Lecture 6

Pain

Autonomic Nervous System

Dr. Ana-Maria Zagrean

Pain

Pain is a protective experience.

1. Somatic pain: - cutaneous sensation = superficial pain

- from muscles, joints, bones, connective tissue

= deep pain

2. Visceral pain: from internal organs (strong contraction, forcible

deformation…)

Pain is sensed by nociceptors (free nerve endings) of C and A fibres that transduce intense stimuli into electrical events.

C-fibres –unmyelinated: for slow, chronic pain, sickening, dull, burning sensation which persists long after the stimulus is removed.

A -fibres –myelinated (smallest-diameter): for fast, acute, sharp intense pain

Types of Pain and Their Qualities:Fast Pain and Slow Pain

• Initial, fast pain (sharp, pricking, acute, electric pain) is felt within about 0.1 second after a pain stimulus is applied.

Fast pain is felt when a needle is stuck into the skin, when the skin is cut with a knife, or when the skin is acutely burned or subject to electric shock.

• Delayed, slow pain (slow burning pain, aching pain, chronic pain)begins only after 1 second or more and then increases slowly over many seconds and sometimes even minutes; it is usually associated with tissue destruction and can lead to prolonged, unbearable suffering.

Pain receptors and their stimulation • Pain receptors are free nerve endings.

The pain receptors are widespread in the superficial layers of the skinas well as in certain internal tissues, such as the periosteum, the arterial walls and the joint surfaces.

N.B. nociceptors are generally absent from the brain substance itself, although they are in the meninges.

• Pain can be elicited by multiple types of stimuli, classified as mechanical, thermal, and chemical pain stimuli.

-In general, fast pain is elicited by the mechanical and thermal types of stimuli, whereas slow pain can be elicited by all three types.

-Some of the chemicals that excite the chemical type of pain are bradykinin, serotonin, histamine. The chemical substances are especially important in stimulating the slow type of pain that occurs after tissue injury (inflammation).

• In contrast to most other sensory receptors of the body, pain receptors adapt very little and sometimes not at all.

TRPA1 ion channel mediates the cellular influx of cations such as calcium ions (Ca2+).

Nociceptors vary in their selectivity

Pain Modalities:1) Mechanical,

2) Heat/Cold,3) Chemical 4) Polymodal (temperature, mechanical and chemical).

1) Mechanical nociceptors -respond to strong pressure (e.g. from sharp objects).-Mas-related G protein–Coupled Receptor D (MrgprD) selectively responsive to noxious mechanical stimuli. -Transient Receptor Potential ankyrin 1 (TRPA1) channels - involved in some forms of pain related mechano-sensation; may transduce stimuli that trigger pain originating from viscera (colon, bladder)

2) Thermal nociceptors -signal either burning heat (above ~45°C, when tissues begin to be destroyed) or unhealthy cold; -the heat-sensitive nociceptive neurons express the TRPV1 and TRPV2 channels, whereas the cold-sensitive nociceptors express TRPA1 and TRPM8 channels. -a uniquely cold-resistant Na+ channel, Nav1.8, allows cold-sensitive nociceptors to continue firing AP even at temperatures low enough to silence other neurons.

3) Chemical nociceptors -respond to K+, extremes of pH, neuroactive substances (histamine, bradykinin)

from the body itself, and various irritants from the environment.-some chemosensitive nociceptors may express TRP channels that can respond to plant-derived irritants such as capsaicin (TRPV1), menthol (TRPM8), and the pungent derivatives of mustard and garlic (TRPA1).

4) Polymodal nociceptors -are sensitive to combinations of mechanical, thermal, and chemical stimuli.

Pain Modalities:1) Mechanical,

2) Heat/Cold,3) Chemical

4) Polymodal (temperature, mechanical and chemical).

Clinical abnormalities of pain and other somatic sensations

Hyperalgesia: can manifest as reduced threshold for pain, an increase in perceived intensity of painful stimuli, or spontaneous pain

A pain nervous pathway sometimes becomes excessively excitable→ hyperalgesia = hypersensitivity to pain.

Possible causes of hyperalgesia are:

(1) excessive sensitivity of the pain receptors themselves, which is called primary hyperalgesia:

occurs within the area of damaged tissue, but within ~20 min after an injury

examples: extreme sensitivity of sunburned skin which results from sensitization of the skin pain endings by local tissue products from the burn (histamine, prostaglandins)

(2) facilitation of sensory transmission - secondary hyperalgesia

seems to involve processes near peripheral receptors as well as mechanisms in the CNS.

frequently results from lesions in the spinal cord or the thalamus.

