Autonomic, Endocrine, and Immune Interactions in Acute and Chronic Pain

Afferent Signals from the Body to the Brain

The brain, notably the hypothalamus, continuously receives physical and chemical signals from the periphery, which are important in normal homeostatic body regulation (e.g., in the control of body core temperature, osmolality of extracellular fluid, and glucose concentration in extracellular fluid) and in the defense of body tissues against viral, bacterial, and other toxic challenges leading to sickness behavior, one component of which is spontaneous pain and hyperalgesia (see later).

Impulse activity in primary afferent neurons from all body domains—superficial (skin), deep somatic, and visceral—is continuously conveyed to the brain. This hard-wired neural impulse transmission system is rapid and continuously monitors the mechanical, thermal, metabolic, and inflammatory states of the somatic and visceral tissues. Nociceptors have unmyelinated or small-diameter myelinated axons and are numerically the largest group of primary afferent neurons. Each body organ is innervated by several functional classes of afferent nociceptive neurons, although it is still a matter of debate in which way noxious events in the viscera are encoded by spinal visceral afferent neurons ( , , , >, Bielefeldt and Gebhart Chapter 51 ). Vagal afferents innervating the gastroduodenal section of the gastrointestinal tract and excited by mucosally applied acid are involved in nociceptive protective reactions but probably not in conscious perception of pain ( ). Afferent signals may also be hormonal and exert their influence in the CNS by action at their respective receptors (e.g., corticosterone, cholecystokinin, progesterone, and leptin).

Inflammatory processes involving the immune system are signaled to the brain by the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6 and may act either directly at the hypothalamus and lower brain stem via circumventricular organs or indirectly via primary afferent neurons with unmyelinated fibers (see later) (for review see ). In the gastrointestinal tract, microorganisms, antigens, and toxic substances activate cells of or related to the gut-associated lymphoid tissue. The state of this cellular defense system is signaled by the pro-inflammatory cytokines or via vagal afferent neurons to the brain. In the skin or deep somatic tissues, inflammatory states involving these interleukins may also be signaled to the brain directly or by small-diameter primary afferent neurons, although the latter has not been fully established.

Efferent Signals from the Brain to Body Tissues

Coordinated activity in somatic motor neurons generates the appropriate protective behavior. Neural signals that target tissues of the body are generated in the sympathetic and parasympathetic efferent pathways. These pathways are distinct with respect to their target tissue and therefore with respect to their functions ( ; ). This applies to the classic functions of autonomic neurons and probably also to functions that are related to protective body reactions (e.g., regulation of immune functions and regulation of inflammatory processes by the sympathetic nervous system; see later and ). Endocrine signals are generated in the hypothalamic–pituitary–adrenal system and in the sympathoadrenal system (adrenal medulla) ( , ).

Central Circuits Involved in Body Protection

Protective reflexes are programmed at the level of the spinal cord. Elementary homeostatic regulatory mechanisms related to the cardiovascular system, the respiratory system, or the gastrointestinal tract are represented in the lower brain stem. Complex homeostatic regulations are represented in the upper brain stem and hypothalamus. These regulatory mechanisms include endocrine, autonomic, and motor components ( , ). Homeostatic regulation of body functions is adapted to the internal state of tissues and environmental perturbations. This process of adaptation has been referred to as allostasis ( Box 13-1 ; ).

The central control circuits include neural systems that powerfully control transmission of nociceptive impulses in the spinal cord. These endogenous neuronal control systems are represented in the brain stem (periaqueductal gray; dorsolateral pontine tegmentum, including area A5; ventromedial medulla; caudal raphe nuclei) and are under the influence of the forebrain (cortex and limbic system). They can attenuate or enhance the transmission of nociceptive impulses, thereby leading to analgesia or hyperalgesia, respectively, and are closely linked with other control systems, such as regulation of body temperature, regulation of sexual function, and regulation of defense behavior ( ).

The afferent and efferent communication channels, as well as the central controls involved in protection of the body, act in both the fast (seconds to hours) and slow (days to months) time domains. They are responsible for generating responses enabling the organism to cope with external and internal stressful challenges. They work continuously under normal biological conditions and are essential for survival of the organism. However, once these allostatic regulations are driven to their extreme or not switched off, they may become deleterious to the organism and result in systemic diseases. These diseases cannot be reduced to specific abnormalities in single cells (e.g., neurons and immune cells), parts of cells (e.g., membrane receptors or intracellular signaling pathways), or molecular substructures (e.g., molecular changes in ionic channels), although specific cellular and subcellular changes are always integral parts of systemic diseases.

