York, N.Y. : 1991) | Year: 2014

Yoga, an increasingly popular discipline among Westerners, is frequently used to improve painful conditions. We investigated possible neuroanatomical underpinnings of the beneficial effects of yoga using sensory testing and magnetic resonance imaging techniques. North American yogis tolerated pain more than twice as long as individually matched controls and had more gray matter (GM) in multiple brain regions. Across subjects, insular GM uniquely correlated with pain tolerance. Insular GM volume in yogis positively correlated with yoga experience, suggesting a causal relationship between yoga and insular size. Yogis also had increased left intrainsular white matter integrity, consistent with a strengthened insular integration of nociceptive input and parasympathetic autonomic regulation. Yogis, as opposed to controls, used cognitive strategies involving parasympathetic activation and interoceptive awareness to tolerate pain, which could have led to use-dependent hypertrophy of insular cortex. Together, these findings suggest that regular and long-term yoga practice improves pain tolerance in typical North Americans by teaching different ways to deal with sensory inputs and the potential emotional reactions attached to those inputs leading to a change in insular brain anatomy and connectivity. Published by Oxford University Press 2013. This work is written by (a) US Government employee(s) and is in the public domain in the US.


Krock E.,McGill University | Krock E.,McGill Scoliosis and Spine Research Group | Rosenzweig D.H.,McGill University | Rosenzweig D.H.,McGill Scoliosis and Spine Research Group | And 11 more authors.
Journal of Cellular and Molecular Medicine | Year: 2014

Intervertebral disc degeneration (IVD) can result in chronic low back pain, a common cause of morbidity and disability. Inflammation has been associated with IVD degeneration, however the relationship between inflammatory factors and chronic low back pain remains unclear. Furthermore, increased levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are both associated with inflammation and chronic low back pain, but whether degenerating discs release sufficient concentrations of factors that induce nociceptor plasticity remains unclear. Degenerating IVDs from low back pain patients and healthy, painless IVDs from human organ donors were cultured ex vivo. Inflammatory and nociceptive factors released by IVDs into culture media were quantified by enzyme-linked immunosorbent assays and protein arrays. The ability of factors released to induce neurite growth and nociceptive neuropeptide production was investigated. Degenerating discs release increased levels of tumour necrosis factor-α, interleukin-1β, NGF and BDNF. Factors released by degenerating IVDs increased neurite growth and calcitonin gene-related peptide expression, both of which were blocked by anti-NGF treatment. Furthermore, protein arrays found increased levels of 20 inflammatory factors, many of which have nociceptive effects. Our results demonstrate that degenerating and painful human IVDs release increased levels of NGF, inflammatory and nociceptive factors ex vivo that induce neuronal plasticity and may actively diffuse to induce neo-innervation and pain in vivo. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.


Abdelaziz D.M.,McGill University | Abdelaziz D.M.,Alan Edwards Center for Research on Pain | Stone L.S.,McGill University | Stone L.S.,Alan Edwards Center for Research on Pain | And 2 more authors.
Breast Cancer Research and Treatment | Year: 2015

Patients with breast cancer metastasis to bone suffer from inadequate pain relief. Animal models provide increased understanding of cancer-induced bone and sensory alterations. The objective of this study was to investigate the measures of pain at distant non-tumor-bearing sites in animals with localized bone metastasis. Immunocompetent BALB/c mice are injected intra-tibially with murine mammary carcinoma cells (4T1) or saline, and the sensitivity to mechanical and thermal stimuli in the contralateral paw was examined. In addition to previously demonstrated development of osteolysis and hypersensitivity to mechanical and thermal stimuli in the cancer-injected tibia, these animals exhibited an increase in sensory hypersensitivity in the contralateral limb. No bone lesions were evident on radiographs of the contralateral limbs. Histomorphometry detected decreased bone volume per tissue volume and increased osteoclast number in the contralateral tibia and vertebral bones of cancer-bearing animals. Neuroplasticity was examined by immunofluorescence for calcitonin gene-related peptide (CGRP) in sensory neurons and glial fibrillary acidic protein (GFAP) in lumbar spinal cords. CGRP-immunoreactivity and GFAP-immunoreactivity were significantly elevated both ipsilateral and contralateral in tumor-bearing animals. The anti-inflammatory and osteolysis-targeting drug rapamycin reduced hypersensitivity to mechanical and cold stimuli, attenuated GFAP over-expression, and lowered osteoclast number. The osteoclast-targeting drug pamidronate reduced sensitivity to cold and protected against bone loss. Localized bone cancer drives hypersensitivity, bone remodeling, and sensory neuron plasticity at sites distant from the primary tumor area. Drugs targeting these mechanisms may be useful in the treatment of pain distant from the primary tumor site. © 2015, Springer Science+Business Media New York.