Inflammatory response

Inflammatory soup from damaged skin include neurotransmitters (glutamate, serotonin, adenosine, ATP), NGF, peptides (substance P, bradykinin), histamine, lipids (PGs), cytokines, chemokines, K+, H+, etc. → trigger local responses → inflammation → leaking blood vessels→ tissue swelling/edema, redness, pain.

Axon reflex – AP can propagate along nociceptive axons from the site of aninjury into side branches of the same axon that innervate neighboring regions of skin; role in sensitizing nociceptors.

Pain transmission, the spinothalamic tract and cortical projection

DRG – dorsal root ganglia

Target sites for drugs which produce pain relief

(Analgesia)

Central

Synapse

Sensory Neurone

1) Block synthesis, release or receptors

for proinflammatory / pronociceptive

agents.

2) Block action potentials 3) Block neurotransmitter release

4) Block pain pathways in the CNS

Types of pain

Referred Pain:

• a person feels pain in a part of the body that is fairly remote from the tissue causing the pain: pain in one of the visceral organs often is referred to an area on the body surface.

• Knowledge of the different types of referred pain is important in clinical diagnosis because in many visceral disorders the only clinical sign is referred pain.

• Mechanism of Referred Pain: branches of visceral pain fibers synapse in the spinal cord on the same second-order neurons that receive pain signals from the skin.

When the visceral pain fibers are stimulated, pain signals from the viscera are conducted through at least some of the same neurons that conduct pain signals from the skin, and the person has the feeling that the sensations originate in the skin itself (in the correspondent dermatome).

Visceral Pain

• In clinical diagnosis, pain from the different viscera of the abdomen and chest is one of the few criteria that can be used for diagnosing visceral disorders.

• Often, the viscera have sensory receptors for no other modalities of sensation besides pain.

• Visceral pain differs from surface pain in several important aspects:

- highly localized types of damage to the viscera rarely cause severe pain,

- a stimulus that causes diffuse stimulation of pain nerve endings causes pain that can be severe (ischemia caused by occluding the blood supply to a large area of gut stimulates many diffuse pain fibers at the same time and can result in extreme pain).

Causes of Visceral Pain

• Any stimulus that excites pain nerve endings in diffuse areas of the viscera can cause visceral pain.

- ischemia of visceral tissue

- chemical damage to the surfaces of the viscera,

- spasm of the smooth muscle, excess distention of a hollow viscus, and stretching of the connective tissue.

• Essentially all visceral pain that originates in the thoracic and abdominal cavities is transmitted through small type C pain fibers and, therefore, can transmit only the chronic-aching-suffering type of pain.

• Ischemia. Ischemia causes visceral pain in the same way that it does in other tissues: formation of acidic metabolic end products or tissue-degenerative products such as bradykinin, proteolytic enzymes, or others that stimulate pain nerve endings.

• Chemical Stimuli. On occasion, damaging substances leak from the gastrointestinal tract into the peritoneal cavity. For instance, proteolytic acidic gastric juice often leaks through a ruptured gastric or duodenal ulcer. This juice causes widespread digestion of the visceral peritoneum, thus stimulating broad areas of pain fibers. The pain is usually extremely severe.

Causes of Visceral Pain

• Spasm of a Hollow Viscera: a portion of the gut, the gallbladder, a bile duct, a ureter, can cause pain -mechanical and chemical stimulation of the pain nerve endings, as the spasm might cause diminished blood flow to the muscle. Often in the form of cramps, with the pain increasing to a high degree of severity and then subsiding. This process continues intermittently, once every few minutes. The cramping type of pain frequently occurs in appendicitis, gastroenteritis, constipation, menstruation, gallbladder disease, or ureteral obstruction.

• Insensitive Viscera. A few visceral areas are almost completely insensitive to pain of any type: parenchyma of the liver and the alveoli of the lungs.

Yet the liver capsule is extremely sensitive to both direct trauma and stretch, and the bile ducts are also sensitive to pain.

In the lungs, even though the alveoli are insensitive, both the bronchi and the parietal pleura are very sensitive to pain.

