Neuropeptide	Central Nervous System Function
HYPOTHALAMIC PEPTIDES MODULATING PITUITARY FUNCTION
Corticotropin (ACTH)-releasing hormone (CRH)	Regulation of ACTH secretion
	Integration of behavioral and biochemical responses to stress
	Modulatory effects on learning and memory
Growth hormone–releasing hormone (GHRH)	Regulation of growth hormone secretion
Growth hormone release–inhibiting hormone (somatostatin)	Regulation of growth hormone secretion
Ghrelin	Regulation of growth hormone secretion
	Regulation of feeding
Thyrotropin-releasing hormone (TRH)	Regulation of thyroid-stimulating hormone secretion
	May be involved in depression
	Enhances neuromuscular function (in the periphery)
Gonadotropin-releasing hormone (luteinizing hormone–releasing hormone) (GnRH)	Regulates gonadotropin secretionControls sexual receptivity
Prolactin-releasing peptide	Stimulates prolactin secretion
Neurotensin	Endogenous neuroleptic
	Regulates mesolimbic, mesocortical, and nigrostriatal dopamine neurons
	Thermoregulation
	Analgesia
Neuropeptide Y	Satiety (induces obesity) and drinking
	Sexual behavior
	Locomotion
	Memory
Orexins (hypocretins)	Stimulates CRH and antidiuretic hormone (ADH)
	Inhibits GHRH
	Stimulates GnRH
	May stimulate preovulatory prolactin release
	Inhibits TRH release
PITUITARY PEPTIDES
Prolactin	Maternal behavior
	Mood
	Anxiety
Growth hormone
Thyroid-stimulating hormone
Follicle-stimulating hormone
Luteinizing hormone	Elevated levels may promote neurodegeneration
Pro-opiomelanocortin
ACTH
ACTH-like intermediate lobe peptides
β-Endorphin	Analgesic mechanisms
	Feeding
	Thermoregulation
	Learning and memory
β-Lipotropic hormone	Skin tanning
Melanocyte-stimulating hormone (α- and γ-)	Weight loss
	Skin tanning
	Increased sexual desire
	Antiinflammatory effect
	Important mediator of leptin control on energy homeostasis
Oxytocin	Anxiety and mood
	Active/passive stress coping
	Maternal behavior, aggression
	Pair bonding
Vasopressin	Active/passive stress coping
	Anxiety
	Spatial memory
	Social discrimination, social interaction
	Pair bonding
Neurophysins
BRAIN–GASTROINTESTINAL TRACT PEPTIDES
Vasoactive intestinal polypeptide	Cerebral blood flow
	Potent antiinflammatory factor
Somatostatin
Insulin	Feeding behavior
	Modulatory effect on learning and memory
	Hunger
Glucagon	Inhibition of feeding
Pancreatic polypeptide
Gastrin
Cholecystokinin	Feeding behavior
	Satiety
	Modulates dopamine neuron activity
	Facilitation of memory processing (especially under stress)
Tachykinins (e.g., substance P)	Substance P co-localizes with serotonin and is involved in nociception
Secretin	Modulates motor and other functions in brain, facilitating GABA
Thyrotropin-releasing hormone
Bombesin	Thermoregulation
	Inhibition of feeding
	Modulatory effect on learning and memory
Orexins (hypocretin)	Gastric and gastrointestinal motility and secretion
	Pancreatic hormone release
	Regulation of energy homeostasis
	Feeding behavior
	Locomotion and muscle tone
	Wakefulness/sleep
Galanin	Modulates release of gonadotropin-releasing hormone, prolactin, insulin, glucagons, growth hormone, and somatostatin
	Affects feeding, sexual behavior, and anxiety
	Potent anticonvulsant effects
Leptin	Satiety factor
GROWTH FACTORS
Insulin-like growth factors (IGF) 1 and 2
Nerve growth factors	Axonal plasticity
OPIOID FAMILY
Endorphins	Analgesia
Enkephalins (met-, leu-)	Analgesic mechanisms
	Feeding
	Temperature control
	Learning and memory
	Cardiovascular control
Dynorphins
Kytorphin
NEUROPEPTIDES MODULATING IMMUNE FUNCTION
ACTH
Endorphins
Interferons
Neuroleukins
Thymosin
Thymopeptin
OTHER NEUROPEPTIDES
Atrial natriuretic factors	?Role in cerebral salt wasting
Bradykinins	Cerebral blood flow
Migraine
OTHER NEUROPEPTIDES
Angiotensin	Hypertension
	Thirst
Synapsins
Calcitonin gene–related peptide	Migraine and other vascular headaches
Calcitonin
Sleep peptides	Regulation of sleep cycles
Orexins (hypocretin)	Sleep-wake regulation
	Narcolepsy
	Energy homeostasis
Carnosine
PRECURSOR PEPTIDES
Pro-opiomelanocortin
Proenkephalins (A and B)
Calcitonin gene product
Vasoactive intestinal polypeptide gene product
Proglucagon
Proinsulin

