Autonomic Nervous System: Introduction

The sympathetic division originates from preganglionic neurons located in the lateral horn of the spinal cord from approximately the first thoracic to the second lumbar segment — the thoracolumbar outflow. These preganglionic neurons send relatively short myelinated axons to ganglia located close to the vertebral column, either in the paired paravertebral sympathetic chain (a longitudinal string of ganglia running on either side of the spine) or in prevertebral ganglia located in the abdomen near the major blood vessels.

The pattern of short preganglionic neurons synapsing on ganglia near the spinal column means that postganglionic neurons project long, unmyelinated axons from these ganglia to distant target organs throughout the body. A single preganglionic fiber can synapse on many postganglionic neurons, which in turn project to multiple organs — an anatomical arrangement that enables the broad, coordinated sympathetic activation that characterizes the fight-or-flight response. Heart rate increases, blood vessels in skeletal muscle dilate, skin and gut vessels constrict, the pupils dilate, and bronchioles dilate — all simultaneously.

Postganglionic sympathetic neurons release norepinephrine as their primary neurotransmitter, which acts on adrenergic receptors in target tissues. The adrenal medulla is a functionally unique structure: it is a modified sympathetic ganglion in which the postganglionic cells have differentiated into chromaffin cells. Rather than extending long axons to target organs, these cells release their catecholamines — approximately 80 percent epinephrine and 20 percent norepinephrine — directly into the bloodstream, effectively creating a hormonal amplification of sympathetic activation.

The enteric nervous system consists of an estimated 200 to 500 million neurons embedded within the wall of the gastrointestinal tract, from the esophagus to the anus. Its neuronal population exceeds that of the spinal cord, and it can maintain coordinated intestinal motility and secretion even when all extrinsic connections to the central nervous system are severed — hence the designation "second brain." Two major networks make up the enteric nervous system: the myenteric plexus (Auerbach's plexus), located between the circular and longitudinal muscle layers and governing motility, and the submucosal plexus (Meissner's plexus), located closer to the intestinal lumen and regulating secretion and local blood flow.

Serotonin (5-hydroxytryptamine) is the dominant signaling molecule coordinating enteric nervous system activity, with approximately 95 percent of the body's total serotonin stored in enterochromaffin cells of the gut epithelium. Serotonin activates enteric neurons to initiate the peristaltic reflex. This pharmacological role of serotonin in the gut is the basis for prokinetic drugs and explains why selective serotonin reuptake inhibitors can produce gastrointestinal side effects. Acetylcholine and nitric oxide are the primary excitatory and inhibitory neurotransmitters, respectively, within the enteric neural circuits that coordinate propulsion.

The enteric nervous system is modulated by — but not wholly dependent on — the sympathetic and parasympathetic divisions. Sympathetic input generally inhibits gut motility and secretion; parasympathetic input generally promotes them. Opioid receptors are densely expressed throughout the enteric nervous system, and activation of these receptors reduces propulsive motility and increases sphincter tone, producing the constipation that accompanies opioid therapy. Peripherally restricted opioid antagonists such as methylnaltrexone and naloxegol are designed to reverse this effect at the enteric nervous system without reversing central analgesia.

The anatomical organization of the autonomic nervous system maps directly onto the pharmacological classification of drugs acting on it. Every autonomic drug acts at one of three anatomical levels: the ganglionic synapse, the neuroeffector junction (where the postganglionic neuron meets its target), or the central nervous system above the ganglia. Correctly identifying the anatomical target of a drug immediately predicts whether it will affect one or both autonomic divisions and which organ systems will be involved.

Drugs acting at the ganglionic synapse block nicotinic N-N receptors and disrupt both sympathetic and parasympathetic outflow simultaneously. Their effects are bilateral and difficult to control, making them poorly tolerated for most clinical applications. Drugs acting at the neuroeffector junction are division-specific: muscarinic receptor agonists and antagonists affect tissues innervated by parasympathetic postganglionic fibers; adrenergic receptor agonists and antagonists affect tissues innervated by sympathetic postganglionic fibers and tissues responding to adrenal medullary catecholamines.

The location of ganglia further predicts accessibility. Sympathetic ganglia in the paravertebral chain are anatomically accessible to regional anesthetics and surgical interventions (sympathetic nerve blocks). Parasympathetic ganglia embedded within target organs are not accessible at normal drug concentrations without systemic effects. This anatomical distinction is why selective peripheral parasympathetic modulation is achieved pharmacologically through muscarinic receptor targeting rather than ganglionic targeting.