The Autonomic Nervous System (ANS)

The ANS- Coordinates cardiovascular, respiratory, digestive, excretory and reproductive

systems

- Mainly constituted from visceral efferents – autonomic motor neurons:• Innervates smooth muscle, cardiac muscle, secretory epithelia and glands

• Regulates visceral functions

Heart rate (HR), blood pressure, digestion, urination, etc

- also receives visceral afferents, interoceptive inputs

- connected with CNS that control the viscera and autonomic functions

Rapidity and intensity in changing visceral functions:

within 3 -5 sec. the heart rate can be doubled

within 10-15 sec. the arterial pressure can be doubled

The ANS has three divisions: sympathetic, parasympathetic, and enteric.

(Langley, 1898)

Autonomic - from the Greek for "self-governing," functioning independently of the will

Enteric ANS is a system of afferent neurons, interneurons, and motor neurons that form neural networks = plexusesthat surround GIT.

Function as a separate and independent nervous system, but it is normally controlled by the CNS through sympathetic and parasympathetic fibers.

Enteric division of ANS

S & PS Divisions of the Autonomic Nervous System

• Sympathetic (S) effects-wide spread, long-lasting mobilization of the “fight, flight, or fright” response-activated during exercise, excitement,

and emergencies-exaggerated reaction - panic attacks…

• Parasympathetic (PS) effects-“rest and digest”-results in conserving energy

• ‘Autonomic conflict’ – in case of a strong, simultaneous activation of both S and PS branches (jumping into cold water →‘cold shock response’ and ‘diving response’.

-work synergistically to control visceral activity and often exert antagonistic/opposite effects on the same target organs-most blood vessels are innervated only by S nerves-PS activity dominates the heart and GI tract.-S and PS exert cooperative effects on the external genitalia.

Sympathetic and parasympathetic ANS divisions

-both have a pathway constituted from a pre- and postganglionic cells

1st preganglionic neuron in the CNS (brainstem or spinal cord) and synapse with

2nd postganglionic neuron in peripheral ganglia that innervate the target cells

Comparison of Autonomic and Somatic Motor Systems• Somatic motor system

• One motor neuron extends from the CNS to skeletal muscle: voluntary, direct synapse, always excitatory (Ach) – nicotinic receptors

• Axons are well myelinated, conduct impulses rapidly

• Autonomic nervous system • Chain of two motor neurons• Involuntary, two-synapsis pathway (Preganglionic & Postganglionic

neurons), either excitatory or inhibitory• Conduction is slower due to thinly or unmyelinated axons

Motor pathways of the somatic (a) & autonomic (b) nervous system

Anatomical differences in Sympathetic and Parasympathetic Divisions

Originate from different CNS regions

• Sympathetic = thoracolumbar division (T1 – L3)

• Parasympathetic = craniosacral division (brainstem and sacral spinal cord S2-S4)

Anatomical differences

-Length of postganglionic fibers

• S: long postganglionic fibers

• PS: short postganglionic fibers

-Branching of axons

• S: highly branched, influences many organs

• PS: few branches, localized effect

Anatomical differences in Sympathetic and Parasympathetic Divisions

Organization of the sympathetic and

parasympathetic divisions of the ANS.

The cell bodies of sympathetic

preganglionic neurons (in red) are in the

lateral horn of the thoracic and lumbar

spinal cord (T1–L3). Their axons project to

paravertebral ganglia (the sympathetic

chain/trunk) and prevertebral ganglia.

Postganglionic neurons (in blue) have

long projections to their targets.

The cell bodies of PS preganglionic

neurons (orange) are either in the brain

(midbrain, pons, medulla) or in the sacral

spinal cord (S2–S4). Their axons project to

ganglia close to or inside the end organs.

Postganglionic neurons (in green) have

short projections to their targets.

Sympathetic Preganglionic

Neurons are located in the

thoracic and upper lumbar spinal

cord between levels T1 - L3 in the

lateral horn, between the dorsal

and ventral horns.

Axons from preganglionic

sympathetic neurons exit the

spinal cord through the ventral

roots along with axons from

somatic motor neurons.

After entering the spinal nerves,

sympathetic efferents diverge

from somatic motor axons to enter

the white rami communicantes

(myelinated).

Anatomical aspects of the Sympathetic division of ANS

Paravertebral Ganglia – sympathetic ganglia adjacent to the vertebral column → form the sympathetic trunk

Axons from preganglionic neurons emerge from T1 to L3, and enter through a white ramus into the nearest S paravertebral ganglion from the chain of sympathetic ganglia (this chain extends all the way from the upper part of the neck to the coccyx, where left and right sympathetic chains merge in the midline to form the coccygeal ganglion).

In general, one ganglion is positioned at the level of each spinal root, but adjacent ganglia are fused in some cases:

The most rostral ganglion, the superior cervical ganglion, arises from fusion of C1 to C4 ganglia and supplies the head and neck.

