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Schema2c of ascending pathways, subcor2cal structures, and cerebral cor2cal structures involved in processing pain. ACC, anterior cingulate cortex; Amyg, amygdala; BG, basal ganglia; M1, primary motor cortex; HT, hypothalamus; PAG, periaqueductal gray; PB, parabrachial nucleus of the dorsolateral pons; PCC, posterior cingulate cortex; PFC, prefrontal cortex; PPC, posterior parietal complex; S1 and S2, primary and secondary somatosensory cor2cal areas; SMA, supplementary motor area. (From Apkarian AV, Bushnell MC, Treede RD et al 2005 Human brain mechanisms of pain percep2on and regula2on in health and disease. European Journal of Pain 9:463484.); (From Apkarian AV, Bushnell MC, Treede RD et al 2005 Human brain mechanisms of pain percep2on and regula2on in health and disease. European Journal of Pain 9:463484.); Representa2on of Pain in the Brain; Apiarian, A. Vania, Wall & Melzack's Textbook of Pain, Chapter 7, 111-128 Copyright 2013 Copyright 2013 by Saunders, an imprint of Elsevier Ltd.

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Protec2ve mechanisms: input, central representa2on, and output. Ac2va2on of the central circuits leads to neuroendocrine, autonomic, somatomotor, and illness responses, as well as to pain and hyperalgesia (as a component of the illness response). The afferent feedback from body 2ssues is neural and hormonal and is mediated by cytokines from the immune system. The central circuits are adapted by the forebrain to the environmental situa2ons. (Modified from Jnig W, Hbler HJ 2000 Sympathe2c nervous system: contribu2on to chronic pain. Progress in Brain Research 129:451468.) (Modified from Jnig W, Hbler HJ 2000 Sympathe2c nervous system: contribu2on to chronic pain. Progress in Brain Research 129:451468.) Autonomic, Endocrine, and Immune Interac2ons in Acute and Chronic Pain; Jnig, Wilfrid, Wall & Melzack's Textbook of Pain, Chapter 13, 198-210; Copyright 2013 Copyright 2013 by Saunders, an imprint of Elsevier Ltd.

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Poten2al mediators of peripheral sensi2za2on afer inflamma2on. Tissue injury and inflamma2on lead to the release of numerous chemicals from non-neuronal and neuronal cells, such as mast cells, macrophages, platelets, immune and endothelial cells, Schwann cells, kera2nocytes, fibroblasts, and peripheral nociceptor terminals. Mediators released include protons (H+ ), purines (adenosine, adenosine triphosphate), nerve growth factor (NGF), cytokines such as tumor necrosis factor (TNF-) and interleukins (IL-1, IL-6), leukemia inhibitory factor (LIF), prostaglandin E2 (PGE2 ), bradykinin, histamine, serotonin (5-HT), platelet ac2va2ng factor (PAF), and endothelin. These mediators may act directly to alter the sensi2vity of peripheral nociceptors or indirectly via coupling to one or more peripheral membrane-bound receptors, including transient receptor poten2al (TRP) channels, acid-sensi2ve ion channels (ASICs), purinergic (P2X) receptors, G proteincoupled receptors (GPCRs), two-pore potassium channels (K2P ), and receptor tyrosine kinase (RTK). Binding of the ligands to these receptors can ini2ate a cascade of events that includes ac2va2on of second-messenger systems (protein kinase A [PKA] and C [PKC] ) and altera2on of gene regula2on. (Artwork by Ian Suk, Johns Hopkins University; adapted from Woolf CJ, Cos2gan M 1999 Transcrip2onal and posrransla2onal plas2city and the genera2on of inflammatory pain. Proceedings of the Na2onal Academy of Sciences of the United States of America 96:77237730.); (Artwork by Ian Suk, Johns Hopkins University; adapted from Woolf CJ, Cos2gan M 1999 Transcrip2onal and posrransla2onal plas2city and the genera2on of inflammatory pain. Proceedings of

