The Autonomic Nervous System in Body Protection ...

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College Medical School, Royal Free Campus, Rowland Hill Street,. London NW3 ... Auto- nomic responses, endocrine responses, somatomotor responses and.


Abstracts / Autonomic Neuroscience: Basic and Clinical 163 (2011) 1–133

PLENARY LECTURES Plenary 1: Purinergic Signalling: Pathophysiology and Therapeutic Potential Geoffrey Burnstock (Autonomic Neuroscience Centre, University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK) After an initial description of some of the important conceptual steps in the establishment of purinergic signalling, the talk will focus on some of the exciting developments relating to purinergic pathophysiology and potential therapeutic applications. There will be discussion of the long-term trophic effects of purines and pyrimidines in blood vessel remodelling in restenosis; plasticity of purinergic cotransmission of diseased urinary bladder and hypertensive rats; sperm motility in IVF; purinergic mechanosensory transduction in visceral pain and the role of spinal microglial purinoceptors in neuropathic pain; the potential for P2X7 receptor antagonists in osteoporosis and kidney failure and P2Y2 receptor agonists for dry eye and cystic fibrosis. Further, there is a growing literature about the roles of purinergic signalling in disorders of the central nervous system; and the role of ATP in the treatment of cancer. Finally, a novel hypothesis will be presented for the involvement of purinergic signalling in acupuncture. doi:10.1016/j.autneu.2011.05.010

Plenary 2: The Spectrum of Baroreflex Failure David Robertson (Vanderbilt University -Medicine, Pharmacology & Neurology, Vanderbilt University -Medicine & Pharmacology, Nashville, TN, USA) Baroreflex failure, in its most acute and complete form, is perhaps the most dramatic of all autonomic disorders. In major referral centers, the highest blood pressures encountered nowadays by Hypertension specialists and Autonomic specialists are often in patients with acute baroreflex failure. Pressure surges above 300 mmHg may occur in some individuals. But the spectrum of baroreflex failure is very broad, and includes individuals with both orthostatic hypertension and orthostatic hypotension, surges in heart rate, and in some cases emotional volatility. It is noteworthy that baroreflexes may become dysfunctional if (1) the baroreceptors themselves fail, (2) if their afferent pathways in the vagal and glossopharyngeal nerves fail, (3) if central cardiovascular control nuclei fail, or(4) if relevant efferent nerves effecting blood pressure control fail. Etiologies are as varied as neck injury, familial paraganglioma syndromes, neck irradiation, familial dysautonomia, and mitochondrial disease. Clinical management is complex, but patients are often improved by carefully tailored regimens of such agents as methyldopa, propranolol, and benzodiazepines. In Jordan´s syndrome of selective baroreflex failure (efferent vagus intact), bradycardia and sinus arrest may occur during sleep, and these patient may require a pacemaker as well. doi:10.1016/j.autneu.2011.05.011

Plenary 3: The Autonomic Nervous System in Body Protection and Pain Wilfrid Jänig (Department of Physiology, University of Kiel, Kiel, Germany)

