40 THE NEUROSCIENTIST Neuroimmune Activation, Neuroinflammation, and Pain Copyright © 2004 Sage Publications ISSN 1073-8584 Chronic pain is among the most disabling and costly afflictions in North America, Europe, and Australia. Its burden is likely to be as prevalent in developing coun- tries although the data are not easily obtainable (Harstall and Ospina 2003). In a recent systematic review using 13 studies, the prevalence of chronic pain in developed nations was reported to range from 10% to 55%. In this review, the International Association of the Study of Pain’s (IASP) definition of chronic pain was used: Pain without biological value that has persisted beyond the normal tissue healing time (usually to be 3 months). These data demonstrated a higher prevalence of chronic pain among females and a significant use of health care resources by chronic pain sufferers. The challenge for effective chronic pain treatment and prevention remains the complexity of pain processing both at physiological and psychological levels. Over the past 20 years, an enormous number of pain mediators have been identi- fied. However, the translation of this knowledge to clin- ically effective therapeutic treatments has been absent. One area that has emerged as a promising therapeutic target is the modulation of the central nervous system (CNS) immunological response to injuries that lead to chronic pain. Immunity, the state of protection from infectious disease and injury, is characterized by non- specific (innate) and specific (adaptive) components. This immune response also occurs in the CNS, and its study is defined as the field of neuroimmunology. Broadly defined, central neuroimmune activation involves the activation of cells that interface with the peripheral nervous system and blood. These cells line the capillary bed (perivascular microglia and endothelial cells) and make up the blood-brain barrier (astrocytes). Activation of these cells as well as parenchymal microglia and astrocytes by stressors leads to subsequent production of cytokines, cellular adhesion molecules, chemokines, and the expression of surface antigens (to be further discussed) that enhance a CNS immune cas- cade. If unchecked, this neuroimmune activation can lead to the trafficking of leukocytes into the area of per- ceived injury as a mechanism for neuroprotection. Therefore, neuroinflammation can be defined as the infiltration of immune cells into the site of injury in response to damage of the peripheral or central nervous system. The hallmark of the inflammatory component of the innate immune response is the infiltration and/or Neuroimmune Activation and Neuroinflammation in Chronic Pain and Opioid Tolerance/Hyperalgesia JOYCE A. DELEO, FLOBERT Y. TANGA, andVIVIANNE L. TAWFIK Department of Anesthesiology and Department of Pharmacology & Toxicology Dartmouth–Hitchcock Medical Center, Lebanon, NH. One area that has emerged as a promising therapeutic target for the treatment and prevention of chronic pain and opioid tolerance/hyperalgesia is the modulation of the central nervous system (CNS) immunolog- ical response that ensues following injury or opioid administration. Broadly defined, central neuroimmune activation involves the activation of cells that interface with the peripheral nervous system and blood. Activation of these cells, as well as parenchymal microglia and astrocytes by injury, opioids, and other stressors, leads to subsequent production of cytokines, cellular adhesion molecules, chemokines, and the expression of surface antigens that enhance a CNS immune cascade. This response can lead to the production of numerous pain mediators that can sensitize and lower the threshold of neuronal fir- ing: the pathologic correlate to central sensitization and chronic pain states. CNS innate immunity and Toll-like receptors, in particular, may be vital players in this orchestrated immune response and may hold the answers to what initiates this complex cascade. The challenge remains in the careful pertur- bation of injury/opioid-induced neuroimmune activation to down-regulate this process without inhibit- ing beneficial CNS autoimmunity that subserves neuronal protection following injury. NEUROSCIENTIST 10(1):40–52, 2004. DOI: 10.1177/1073858403259950 KEY WORDS Astrocyte, Chemokines, Cytokines, Glia, MHC II, Microglia, Neuropathic pain, Toll-like receptor 4 The authors thank the following for grant support: National Institute of Drug Abuse DA11276 (JAD); the National Institute of Arthritis and Musculoskeletal and Skin Diseases AR44757 (JAD); Bristol-Myers Squibb/Zimmer Orthopaedic Foundation (JAD). They also sincerely acknowledge the excellent editorial assistance by Tracy Wynkoop. Address correspondence to: Joyce A. DeLeo, PhD, Department of Anesthesiology, Dartmouth–Hitchcock Medical Center, HB 7125 One Medical Center Drive, Lebanon, NH 03756 (e-mail: Joyce.A.DeLeo@ Dartmouth.edu). REVIEW ■