The next two ganglia are the middle cervical ganglion, which arises from fusion of C5 and C6.

The inferior cervical ganglion (C7 and C8), which is usually fused with the first thoracic (T1) ganglion to form the stellate ganglion.

Anatomical aspects of the Sympathetic division of ANS

After entering a paravertebral ganglion, a preganglionic sympathetic axon has one or more of three fates:

(1) synapse within the paravertebral ganglion at the same level,(2) travel up or down the sympathetic chain to synapse within a neighboring paravertebral ganglion, or (3) enter the greater or lesser splanchnic nerve to synapse within one ofthe ganglia of the prevertebral plexus.

Anatomical aspects of the Sympathetic division of ANS

The major prevertebral ganglia are named

according to the arteries that they are adjacent to

and include the celiac, superior mesenteric,

aorticorenal, and inferior mesenteric ganglia.

Each preganglionic sympathetic fiber synapses on

many postganglionic sympathetic neurons that are

located within one or several nearby paravertebral

or prevertebral ganglia.

It has been estimated that each preganglionic

sympathetic neuron branches and synapses

on as many as 200 postganglionic neurons,

which enables the sympathetic output to have

more widespread effects.

Anatomical aspects of the Sympathetic division of ANS

Parasympathetic fibers :-leave CNS through cranial n. III (pupillary sphincter and ciliary muscle of the eye), VII (lacrimal, nasal, and submandibular glands), IX (parotid gland), X (heart, lungs, esophagus, stomach, entire small intestine, proximal half of the colon, liver, gallbladder, pancreas, kidneys, and upper portions of the ureters);

-additional PS fibers leave the lowermost part of the spinal cord S2-S3 spinal nerves (pelvic nerves) and occasionally S1, S4 nerves (descending colon, rectum, urinary bladder, and lower portions of the ureters).

-about 75 % of all PS nerve fibers are in the vagus nerves (cranial nerve X),passing to the entire thoracic and abdominal regions of the body.

The visceral control system also has an important afferent pathway

All internal organs are densely innervated by visceral afferents.

-nociceptive (painful) inputs that travel in sympathetic nerves

-mechanical and chemical (physiological) stimuli, including stretch of the

heart, blood vessels, and hollow viscera, as well as PCO2, PO2, pH, blood glucose,

and temperature of the skin and internal organs. Most axons from physiological

receptors travel with parasympathetic fibers (mostly vagus nerve).

Cell bodies of visceral afferent fibers are located within the dorsal root ganglia or

cranial nerve ganglia (e.g., nodose and petrosal ganglia). 90% of these visceral

afferents are unmyelinated.

The largest concentration of visceral afferent axons can be found in the vagus nerve,

which carries non-nociceptive afferent input to the CNS from all viscera of the thorax

and abdomen. - Most fibers in the vagus nerve are afferents, even though all parasympathetic preganglionic

output (i.e., efferents) to the abdominal and thoracic viscera also travels in the vagus nerve.

- Vagal afferents carry information about the distention of hollow organs (e.g., blood vessels,

cardiac chambers, stomach, bronchioles), blood gases (e.g., PO2, PCO2, pH from the aortic

bodies), and body chemistry (e.g., glucose concentration) to the medulla.

Neurotransmitters of Autonomic Nervous System• Neurotransmitter released by preganglionic axons

• Acetylcholine for both S & PS branches (cholinergic)

• Neurotransmitter released by postganglionic axons

• Sympathetic – most release norepinephrine (adrenergic), also neuropeptide Y and ATP.

• Parasympathetic – release acetylcholine, also neuropeptides (VIP)

Secretion of Acetylcholine and Norepinephrine by Postganglionic Nerve Endings

• Many of the PS nerve fibers and almost all the S fibers connect with the effector cells or terminate in connective tissue adjacent to the target cells

• Postganglionic fibers present bulbous enlargements =varicosities• transmitter vesicles of Ach or NE are synthesized here and stored.

• large numbers of mitochondria that supply ATP, required to energize Ach or NE synthesis.

• AP → depolarization → calcium ions inflow into nerve → transmitter substance is secreted.