The autonomic nervous system is not only involved in the regulation of various target organs related to regulation of cardiovascular system, body core temperature, gastrointestinal tract, pelvic organs etc. but has functions that are conceptually best described in the context of regulating the protection of body tissues during ongoing challenges from within the body or from the environment. Responses of the organism during these challenges involve autonomic, neuroendocrine and somatic motor systems, the corresponding afferent (neural, hormonal and humoral) feedbacks from the body tissues and the representations of these motor and afferent systems in the central nervous system. These systems serve to adapt organ functions to the changing behavior and the behavior to changing threatening environments. The coordinated responses shown by the organism are states of the organism that are represented in the brain preparing the organism to generate the appropriate responses against threatening events. Autonomic responses, endocrine responses, somatomotor responses and interoceptive body sensations occur principally in parallel and are therefore parallel read-outs of these central representations. The central representations receive neuronal afferent, hormonal and humoral signals that monitor continuously the mechanical, thermal, metabolic and chemical states of the tissues. Control of the protective body reactions (including inflammation and hyperalgesia) by the CNS are integral components in this scenario and require autonomic, in particular sympathetic, systems which function in a differentiated way. During real or impending tissue damage the integrated protective systems are activated by the brain leading to illness responses including pain, hyperalgesia and other adverse body sensations. The patterning of the neural feedback via the small-diameter afferents from the body tissues may also depend on the activity in the (efferent) neurons of the peripheral autonomic pathways. In fact in view of the functional differentiation of these autonomic pathways with respect to the target cells it is hypothesized that autonomic outflows, target cells and afferent neurons form feedback body loops that lead to spatially and temporally patterned activation of the central representations of the body tissues and the autonomically dependent activation leads to typical illness responses. Regulation of pain and hyperalgesia are integral components of the fast and the slow defense systems that are organized in the hypothalamus and mesencephalon. During fast defense, two alternative strategies are taken by the organism: (1) Fight (confrontational defense) or flight (avoidance) is taken if the environmental threat is escapable. Both are characterized by mobilization of energy, activation of various sympathetic channels (including the sympathoadrenal system), activation of the hypothalamo-pituitary adrenal (HPA) axis and a fast non-opioid-mediated hypoalgesia. They are enhanced by activation of superficial (cutaneous) nociceptive afferent neurons. (2) A passive coping strategy is taken if the threat is inescapable. The organism is in a state of quiescence, rest, immobility and decreased responsiveness to environmental stimuli. This state is characterized by low blood pressure, low heart rate and an opioidmediated hypoalgesia. It is enhanced by activation of deep (somatic or visceral) nociceptive afferents and during chronic activation of nociceptors. During slow defense the organism is in a state of healing (recuperation). The physiological characteristics during slow defense are similar to those of the passive coping strategy. An important component of this protective system, promoting tissue repair and recuperation, is the brain-immune system. The brain is continuously influenced by signals from the immune system (e.g., by cytokines mediated directly or by afferents) and modulates the reactivity of the immune system, mainly via the sympatho-neural system and the hypothalamo-pituitary system. This bidirectional brain-immune system is probably particularly important during slow defense and furthers recuperation and tissue healing under biological conditions, although it appears to be switched on rather quickly. The defense systems organized in the brain are activated by peripheral

Abstracts / Autonomic Neuroscience: Basic and Clinical 163 (2011) 1–133

signals from the immune system via afferent neurons (e.g., vagal afferent neurons projecting to the nucleus tractus solitarii) or by cytokines via the circumventricular organs. It is unclear whether signaling from the brain to the immune system via the sympathetic nervous system occurs by a specific sympathetic channel, which is anatomically and functionally different from sympathetic channels to other target cells, or whether this brain-to-immune system signaling is a general functional characteristic of the peripheral sympathetic nervous system. The lecture will concentrate on the following topics: • Autonomic nervous system, body protection and pain: a concept. • Role of the (efferent) autonomic (visceromotor) nervous system and neuroendocrine (neurosecretory) system to the body tissues in pain and disease. • Reactions of the sympathetic nervous system during nociception and pain. • Coupling (cross-talk) from sympathetic postganglionic neurons to afferent neurons in the generation of pain. • Sympathetic nervous system, hyperalgesia, inflammation and the vagal afferent feedback. • The vagal cholinergic anti-inflammatory pathway: fact or fiction? • Autonomic nervous system, disease and central mechanisms. Cannon WB (1939) The Wisdom of the Body. 2nd revised and enlarged edition. New York: Norton. Jänig W (2006) The Integrative Action of the Autonomic Nervous System. Neurobiology of Homeostasis. Cambridge, New York: Cambridge University Press. Jänig W (2009a) Autonomic nervous system dysfunction. In: Mayer AE, Bushnell MC, eds. Functional Pain Syndromes: Presentation and Pathophysiology. Seattle: IASP Press, pp 265-300. Jänig W (2009b) Autonomic nervous system and pain. In: Basbaum AI, Bushnell MC, eds. Science of Pain. Oxford San Diego: Academic Press, pp 193-225. Jänig W (2011) Basic science on somato-visceral interactions: peripheral and central evidence base and implications for research. In King HH, Jänig W, Patterson MM (eds) The Science and Clinical Application of Manual Therapy. Churchill Livingstone Elsevier, Edinburgh, pp. 272-298. Jänig W, Baron R (2003) Complex regional pain syndrome: mystery explained? Lancet Neurol 2:687-697. Jänig W, Levine JD (2006) Autonomic-neuroendocrine-immune responses in acute and chronic pain. In: McMahon SB, Koltzenburg M, eds. Wall & Melzack's Textbook of Pain. 5th edition. Edinburgh: Elsevier Churchill Livingstone, pp 205-218 King HH, Jänig W, Patterson MM (eds) (2011) The Science and Clinical Application of Manual Therapy. Churchill Livingstone Elsevier, Edinburgh. Swanson LW (2000). Cerebral hemisphere regulation of motivated behavior. Brain Res 886: 113-164. Swanson LW (2003). The architecture of the nervous system. In Fundamental Neuroscience. In Squire LR Bloom FE, McConnell SK, Roberts JL, Spitzer NC, Zigmond MJ, eds. 2nd edition. San Diego: Academic Press, pp 15-45. doi:10.1016/j.autneu.2011.05.012