Abdelaziz D.M.,McGill University | Abdelaziz D.M.,Alan Edwards Center for Research on Pain | Stone L.S.,McGill University | Stone L.S.,Alan Edwards Center for Research on Pain | And 2 more authors.
Breast Cancer Research and Treatment | Year: 2014

In advanced breast cancer, bone metastases occur in 70 % of patients. Managing the devastating pain associated with the disease is difficult. Rapamycin is an immunomodulatory drug that targets the mammalian target of rapamycin pathway. Rapamycin has been shown to decrease osteolysis associated with metastatic breast cancer in pre-clinical models and to reduce pain in inflammatory and neuropathic models. The aim of this study was to evaluate the effectiveness of rapamycin in reducing pain associated with experimental osteolytic metastases. Bone cancer was induced by intra-tibial injections of murine mammary carcinoma cells (4T1) in immunocompetent BALB/c mice and treated intraperitoneally for up to 5 weeks with vehicle, rapamycin or pamidronate (a bisphosphonate currently used to reduce bone loss in bone cancer patients). The control group received intra-tibial injection with saline (sham) and was treated with vehicle intraperitoneally. Cancer-induced osteolysis was observed histologically and radiographically 2-3 weeks following cancer inoculation and gradually increased with time. Measures of evoked nociceptive behaviors including sensitivity to mechanical, thermal, and cold stimuli and spontaneous nociceptive behaviors (limping, guarding) were evaluated. Significant hypersensitivity to sensory stimuli developed in cancer-bearing mice compared to sham 3 weeks following inoculation. Rapamycin decreased or delayed the development of cancer-induced mechanical, heat, and cold hypersensitivity, while pamidronate reduced heat and cold hypersensitivity. Both rapamycin and pamidronate had a partial protective effect on the spontaneous nociceptive behaviors, limping and guarding. Our data suggest that rapamycin may have efficacy in the management of pain associated with metastatic breast cancer. © 2013 Springer Science+Business Media New York.


PubMed | McGill University, National Center for Complementary and Integrative Health, Alan Edwards Center for Research on Pain and University of Maryland, Baltimore
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2015

In studies of cognitive processing using tasks with externally directed attention, regions showing increased (external-task-positive) and decreased or negative [default-mode network (DMN)] fMRI responses during task performance are dynamically responsive to increasing task difficulty. Responsiveness (modulation of fMRI signal by increasing load) has been linked directly to successful cognitive task performance in external-task-positive regions but not in DMN regions. To investigate whether a responsive DMN is required for successful cognitive performance, we compared healthy human subjects (n = 23) with individuals shown to have decreased DMN engagement (chronic pain patients, n = 28). Subjects performed a multilevel working-memory task (N-back) during fMRI. If a responsive DMN is required for successful performance, patients having reduced DMN responsiveness should show worsened performance; if performance is not reduced, their brains should show compensatory activation in external-task-positive regions or elsewhere. All subjects showed decreased accuracy and increased reaction times with increasing task level, with no significant group differences on either measure at any level. Patients had significantly reduced negative fMRI response (deactivation) of DMN regions (posterior cingulate/precuneus, medial prefrontal cortex). Controls showed expected modulation of DMN deactivation with increasing task difficulty. Patients showed significantly reduced modulation of DMN deactivation by task difficulty, despite their successful task performance. We found no evidence of compensatory neural recruitment in external-task-positive regions or elsewhere. Individual responsiveness of the external-task-positive ventrolateral prefrontal cortex, but not of DMN regions, correlated with task accuracy. These findings suggest that a responsive DMN may not be required for successful cognitive performance; a responsive external-task-positive network may be sufficient.We studied the relationship between responsiveness of the brain to increasing task demand and successful cognitive performance, using chronic pain patients as a probe. fMRI working memory studies show that two main cognitive networks [external-task positive and default-mode network (DMN)] are responsive to increasing task difficulty. The responsiveness of both of these brain networks is suggested to be required for successful task performance. The responsiveness of external-task-positive regions has been linked directly to successful cognitive task performance, as we also show here. However, pain patients show decreased engagement and responsiveness of the DMN but can perform a working memory task as well as healthy subjects, without demonstrable compensatory neural recruitment. Therefore, a responsive DMN might not be needed for successful cognitive performance.

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