MECHANI SMS DRUGDISCOVERY TODAY D I SEASE Shared mechanisms between chronic pain and neurodegenerative disease A. Vania Apkarian 1, * , Joachim Scholz 2 1 Department of Physiology, Northwestern University, Feinberg School of Medicine, 303 E Chicago Ave, Chicago III, IL, USA 2 Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 4309, Charlestown, MA, USA Accumulating evidence indicates that chronic pain provokes morphological changes in the central nervous system. Animal models of neuropathic pain have revealed that degeneration of inhibitory interneurons in the dorsal horn of the spinal cord contributes to persistent pain after peripheral nerve injury. Brain imaging in patients with chronic pain demonstrates a decrease in neocortical gray matter and in brain meta- bolites, a sign of reduced neuronal density. Shared disease mechanisms suggest that chronic pain should be considered a neurodegenerative disorder. Section Editors: Frank Porreca – University of Arizona, Tucson, USA Michael Ossipov – University of Arizona, Tucson, USA Introduction Acute (nociceptive) pain serves as a warning device that indicates imminent tissue damage. Chronic pain lacks such protective function as it persists for months or years after injury without reflecting the severity of a lesion or disease, nor does chronic pain necessarily respond to treatment of the underlying disease cause. Chronic pain is associated with a variety of diseases (Box 1). More than 90% of patients with cancer, for example, experi- ence persistent pain; in 21% of these patients, the pain is linked to tumor therapy [1]. Once pain has become chronic, it is difficult to provide satisfactory relief. Ongoing pain, how- ever, has a major impact on daily life. Pain impairs social interaction, reduces the ability to work, and causes sleep deprivation and depression. Both, treatment-related costs and the loss of workforce that is caused by insufficient pain control create an enormous economic burden for society. Multiple factors contribute to the development of clinical pain Mechanical force, chemical, or thermal stimulation causes activation of nociceptors, which convey information about the nature and extent of the stimulus to the dorsal horn of the spinal cord [2]. Dorsal horn interneurons and descending pathways from brainstem nuclei regulate the transmission of nociceptive input to the brain. This balance between excitation, facilitation and inhibition is lost in conditions of chronic inflammatory pain or pain caused by a lesion or functional disorder of the nervous system (neuropathic pain) [3]. Tissue damage and inflammation elicit the release of multiple mediators including serotonin, bradykinin and prostaglandins. Bind- ing of these ligands to G-protein-coupled receptors leads to the phosphorylation of receptors and ion channels, causing nociceptor terminals to respond with increased excitation to noxious stimuli (peripheral sensitization) [4]. Peripheral nerve injury prompts an immediate barrage of action potentials (injury discharge) that is followed by sus- tained spontaneous (ectopic) activity. In injured neurons, membrane excitability changes owing to increased transcrip- tion and altered trafficking of voltage-gated sodium channels and a decrease in potassium channels. Altered regulation of Drug Discovery Today: Disease Mechanisms Vol. 3, No. 3 2006 Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA Pain *Corresponding author: A.V. Apkarian (a-apkarian@northwestern.edu) 1740-6765/$ ß 2006 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddmec.2006.09.006 319