Rodent functional and anatomical imaging of pain

Human brain imaging has provided much information about pain processing and pain modulation, but brain imaging in rodents can provide information not attainable in human studies. First, the short lifespan of rats and mice, as well as the ability to have homogenous genetics and environments, allows for longitudinal studies of the effects of chronic pain on the brain. Second, brain imaging in animals allows for the testing of central actions of novel pharmacological and nonpharmacological analgesics before they can be tested in humans. The two most commonly used brain imaging methods in rodents are magnetic resonance imaging (MRI) and positron emission tomography (PET). MRI provides better spatial and temporal resolution than PET, but PET allows for the imaging of neurotransmitters and non-neuronal cells, such as astrocytes, in addition to functional imaging. One problem with rodent brain imaging involves methods for keeping the subject still in the scanner. Both anesthetic agents and restraint techniques have potential confounds. Some PET methods allow for tracer uptake before the animal is anesthetized, but imaging a moving animal also has potential confounds. Despite the challenges associated with the various techniques, the 31 studies using either functional MRI or PET to image pain processing in rodents have yielded surprisingly consistent results, with brain regions commonly activated in human pain imaging studies (somatosensory cortex, cingulate cortex, thalamus) also being activated in the majority of these studies. Pharmacological imaging in rodents shows overlapping activation patterns with pain and opiate analgesics, similar to what is found in humans. Despite the many structural imaging studies in human chronic pain patients, only one study has been performed in rodents, but that study confirmed human findings of decreased cortical thickness associated with chronic pain. Future directions in rodent pain imaging include miniaturized PET for the freely moving animal, as well as new MRI techniques that enable ongoing chronic pain imaging.

[1]  Z. Wiesenfeld‐Hallin,et al.  Chronic pain-related syndrome in rats after ischemic spinal cord lesion: a possible animal model for pain in patients with spinal cord injury , 1992, Pain.

[2]  T. Hökfelt,et al.  Chronic pain-related behaviors in spinally injured rats: Evidence for functional alterations of the endogenous cholecystokinin and opioid systems , 1994, Pain.

[3]  Karin N. Westlund,et al.  fMRI of supraspinal areas after morphine and one week pancreatic inflammation in rats , 2009, NeuroImage.

[4]  E. De Schutter,et al.  Comparing BOLD fMRI signal changes in the awake and anesthetized rat during electrical forepaw stimulation. , 2001, Magnetic resonance imaging.

[5]  M. Bushnell,et al.  How neuroimaging studies have challenged us to rethink: is chronic pain a disease? , 2009, The journal of pain : official journal of the American Pain Society.

[6]  S Minoshima,et al.  Selective opiate modulation of nociceptive processing in the human brain. , 2000, Journal of neurophysiology.

[7]  P. Hof,et al.  A three-dimensional digital atlas database of the adult C57BL/6J mouse brain by magnetic resonance microscopy , 2005, Neuroscience.

[8]  D. Dubuisson,et al.  The formalin test: A quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats , 1977, Pain.

[9]  M Jarmasz,et al.  Functional magnetic resonance imaging in rats subjected to intense electrical and noxious chemical stimulation of the forepaw , 2000, Pain.

[10]  Joshua A. Bueller,et al.  Regional Mu Opioid Receptor Regulation of Sensory and Affective Dimensions of Pain , 2001, Science.

[11]  K. Sluka,et al.  Knee joint mobilization reduces secondary mechanical hyperalgesia induced by capsaicin injection into the ankle joint , 2001, European journal of pain.

[12]  C. A. Marsden,et al.  Functional magnetic resonance imaging studies of opioid receptor-mediated modulation of noxious-evoked BOLD contrast in rats , 2005, Psychopharmacology.

[13]  Mathias Hoehn,et al.  High field BOLD response to forepaw stimulation in the mouse , 2010, NeuroImage.

[14]  Fu-Shan Jaw,et al.  Whole‐brain functional magnetic resonance imaging mapping of acute nociceptive responses induced by formalin in rats using atlas registration‐based event‐related analysis , 2008, Journal of neuroscience research.