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Efferent ac2ons of nociceptors. A noxious s2mulus leads to ac2on poten2als in nocicep2ve fibers that propagate not only to the central nervous system but also an2dromically into peripheral branches. These an2dromic ac2on poten2als lead to the release of neuropep2des such as substance P, calcitonin generelated pep2de (CGRP), and neurokinin A (NKA). These substances can s2mulate epidermal cells (1) and immune cells (2) or lead to vasodilata2on (3), plasma extravasa2on (4), and smooth muscle contrac2on (5). (Artwork by Ian Suk, Johns Hopkins University.) (Artwork by Ian Suk, Johns Hopkins University.) Peripheral Mechanisms of Cutaneous Nocicep2on Ringkamp, Marhias, Wall & Melzack's Textbook of Pain, Chapter 1, 1-30

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Role of cytokines in sensi2za2on of nociceptors during inflamma2on and the underlying puta2ve mechanisms leading to hyperalgesia. Pathogenic s2muli ac2vate resident cells and lead to the release of inflammatory mediators (such as bradykinin). Pro-inflammatory cytokines are synthesized and released by macrophages and other immune or immune-related cells. Nociceptors are postulated to be sensi2zed by two pathways involving the cytokines. First, tumor necrosis factor- (TNF-) induces the synthesis and release of interleukin-1 (IL-1) and IL-6, which in turn induce the release of eicosanoids (prostaglandin E2 and I2 ) by ac2va2ng cyclooxygenase-2 (Cox-2). Second, TNF- induces the synthesis and release of IL-8. IL-8 ac2vates sympathe2c terminals that sensi2ze nociceptors via 2 -adrenoceptors. Glucocor2coids inhibit the synthesis of cytokines and ac2va2on of Cox-2 (indicated by asterisks). An2-inflammatory cytokines (such as IL-4 and IL-10), which are also synthesized and released by immune cells, inhibit the synthesis and release of pro-inflammatory cytokines (indicated by pound signs). This scheme is fully dependent on behavioral experiments and pharmacological interven2ons. The different steps will need to be verified experimentally in neurophysiological experiments. (Modified from Poole S, Cunha FQ, Ferreira SH 1999 Hyperalgesia from subcutaneous cytokines. In: Watkins LR, Maier SF (eds) Cytokines and pain. Basel, Birkhuser Verlag, p 5987.) (Modified from Poole S, Cunha FQ, Ferreira SH 1999 Hyperalgesia from subcutaneous cytokines. In: Watkins LR, Maier SF (eds) Cytokines and pain. Basel, Birkhuser Verlag,

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Schema2c of pain and pain modula2on. (a) Classical pain signaling. When a painful s2mulus is encountered (such as stepping on a tack, as shown), peripheral pain-responsive nerves (A- and C fibers) are excited. These axons transmit ac2on poten2als to their presynap2c terminals in the spinal cord dorsal horn. Neurotransmirers released here bind to and ac2vate postsynap2c receptors on pain transmission neurons (PTNs). In turn, the axons of PTNs ascend contralaterally to the brain, carrying the pain message to higher centers. The box encompassing the sensory presynap2c terminal and the postsynap2c region of the PTN indicates the area shown in detail in (b)(d). (b) Normal pain. Under normal, every day situa2ons where pain is experienced, glia are present but quiescent. Pain signals arriving from the periphery along A- and C fibers cause release of substance P and excitatory amino acids (EAAs) in amounts appropriate to the intensity and dura2on of the ini2a2ng pain s2mulus. Ac2va2on of NK-1 receptors by substance P and ac2va2on of AMPA receptors by EAAs cause transient depolariza2on of the PTNs, thereby genera2ng ac2on poten2als that are relayed to higher brain areas. NMDA-linked channels are inopera2ve as they are chronically plugged by Mg2+. (c) Pathological pain: classic view. In response to intense and/or prolonged barrages of incoming pain signals, the PTNs become sensi2zed to over-respond to subsequent incoming pain signals. The intense and/or prolonged barrage depolarizes the PTNs sufficiently such that the Mg2+ exits the NMDA-linked channel. The resultant influx of Ca2+ ac2vates cons2tu2vely expressed nitric oxide synthase (cNOS), causing conversion of

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