Date sent: Sun, 17 Dec 2000 Pharmacological Reviews Vol. 52, Issue 4, 595-638 December 2000 http://intl-pharmrev.aspetjournals.org (home page) http://pharmrev.aspetjournals.org/cgi/content/full/52/4/595 (text) The Sympathetic Nerve - An Integrative Interface between Two Supersystems: The Brain and the Immune System -------------------------------------------------------------------------- Ilia J. Elenkov, Ronald L. Wilder, George P. Chrousos and E. Sylvester Vizi(1) Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland (I.J.E., R.L.W.); Pediatric Endocrinology Section, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (I.J.E., G.P.C.); Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary (E.S.V.); and Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (E.S.V.) Abstract -------- The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta 2-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor- alpha , and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor- beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha , and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha 2- and beta 2-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome. (...) XIII. Clinical Implications --------------------------- (...) E. Fibromyalgia and Chronic Fatigue Syndrome -------------------------------------------- Patients with unexplained chronic pain and/or fatigue have been described for centuries in the medical literature, although the terms used to describe these symptom complexes have changed frequently. The currently preferred terms for these syndromes are fibromyalgia and chronic fatigue syndrome (CFS) (for details see Clauw and Chrousos, 1997). Fibromyalgia is the second most common rheumatologic disorder, behind osteoarthritis. To fulfill the criteria for fibromyalgia, an individual must have both chronic widespread pain and the presence of "tender points" on examination. The current definition of CFS requires that the affected individual display severe chronic fatigue without a defined cause, as well as the presence of four of the eight following symptoms: myalgia, arthralgia, sore throat, tender nodes, cognitive difficulty, headache, postexertional malaise, or sleep disturbance (cf. Clauw and Chrousos, 1997). There has been little study of underlying pathophysiologic mechanisms of fibromyalgia and CFS. Clauw and Chrousos (1997) recently suggested that a blunting of human stress response predisposes and/or mediates these syndromes. This may be manifested as: blunting of one or more hypothalamic-pituitary axes, globally increased peripheral and/or visceral nociception, or instability of the autonomic nervous system. In fact, several lines of evidence indicate that a dysregulation of the autonomic nervous system might play a role in fibromyalgia. Thus, muscle sympathetic activity appears to be reduced in fibromyalgia (Elam et al., 1992). Qiao et al. (1991) demonstrated decreased microcirculatory vasoconstrictor esponses to both cold and auditory stimulation and a high baseline skin conductance. More recently, a blunted sympathetic response to stressors was reported when heart rate variability or tilt table testing has been used to analyze autonomic responses (Clauw et al., 1996a ,b). Perhaps the most consistent finding regarding autonomic function is that fibromyalgia patients have an impaired sympathetic ability to respond to stressors such as exercise, muscle contraction, and noise (Qiao et al., 1991; Elam et al., 1992; van Denderen et al., 1992). The autonomic nervous system has not been as extensively studied in CFS, although these patients have been found to experience a high prevalance of neurally mediated hypotension on tilt table testing, which is related to autonomic dysfunction (Rowe et al., 1995), since alpha 2-AR antagonists increase sympathetic outflow (see Section XIV.) and inhibit TNF- alpha production (Hasko et al., 1995a; Elenkov et al., 1996). Taking these interactions into account, alpha 2-AR antagonists are recommended for the treatment of fibromyalgia and chronic fatigue syndrome. Footnotes --------- (1) Address for correspondence: Dr. E. Sylvester Vizi, Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, P.O. Box 67, Hungary. E-mail: esvizi@koki.hu -------- (c) 2000 The American Society for Pharmacology and Experimental Therapeutics