ACTH, Adrenocorticotropic hormone; GABA, γ-aminobutyric acid.

* This is only a partial list of all of the neuropeptides that have been found in the brain, and not all of the putative functions have been listed.

Neuropeptides and the Immune System

It has been known for many years that stress, acting through the hypothalamic-pituitary-adrenal axis, modulates the function of the immune system (Tsigos and Chrousos, 2002; Wrona, 2006). Certain peptides and their receptors, once thought to be unique to either the immune or the neuroendocrine systems, actually are found in both.

Cytokines—interleukins (IL)-1, -2, -4, and -6 and tumor necrosis factor (TNF)—are synthesized by glial cells in the CNS in response to cell injury. IL-1 and the other cytokines, through their ability to stimulate the synthesis of nerve growth factor, may be important promoters of neuron damage repair. Circulating cytokines have been thought to play a role in the hypothalamus to activate the hypothalamic-pituitary-adrenal axis in response to inflammation elsewhere in the body (see Fever, later in this chapter) and inhibit the pituitary-thyroid and pituitary-gonadal axes in response to systemic disease.

Several other hormones and neuropeptides have modulatory effects on immune function. Similarly, immunocompetent cells contain hormones and neuropeptides that may affect neuroendocrine and brain cells (Table 42.2). Despite speculation about the ability of the psyche to influence immunological function and therefore disease outcome, conclusive evidence suggesting a clinically significant effect remains lacking (Padgett and Glaser, 2003).

Table 42.2 Immunoregulatory Effects of Several Hormones and Peptides

Hormone or Peptide	Immunocompetent Cell in which Hormone Is Found	Comments
INHIBITORY
Glucocorticoids		Inhibit lymphokine synthesis, inflammation
Corticotropin (ACTH)	B lymphocytes	Stimulated by corticotropin-releasing hormone; inhibited by cortisol
		Macrophage activation, synthesis of IgG and γ-interferon
Chorionic gonadotropin	T cells	Stimulated by thyrotropin-releasing hormone; inhibited by somatostatin
		Activity of T cells and natural killer cells
α-Endorphin		IgG synthesis, T-cell proliferation
Somatostatin	Mononuclear leukocytes, mast cells	T-cell proliferation, inflammatory cascade
Vasoactive intestinal peptide	Mononuclear leukocytes, mast cells	T-cell proliferation and migration in Peyer’s patches
		Potent antiinflammatory effect
α-Melanocyte-stimulating hormone		Fever, prostaglandin synthesis, secretion of interleukin 2
		Impairs function of antigen-producing cells and T cells
		Antiinflammatory effects
STIMULATORY
Estrogens		Lymphocyte proliferation and secretion
Growth hormone	T lymphocytes	Stimulated by growth hormone
		Thymic growth, lymphocyte reactivity
Prolactin	Mononuclear cells	Thymic growth, lymphocyte proliferation
STIMULATORY
Thyrotropin (TSH)	T cells	Stimulated by thyrotropin-releasing hormone; inhibited by somatostatin
		IgG synthesis
β-Endorphin		Activity of T, B, and natural killer cells
Substance P		Proliferation of T cells and macrophages, inflammatory cascade
Corticotropin (ACTH)-releasing hormone		Lymphocyte and monocyte proliferation and activation
NOT KNOWN TO BE STIMULATORY OR INHIBITORY
Enkephalins	B lymphocytes
Vasopressin	Thymus
Oxytocin	Thymus
Neurophysin	Thymus

ACTH, Adrenocorticotropic hormone; IgG, immunoglobulin G; TSH, thyroid-stimulating hormone.

Modified from Reichlin, S., 1993. Neuroendocrine-immune interactions. N Engl J Med 329, 1246-1253.