[15]  Toshiki Endo,et al.  Functional MRI of the brain detects neuropathic pain in experimental spinal cord injury , 2008, PAIN.

[16]  Katja Wiech,et al.  Prestimulus functional connectivity determines pain perception in humans , 2009, Proceedings of the National Academy of Sciences.

[17]  David A. Seminowicz,et al.  MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain , 2009, NeuroImage.

[18]  U. Tuor,et al.  Functional magnetic resonance imaging of tonic pain and vasopressor effects in rats. , 2002, Magnetic resonance imaging.

[19]  Wei Chen,et al.  Procedure for minimizing stress for fMRI studies in conscious rats , 2005, Journal of Neuroscience Methods.

[20]  M. Rudin,et al.  Assessment of brain responses to innocuous and noxious electrical forepaw stimulation in mice using BOLD fMRI , 2010, PAIN®.

[21]  R. Treede,et al.  Human brain mechanisms of pain perception and regulation in health and disease , 2005, European journal of pain.

[22]  Irene Tracey,et al.  Determining anatomical connectivities between cortical and brainstem pain processing regions in humans: A diffusion tensor imaging study in healthy controls , 2006, Pain.

[23]  B. Shyu,et al.  A fMRI study of brain activations during non-noxious and noxious electrical stimulation of the sciatic nerve of rats , 2001, Brain Research.

[24]  M. Bushnell,et al.  Pain imaging in health and disease--how far have we come? , 2010, The Journal of clinical investigation.

[25]  Nora D. Volkow,et al.  The Effect of Intravenous Lidocaine on Brain Activation During Non-Noxious and Acute Noxious Stimulation of the Forepaw: A Functional Magnetic Resonance Imaging Study in the Rat , 2009, Anesthesia and analgesia.

[26]  Arend Heerschap,et al.  Isoflurane anesthesia is a valuable alternative for α‐chloralose anesthesia in the forepaw stimulation model in rats , 2009, NMR in biomedicine.

[27]  F. Jaw,et al.  Brain nociceptive imaging in rats using 18f-fluorodeoxyglucose small-animal positron emission tomography , 2008, Neuroscience.

[28]  Fuqiang Zhao,et al.  fMRI of pain processing in the brain: A within-animal comparative study of BOLD vs. CBV and noxious electrical vs. noxious mechanical stimulation in rat , 2012, NeuroImage.

[29]  J. Pratte,et al.  Simultaneous assessment of rodent behavior and neurochemistry using a miniature positron emission tomograph , 2011, Nature Methods.

[30]  M. Ueki,et al.  Effect of alpha‐chloralose, halothane, pentobarbital and nitrous oxide anesthesia on metabolic coupling in somatosensory cortex of rat , 1992, Acta anaesthesiologica Scandinavica.

[31]  M Hoehn-Berlage,et al.  Variation of functional MRI signal in response to frequency of somatosensory stimulation in α‐chloralose anesthetized rats , 1996, Magnetic resonance in medicine.

[32]  Pen-Li Lu,et al.  MicroPET imaging of noxious thermal stimuli in the conscious rat brain , 2010, Somatosensory & motor research.

[33]  Frank S. Prato,et al.  Using perfusion MRI to measure the dynamic changes in neural activation associated with tonic muscular pain , 2010, PAIN®.

[34]  Patrick W Stroman,et al.  Functional MRI of the rat lumbar spinal cord involving painful stimulation and the effect of peripheral joint mobilization , 2003, Journal of magnetic resonance imaging : JMRI.

[35]  C. Ferris,et al.  Functional Magnetic Resonance Imaging in Conscious Animals: A New Tool in Behavioural Neuroscience Research , 2006, Journal of neuroendocrinology.

[36]  R. Wilkins,et al.  Principles of Neurosurgery , 2004 .

[37]  David Borsook,et al.  CNS activation maps in awake rats exposed to thermal stimuli to the dorsum of the hindpaw , 2011, NeuroImage.