Synthesis of Ach→ acetate & choline, catalyzed by acetylcholinesterase (bound with collagen and glycosaminoglycans in the local connective tissue) → fast end of Ach action

Synthesis of norepinephrine (NE) begins in the axoplasm of the terminal adrenergic nerve endings, completed inside the secretory vesicles. In the adrenal medulla, this reaction goes still one step further to transform about 80 % of the NE into E:

Transport of dopamine into the secretory vesicles

NE is removed from the secretory site by:

(1) reuptake into the adrenergic nerve endings by an active transport process (50 - 80 % );

(2) diffusion away from the nerve endings into the surrounding body fluids and then into the blood - accounting for removal of most of the remaining NE;

(3) destruction of small amounts by tissue enzymes - monoamine oxidase (MAO) in the nerve endings, and catechol-O-methyl transferase (COMT), in all tissues.

Signal transmission in ANSA. Sympathetic

• Preganglion neuron secretes Acetylcholine (Cholinergic)

Receptor on the Postganglionic neuron = Nicotinic Rec.

• Postganglionic neuron secretes Norepinephrine, NPY, ATP

• Target (smooth muscle, cardiac muscle, glands)

Receptor = Adrenergic rec. (α1, α2; β1, β2, β3)

! Sweat glands, some blood vessels, piloerector muscle:

• Postganglionic S neuron secretes Acetylcholine/NO (Cholinergic/nitroxidergic)

• Target: -sweat gland – muscarinic receptor -smooth m. in the small arteries from the skeletal muscles and the brain: NO released promotes vasodilation.

• Stimulation of S division has two distinctive results:

- release of NE at specific locations

- secretion of E and NE (4:1) into the general circulation.

- alpha receptors : activated by NE > E, isoproterenol; blocked by: phenoxybenzamine

- beta receptors: activated more by E; blocked by propranolol

Signal transmission in ANS

B. Parasympathetic

• Preganglionic neuron secretes Acetylcholine (Cholinergic)

• Receptors on postganglionic neurons = Nicotinic

• Postganglionic neuron secretes Acetylcholine, VIP

• Target receptor = muscarinic (smooth muscle, heart, glands)

Outflow via the Vagus Nerve (X)

• Preganglionic cell bodies: located in dorsal motor nucleus in the medulla

• Ganglionic neurons: located within the walls of organs being innervated

• Fibers innervate visceral organs of the thorax and most of the abdomen (75%...)

• Stimulates digestion, reduces heart rate and blood pressure, etc

Sacral Outflow

• Preganglionic cell bodies: located in visceral motor region of spinal gray matter (S2-S4)

• Innervates organs of the pelvis and lower abdomen

Postganglionic sympathetic and parasympathetic neurons often have

nicotinic as well as muscarinic receptors

-Some postganglionic neurons, both sympathetic and parasympathetic, have

muscarinic in addition to nicotinic receptors.

-At all levels of the ANS, certain neurotransmitters and postsynaptic receptors

are neither cholinergic nor adrenergic. If we stimulate Ach release from preganglionic neurons, many postganglionic neurons

exhibit both nicotinic and muscarinic responses.

-Because nicotinic receptors (N2) are ligand-gated ion channels, nicotinic

neurotransmission causes a fast, monophasic excitatory postsynaptic potential

(EPSP).

In contrast, because muscarinic receptors are GPCRs, neurotransmission by this

route leads to a slower electrical response that can be either inhibitory or excitatory.

-Thus, depending on the ganglion, the result is a multiphasic postsynaptic response

that can be a combination of a fast EPSP through a nicotinic receptor plus either a

slow EPSP or a slow inhibitory postsynaptic potential (IPSP) through a muscarinic

receptor.

Transmitters released at each level of the ANS

Central Control of the ANS

•Control by the brain stem and spinal cord• Reflex activity is mediated by spinal cord and brain stem

(medullary centers).• Reticular formation exerts most direct influence

• Medulla oblongata

• Periaqueductal gray matter

• Control by the hypothalamus and amygdalaHypothalamus – the main integration center of the ANS that interact with both higher and lower centers to orchestrate autonomic, somatic and endocrine responses.Amygdala – main limbic region for emotions

• Control by the cerebral cortex via connections with the limbic system

Basic Structure of a Visceral Reflex

2nd processing center

Visceral reflex: visceral sensory and autonomic neurons

PS reflexes: gastric and intestinal reflexes, defecation, urination, swallowing, coughing reflex, baroreceptor reflex and sexual arousal.

S reflexes: cardioaccelaratory reflex, vasomotor reflex, pupillary reflex and ejaculation.

A variety of brainstem nuclei provide basic control of the ANSNucleus tractus solitarii (NTS) in the medulla contains second-order sensory neurons

that receive all input from peripheral chemoreceptors and baroreceptors input, as well

as non-nociceptive afferent input from every organ of the thorax and abdomen.