Nonendocrine Hypothalamus

Temperature Regulation

The hypothalamus plays a key role in ensuring that body temperature is maintained within narrow limits by balancing the heat gained from metabolic activity and the environment with the heat lost to the environment. A theoretical schema of the mechanisms of hypothalamic temperature regulation is depicted in Fig. 42.1. Although numerous neurotransmitters and peptides alter body temperature, their physiological roles remain unclear.

Fig. 42.1 Schematic representation of hypothalamic temperature regulation mechanisms. Preoptic anterior hypothalamus functions as a thermostat and contains mechanisms for regulation of heat loss. Posterior hypothalamus integrates heat production mechanisms. Lesions of the preoptic anterior hypothalamus result in hyperthermia; lesions of the posterior hypothalamus cause hypothermia or poikilothermia.

(Reprinted with permission from Cooper, P.E., Martin, J.B., 1983. Neuroendocrine disease, in: Rosenberg, R.N. (Ed.), The Clinical Neurosciences. Churchill Livingstone, New York.)

Hypothalamic injury can cause disordered temperature regulation. One potentially serious consequence is the hyperthermia that may occur when the preoptic anterior hypothalamic area is damaged or irritated by ischemia, subarachnoid hemorrhage, trauma, or surgery. In some patients, the marked impairment of heat-loss mechanisms and the resulting hyperthermia may be fatal. In those individuals who survive, temperature control usually returns to normal over a period of days to weeks. Chronic hyperthermia of hypothalamic origin is extremely uncommon; it may occur with continued impairment of ability to dissipate heat adequately or with difficulty sensing temperature elevations. Chronic hypothalamic hyperthermia does not respond to salicylates and other antipyretics because it is not prostaglandin mediated. Both acute and chronic hypothermia can be due to hypothalamic injury, the most common causes being head trauma, infarction, and demyelination. Other entities to be considered in the differential diagnosis are severe hypothyroidism, Wernicke disease, and drug effect. Some patients with no apparent hypothalamic structural abnormalities may have episodes of recurrent hypothermia. The cause of this syndrome is unclear, although the response of some patients to anticonvulsant agents and of others to clonidine or cyproheptadine suggests a possible neurotransmitter abnormality. Agenesis of the corpus callosum in association with episodic hyperhidrosis and hypothermia (Shapiro syndrome) is caused in some individuals by an abnormally low hypothalamic set point. These symptoms may respond to clonidine (a centrally acting α₂-adrenergic agonist). A similar condition associated with hyperthermia (so-called reverse Shapiro syndrome) has been found to respond with normalization of temperature to low-dose l-dopa; higher doses cause hypothermia. Large lesions in the posterior hypothalamus may impair both heat production (by altering the set point) and heat loss (by damaging the outflow from the preoptic anterior hypothalamic area). This results in poikilothermia, a condition in which body temperature varies with the environmental temperature.

Fever

Classical teaching has been that inflammatory cells in the periphery (primarily monocytes) released cytokines in response to infection and inflammation. These cytokines were thought to act on the hypothalamus to induce production of prostaglandin E₂ (PGE₂) and cause elevation of the body temperature set point. The body then used its normal physiological mechanisms of vasoconstriction, vasodilation, sweating, and shivering to maintain this new higher set point (i.e., fever). This view of the mechanism by which bacterial infections cause fever probably is incorrect. Bacterial endotoxic lipopolysaccharide (LPS) does appear to work in the periphery to cause macrophages to release a variety of factors; however, the initial signal to the brain probably travels by vagal afferents to the preoptic anterior hypothalamus via norepinephrine, which activates the cyclo-oxygenase isoenzyme, COX-2, to generate and release PGE₂. The slower or second febrile increase in PGE₂ is due to COX-2 activation by IL-1β produced locally in the brain, not to circulating factors (Blatteis et al., 2000). Interference with prostaglandins is probably how drugs such as acetylsalicylic acid and acetaminophen act to treat fever.

In otherwise healthy persons, extreme elevations of body temperature (as high as 41.1°C [106°F]) sometimes can be tolerated without serious effects. Hyperthermia associated with prolonged exertion, heatstroke, malignant hyperthermia, neuroleptic malignant syndrome, hyperthyroidism, pheochromocytoma crisis, and some drugs, however, may have serious and even fatal consequences. Exertional hyperthermia occurs with prolonged physical activity, particularly in hot, humid weather. It usually decreases athletic performance initially and can cause muscle cramps or heat exhaustion. When severe, it may result in heatstroke, a syndrome characterized by hyperthermia, hypotension, tachycardia, hyperventilation, and decreased level of consciousness.