Sickness Behavior, Pain, Hyperalgesia, and Primary Afferent Neurons

When injected intraperitoneally or into somatic tissues, illness-inducing agents such as the bacterial cell wall endotoxin lipopolysaccharide, which activates the innate immune system, produce sickness behavior in rats ( Fig. 13-3 ). This sickness behavior consists of immobility, decreased social interaction, decrease in food intake, formation of a taste aversion to novel foods, decrease in digestion, loss of weight (anorexia), fever, increase in sleep, change in endocrine functions (activation of the hypothalamic–pituitary–adrenal axis), cognitive alterations, depressed mood, malaise (fatigue), and pain and hyperalgesia ( ). These functional characteristics are typical for further recuperation of the organism. Thus, sickness behavior is “… not simply the result of a debilitated state. Instead, sickness behavior represents a motivational state that is shaped by both the internal and external needs of the organism” ( ). This protective behavior organized by the brain evolves during noxious events, including invasion of infectious pathogens into body tissues, and results in recuperation of the organism.

Communication between the peripheral (innate) immune system and central neurons by way of cytokines occurs via circumventricular organs (e.g., the organum vasculosum of the lamina terminalis, the subfornical organ or the median eminence in the hypothalamus, or the area postrema in the lower brain stem), via saturable transporters across the blood–brain barrier (involving endothelial cells and perivascular macrophages), or via small-diameter primary afferent neurons (e.g., vagal abdominal afferents projecting to the nucleus of the solitary tract or possibly also afferent neurons projecting to the spinal or caudal trigeminal dorsal horn; see later). Transmission from the immune system to the brain is fast via peripheral afferent pathways and slow via the humoral and transport pathways. In the brain, notably at ports of entry such as the hypothalamus, nucleus of the solitary tract, and spinal dorsal horn, microglial cells and astrocytes are activated. Inflammatory cytokines are produced locally (by microglia and other immune-competent cells), and the excitability of neurons is increased by a process involving prostaglandin E ₂ (PGE ₂ ), adenosine triphosphate (ATP), and many other compounds and their receptors. Thus, peripheral pro-inflammatory cytokines reaching the brain switch on cytokine networks within the brain that activate and sensitize the neuronal pathways involved in the generation of sickness behavior, which includes pain and hyperalgesia. These central changes do not occur or are significantly attenuated in subdiaphragmatically vagotomized animals into which illness-inducing agents have been injected intraperitoneally (for discussion see ; ).

The pain and hyperalgesia that occur following activation of the innate immune system by intraperitoneal injection of lipopolysaccharide are suggested to be produced by activity in the subdiaphragmatic vagal afferents, specifically those running in the hepatic branch. Lipopolysaccharide activates hepatic macrophages (Kupffer cells), which release IL-1β and TNF-α. This in turn activates the vagal afferents. By the same token, IL-1β or TNF-α injected intraperitoneally generates hyperalgesia, which is also abolished by vagotomy ( , , ). These results suggest that vagal afferents, probably those innervating the liver, are activated by pro-inflammatory cytokines released by activated macrophages (Kupffer cells), dendritic cells, and leukocytes. The pro-inflammatory cytokines either activate the vagal afferents directly or bind specifically to glomus cells in the abdominal paraganglia that are innervated by vagal afferents. Activation of vagal afferents in this way leads to activation of neurons in the nucleus tractus solitarii and subsequently activation of noradrenergic neurons in the A1 and A2 areas of the brain stem that project to the hypothalamus. Stimulation of somatic tissues by lipopolysaccharide with resultant local release of inflammatory cytokines also generates a febrile response, which is a component of the protective sickness behavior. This response is also, at least in part, mediated by spinal or trigeminal primary afferent neurons. The functional nature of these afferent neurons is unknown ( , ).

Watkins, Maier, and co-workers developed the general thesis that vagal abdominal afferents projecting through the hepatic branch of the abdominal vagus nerve form an important neural interface between the immune system and the brain. Activation of these afferents by signals from the immune system (pro-inflammatory cytokines IL-1β, TNF-α, and IL-6) trigger—via different centers in the brain stem and hypothalamus—illness responses, one component being pain with hyperalgesia ( ; ). The physiology of the vagal afferents involved in communication between the immune system of the gastrointestinal tract and the brain, and the mechanisms by which activation of vagal afferents leads to pain, have to be worked out. It is hypothesized that activation of hepatic vagal afferents is followed by facilitation of nociceptive impulse transmission (see Fig. 13-3 ). These hepatic vagal afferents must be different from vagal afferents passing through the celiac branches of the abdominal vagal nerves since activation of the first is followed by hyperalgesia and activation of the latter by hypoalgesia (see the later section entitled Neuroendocrine Modulation of Hyperalgesia ).