Visceral afferents from the vagus nerve make their first synapse within the NTS, where they

combine with other visceral (largely unconscious) afferent impulses derived from the

glossopharyngeal (CN IX), facial (CN VII), and trigeminal (CN V) nerves.

These visceral afferents form a large bundle of nerve fibers - the tractus solitarius - that the NTS

surrounds.

Afferent input is distributed to the NTS in a viscerotopic manner, with major subnuclei devoted to

respiratory, cardiovascular, gustatory, and GI input.

The NTS also receives input and sends output to many other CNS regions including the brainstem

nuclei described above as well as the hypothalamus and the forebrain.

Hypothalamus (HT)

- part of diencephalon (1% of brain volume), located within the walls & floor of 3rd

ventricle, constitutes an integrative center essential for survival & reproduction, that

regulates and controls the complex interactions between physiology and behavior

(temperature regulation, heart rate, blood pressure, blood osmolarity, food and water

intake, emotion and sex drives).

- structure – cytoarchitecture – neurochemistry → functional specializations (e.g.,

appetite, weight control, water balance, autonomic control, reproductive function,

emotional behavior)

- reciprocal connections with

-almost every major subdivision of the CNS (bidirectional)

-peripheral organ systems by converting synaptic information to hormonal

signals (neuroendocrine regulation)

- “Here in this well concealed spot, almost to be covered with a thumb nail, lies

the very mainspring of primitive existence – vegetative, emotional, reproductive-

on which, with more or less success, man has come to superimpose a cortex of

inhibitions.” (Cushing, 1929).

HT Cytoarchitecture

• HT is organized into 3 longitudinal columns on either side of the 3rd ventricle, that extend through the entire rostrocaudal extent of the HT

• periventricular (suprachiasmatic and arcuate nuclei),

• medial (contains distinct nuclei),

• lateral (neurons diffusely distributed)

Functional organization:

Integrative processing in the HT

• HT: Brain-periphery interconnections: nervous, hormonal…

• HT receive:• Monosynaptic projections, such as first-order information from the

periphery (retina)

• Multisynaptic cerebral pathways (limbic projections)

• HT integrate information

• HT regulatory outputs on physiology and behavior: hormonal and synaptic

HT & Visceral sensation

-Sensory information (visceral, CV, respiratory, taste): topographically organized input through cranial nerves X & IX → nucleus of solitary tract (NST) of the caudal brain stem → ascending direct projections to paraventricular HT nucleus (PVH) & lateral HT area (LHA)

Nucleus tractus solitarii (NST) coordinates reflex regulation of peripheral organ

function

-send processed sensory information to forebrain nuclei, to be integrated in the control of more complex physiological processes and behaviors.

-together with the parabrachial nucleus relay splanchnic visceral and nociceptive sensory information from the spinal cord

- indirect projections to HT through ventrolateral medulla and parabrachial nucleus in the pons

- many of these projections are bidirectional

- connections with amygdala, stria terminalis, insular cortex

→ interoceptive sensory feedback that influences autonomic and endocrine outputs of HT → homeostasis, mood

! Stress induces activation of the autonomic and endocrine axes

HT & Central integration of autonomic function

• descending projection from the HT to autonomic cell groups in the brainstem and spinal cord exerts a strong influence upon the S (thoracic) and PS (cranial-lumbosacral) divisions of the ANS

• there are also indirect influences from HT cell groups on preganglionic neurons of the spinal cord

→ Coordination of autonomic functions and behavioral responses to environmental challenges → coordinates the “the wisdom of the body” (Cannon, 1937): tissue-, organ-, and system-level integration of the body’s physiology to achieve homeostasis and support behavior; continuous and automatically.

HT & immune function & thermoregulation

• HT influences immune system through neuroendocrine and autonomic outputs:

- activity of immune cells of the spleen is influenced directly by synaptic-like contacts of NA neurons of the sympathetic ANS

- immune system activation → fever

- HT neurons stimulate or inhibit heat production:

heat sensitive neurons in the medial preoptic area act to reduce core body temperature by inhibiting other neurons in

the HT and caudal brainstem to induce thermogenesis

- nonshivering thermogenesis in small animals is achieved through the activation of sympathetic activation of brown adipose tissue (BAT)- its mitochondria converts energy from fatty acids metabolism into heat

• There is a considerable overlap of cell groups that regulate energy balance, stress and fever !