Drug-induced hyperthermic syndromes include anticholinergic poisoning, sympathomimetic poisoning, malignant hyperthermia, neuroleptic malignant syndrome, and serotonin syndrome. In malignant hyperthermia, a syndrome associated most often with the use of various general anesthetic agents and muscle relaxants, an inherited defect leads to excessive release of calcium from sarcoplasmic reticulum, stimulating severe muscle contraction (see Chapters 64 and 79). The neuroleptic malignant syndrome (NMS) is characterized by diffuse muscular rigidity, akinesia, and fever accompanied by a decreased consciousness level and evidence of autonomic dysfunction—namely, labile blood pressure, tachyarrhythmias, excessive sweating, and incontinence. NMS can be associated with administration of major tranquilizers (primarily those that work by blocking dopamine receptors), with rapid withdrawal from dopaminergic agents, including entacapone, and less commonly with administration of tricyclic antidepressants. It appears to result from an alteration of temperature control mechanisms in the hypothalamus. As part of treatment, withdrawal of all neuroleptics is mandatory. In addition to general supportive measures and cooling, the use of bromocriptine (2.5 to 10 mg 4 times daily, increasing by 7.5 mg daily in divided doses to a maximum of 60 mg daily) is helpful. Hypotension, psychosis, and nausea are possible side effects. An alternative is dantrolene (50 to 200 mg/day orally, or 2 to 3 mg/kg/day intravenously (IV), to a maximum of 10 mg/kg/day). The serotonin syndrome is characterized by mental status changes, neuromuscular symptoms, autonomic dysfunction, and gastrointestinal dysfunction. In addition to tremor and rigidity (seen also in NMS), other features may include shivering, myoclonus, and hyperreflexia. Nausea, vomiting, and diarrhea are common in serotonin syndrome but are uncommon in NMS. Treatment entails withdrawal from the offending drug and general supportive care.

Appetite

Given free access to food and water, most animals maintain their body weight within narrow limits. With a change in energy intake/expenditure (a change in the size or number of individual meals that is not balanced by an equal and opposite change in energy use), the animal experiences a change in weight. One possible model of nutrient balance is depicted in Fig. 42.2. The four components of energy balance are (1) the afferent system, (2) the CNS processing unit, (3) the efferent system, and (4) the absorption of food from the gut and its metabolism in the liver. Defects at any point in these systems may lead to weight loss or weight gain (Wynne et al., 2005).

Fig. 42.2 Sympathetic nervous system. In the regulation of energy balance, the brain is the central processing unit. It receives afferent neuronal signals from the vagus nerve, via the brainstem and hormonal signals—ghrelin (from the stomach), insulin (from the pancreas), and leptin (from adipocytes). The brainstem also has input to the hypothalamus via norepinephrine (NE) (from the locus ceruleus) and serotonin, or 5-hydroxytryptamine (5-HT) (from the raphe nuclei). These afferent signals are interpreted both in the brainstem (in the nucleus of the tractus solitarius) and in the hypothalamus (in the ventromedial nucleus). The ventromedial nucleus of the hypothalamus communicates with the lateral hypothalamic area (LHA) and the paraventricular nucleus (PVN) by means of pro-opiomelanocortin-cocaine/amphetamine-regulated transcript (POMC-CART), an anorexigenic peptide (the release of which is stimulated by insulin and leptin), and by neuropeptide Y/agouti-related protein (NPY/AGRP), an orexigenic peptide (the release of which is stimulated by ghrelin and inhibited by leptin and insulin)—or through the parasympathetic nervous system. Output from the LHA and PVN is either via the sympathetic nervous system, which leads to energy expenditure through physical activity, activation of β₂-adrenergic receptors, and uncoupling proteins in the adipocyte to cause energy release through lipolysis, or through the parasympathetic nervous system. Output via the vagus nerve leads to increased insulin secretion, which causes adipogenesis and energy storage. For a more complete explanation of this control of energy balance, the interested reader is directed to the article by Lustig (2001). DMV, Dorsal motor nucleus of the vagus; GI, gastrointestinal; NTS, nuclear tractus solitarius.