[38]  Andreas Hess,et al.  Imaging of hyperalgesia in rats by functional MRI , 2007, European journal of pain.

[39]  Ricardo Jose Moylan Governo,et al.  Capsaicin-evoked brain activation and central sensitization in anaesthetised rats: A functional magnetic resonance imaging study , 2006, Pain.

[40]  Seong-Gi Kim,et al.  Relationship between neural, vascular, and BOLD signals in isoflurane-anesthetized rat somatosensory cortex. , 2006, Cerebral cortex.

[41]  P G Morris,et al.  Gabapentin evoked changes in functional activity in nociceptive regions in the brain of the anaesthetized rat: an fMRI study , 2008, British Journal of Pharmacology.

[42]  Gilles Plourde,et al.  Dose-dependent Effects of Propofol on the Central Processing of Thermal Pain , 2004, Anesthesiology.

[43]  P. Morris,et al.  Identification of discrete sites of action of chronic treatment with desipramine in a model of neuropathic pain , 2009, Neuropharmacology.

[44]  K. Malisza,et al.  Capsaicin as a source for painful stimulation in functional MRI , 2001, Journal of magnetic resonance imaging : JMRI.

[45]  Rex E. Jung,et al.  A novel technique to study the brain's response to pain: Proton magnetic resonance spectroscopy , 2005, NeuroImage.

[46]  Andrew S. Lowe,et al.  Small animal, whole brain fMRI: Innocuous and nociceptive forepaw stimulation , 2007, NeuroImage.

[47]  Klaus Sartor,et al.  In vivo monitoring of age-related changes in rat brain using quantitative diffusion magnetic resonance imaging and magnetic resonance relaxometry , 2002, Neuroscience Letters.

[48]  Ricardo Jose Moylan Governo,et al.  Validation of an automated punctate mechanical stimuli delivery system designed for fMRI studies in rodents , 2007, Journal of Neuroscience Methods.

[49]  R. Fish Pharmacology of Injectable Anesthetics , 1997 .

[50]  F. Hyder,et al.  Dynamic Magnetic Resonance Imaging of the Rat Brain during Forepaw Stimulation , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[51]  L. Chen,et al.  MicroPET detection of regional brain activation induced by colonic distention in a rat model of visceral hypersensitivity. , 2008, The Journal of veterinary medical science.

[52]  A. Vania Apkarian,et al.  Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study , 2000, Pain.

[53]  J. Herance,et al.  A 18F-fluorodeoxyglucose MicroPET Imaging Study to Assess Changes in Brain Glucose Metabolism in a Rat Model of Surgery-induced Latent Pain Sensitization , 2011, Anesthesiology.

[54]  Osamu Inanami,et al.  A BOLD-fMRI study of cerebral activation induced by injection of algesic chemical substances into the anesthetized rat forepaw. , 2008, The Japanese journal of veterinary research.

[55]  Fu-Shan Jaw,et al.  BOLD fMRI mapping of brain responses to nociceptive stimuli in rats under ketamine anesthesia. , 2008, Medical engineering & physics.

[56]  M. Devor Pain, cortex, and consciousness , 2007, Behavioral and Brain Sciences.

[57]  R. Constable,et al.  Anesthetic effects on regional CBF, BOLD, and the coupling between task‐induced changes in CBF and BOLD: An fMRI study in normal human subjects , 2008, Magnetic resonance in medicine.

[58]  Nicholas A Bock,et al.  Manganese-enhanced MRI: an exceptional tool in translational neuroimaging. , 2007, Schizophrenia bulletin.

[59]  Andreas Hess,et al.  Combining functional magnetic resonance imaging with mouse genomics: new options in pain research , 2010, Neuroreport.

[60]  M. Baliki,et al.  The Cortical Rhythms of Chronic Back Pain , 2011, The Journal of Neuroscience.

[61]  P. Stroman,et al.  Functional MRI involving painful stimulation of the ankle and the effect of physiotherapy joint mobilization. , 2003, Magnetic resonance imaging.