Plenary 4: Neural Mechanisms of Chronic Pain: Lessons from Translational Studies of Endometriosis Karen J. Berkley (Program in Neuroscience, Florida State University, Tallahassee, FL 32306-SA) Severe dysmenorrhea (menstrual pain), now considered a chronic pain condition, [1] is often associated with endometriosis, a painful


disorder considered to be “estrogen-dependent” and defined by its signs: extrauteral endometrial growths [10]. Many women with endometriosis also suffer from other, mainly pelvic pains and conditions. Little is known about how the signs relate to the symptoms (pains), making the pains of ENDO notoriously difficult to treat. If analgesics are ineffective (often the case), then hormonal treatments are added or surgery is done to remove ectopic growths. Hormonal treatments alleviate the pain, but produce intolerable side effects, and pains generally resume when therapy stops. Furthermore, surgery is effective at best in only half of selected patients. New treatment approaches are badly needed [10]. A rat model of endometriosis is created by autotransplanting on abdominal arteries small pieces of uterus (ENDO), which form vascularized and innervated cysts [11] As a control, small pieces of fat, which do not form cysts, are autotransplanted (shamENDO). Similar to women, rats with ENDO exhibit vaginal hyperalgesia (dyspareunia), whose severity varies with estrous stage in parallel with estradiol levels [4]. Rats with ENDO also exhibit symptoms of other pains [6,8,9]. Similar to women with endometriosis, severity of symptoms in the rat does not correlate with the amount of ectopic growth [7,9]. The ectopic growths in rats and women develop their own sensory and sympathetic nerve supply [2,3]. In rats, characteristics of both sensory and sympathetic innervation vary with estrous stage in parallel with changes in the severity of ENDO-induced vaginal hyperalgesia [12]. This finding and others indicate that it is the cysts’ coupled sensory and sympathetic innervation that is a major contributor to the ENDO-induced hyperalgesia [7,10]. Recent studies in rats and women will be discussed in support of this hypothesis. An attendant question concerns how the coupled innervation contributes to symptoms and their cyclical variations. Recent studies in our lab suggest that the endocannabinoid system (ECS) is involved [5]. These findings implicate the entire PNS (i.e., including the ANS) and thus the CNS, together with the neuroendocrine system, in a pain condition whose mechanisms in the past had been thought by most clinicians to be dominated by “simply” the abnormal peripheral pathology. The findings have raised awareness among the clinical community (mainly gynecology) to change their focus and strategies for pain management; i.e., a deliberate multifactorial approach to assessment and diagnosis, followed by an individualized multifactorial approach to treatment that in some women might eventually include the use of endocannabinoid-related agents [10]. [1] Berkley KJ, McAllister SL. Don't dismiss dysmenorrhea! Pain 2011 Apr 20.[Epub ahead of print]. [2] Berkley KJ, Dmitrieva N, Curtis KS and Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. PNAS 2004;101:11094-8. [3] Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science 2005;306:1587-9. [4] Cason AM, Samuelsen CL, Berkley KJ. Estrous changes in vaginal nociception in a rat model of endometriosis. Horm Behav 2003;44:123-31. [5] Dmitrieva N, Nagabukuro H, Reseuhr D, Zhang GH, McAllister SM, McGinty KA, Mackie K, Berkley KJ. Endocannabinoid involvement in endometriosis. Pain 2010;151:703-10. [6] Giamberardino MA, Berkley KJ, Affaitati G, Lerza R, Centurione L, Lapenna D and Vecchiet L. Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats. Pain 2002;95:247-57. [7] McAllister SL, McGinty KA, Resuehr D, Berkley KJ. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation. Pain 2009;147:255-64. [8] Morrison TC, Dmitrieva N, Winnard KP, Berkley KJ. Opposing viscerovisceral effects of surgically induced endometriosis and a control abdominal surgery on the rat bladder. Fertil Steril 2006;86:1067-73.

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