In response to a meal or to starving, hormonal and neural signals are generated in the periphery. Some are of short duration, and others are of long duration. Some relate to satiety, others relate to feeding behavior, and still others relate to “thinness and fatness.” Ghrelin, a stimulator of growth hormone (GH) release, is released from the stomach in the fasting state. Ghrelin activates neuropeptide Y and agouti-related protein in the hypothalamus, leading to increased feeding and deposition of energy into body fat. Peripheral insulin seems to mediate a satiety signal in the ventromedial hypothalamus. Leptin is the other component of the afferent system.

Destruction of the ventromedial hypothalamus, both in animals and in humans, leads to obesity. Lesions in the paraventricular nucleus have a similar effect. Overeating (hyperphagia) is only one of the mechanisms that produces hypothalamic obesity; more efficient handling of calories by the eater is probably another important factor. Hypothalamic lesions also can cause weight loss. Lesions in the dorsomedial nucleus lead to a reduction in body weight and fat stores, as do lesions in the lateral hypothalamus. Studies in the decerebrate rat suggest that oral motor and meal-size responses are dependent on centers in the caudal brainstem, on which the hypothalamus has only a modulatory effect (Grill and Kaplan, 2002).

Meal size and food intake are influenced by many different stimuli. Sensory cues such as the sight, aroma, and taste of food are major factors in dietary obesity. A decrease in blood glucose or a decrease in the oxidation of fatty acids in the liver stimulates the act of eating. Stomach distention gives rise to neural and hormonal signals that reduce food intake. Gastrointestinal peptides such as cholecystokinin, bombesin, and glucagon inhibit feeding by their actions on the autonomic nervous system, particularly the vagal nucleus. Increased fatty acid oxidation leads to higher levels of 3-hydroxybutyrate, which then acts on the hypothalamus to reduce food intake. Interference with any of these sensing systems in the CNS can lead to obesity. Neuropeptide Y infused into the ventromedial nucleus of the hypothalamus induces obesity, perhaps by inhibiting sympathetic drive and stimulating insulin release. Although this may explain obesity with hypothalamic lesions, obesity related to eating highly palatable food probably is not related to central changes in neuropeptide Y.

In animals, the ob, db, and fa genes play a role in the ability of adipose tissue to regulate feeding through a circulating factor. When the product of the ob gene, leptin, is administered peripherally to a genetically obese (ob/ob) mouse deficient in leptin, the animal reduces its intake of food, with a resulting decrease in body weight. The role of leptin in appetite regulation is complex. Leptin does not reverse the obesity seen in db/db mice and in obese humans. In these groups, serum leptin concentrations are higher than in subjects of normal weight, suggesting an insensitivity to endogenous leptin production.

When α-melanocyte-stimulating hormone (α-MSH) binds to its receptor in the hypothalamus, it causes satiety. Up to 5% of obese children have been found to have an abnormality of the α-MSH receptor, MC₄R, as a cause of their obesity (Lustig, 2001).

The orexins (hypocretins) are neuropeptides that play a role in energy balance and arousal (Ferguson and Samson, 2003). Narcolepsy is caused by failure of orexin-mediated signaling. Orexins are found in the hypothalamus, where they regulate sleep/wake cycles (Baumann and Bassetti, 2005), and in the GI tract, where they excite secretomotor neurons and modulate gastric and intestinal motility and secretion (Kirchgessner, 2002).

Anorexia nervosa and bulimia nervosa are clinical eating disorders of unknown etiology seen primarily in young women and girls. Anorexia nervosa is characterized by reduced caloric intake and increased physical activity associated with weight loss, a distorted body image, and a fear of gaining weight. Bulimia nervosa is characterized by episodic gorging followed by self-induced vomiting or laxative and diuretic abuse or dieting and exercise to reduce weight. Initially these syndromes were considered to be neuroendocrine in origin, then for many years, they were assumed to be purely psychiatric. Although malnutrition produces changes in neuroendocrine function, disturbances in corticotropin-releasing hormone (CRH), opioids, neuropeptide Y, vasopressin, oxytocin, cholecystokinin (CCK), and leptin as well as the monoamines—serotonin, dopamine, and norepinephrine—have been found in patients with eating disorders (Barbarich et al., 2003). These neurotransmitters play a role not only in appetite but in mood and impulse control. The abnormalities have been found to persist, in some instances, long after recovery. Furthermore, patients with anorexia nervosa seem to have an increased total daily energy expenditure because of their increased physical activity. All of this suggests a complex interaction between the psyche and the endocrine system as a cause for these syndromes.