HST-151 1 Autonomic Pharmacology Reading: Chapters 6-10 in Katzung are quite good; those in Goodman and Gilman are based on the same fundamental outline. Overview As you will see throughout the course, the autonomic nervous system (ANS) is a very important topic for two reasons: First, manipulation of ANS function is the basis for treating a great deal of cardiovascular, pulmonary, gastrointestinal and renal disease; second, there is hardly a drug worth mentioning without some major autonomic side effects (cf. antihistamines). You have already heard something about the ANS and its wiring diagram in the lecture by Dr. Strichartz on cholinergic receptors, and it is certainly not my intent to reproduce these pictures or the various diagrams in your text. I hope to give you a slightly different presentation which highlights the important points in this rather long textbook assignment. You have already heard about nicotinic cholinergic receptors and the somatic nervous system (SNS) control of voluntary striated muscle. The ANS, simply put, controls everything else: smooth muscle, cardiac muscle, glands, and other involuntary functions. We usually think about the ANS as a motor system -- although it does have sensory nerves, there is nothing particularly distinctive about them. Anatomy The sympathetic division of the ANS is called THORACOLUMBAR, but it has input from higher brain centers like hypothalamus, limbic cortex, etc. The preganglionic sympathetic nerves have cell bodies in the intermediolateral column of the spinal cord from about T1 to L3. The efferent fibers exit with the ventral roots of the spinal nerves and then leave in a white ramus which leads to a GANGLION (i.e., a collection of cell bodies of postganglionic neurons). The preganglionic nerves may stimulate several postganglionic nerves which rejoin the spinal nerve by way of a grey ramus. The ganglia are located in several places: 1. Paravertebral: 22 pairs located on either side of the vertebral column. The uppermost ganglia are fused to form the superior and middle cervical ganglia and the stellate ganglion, which is located at about C6. The preganglionic neuron may travel up or down several dermatomal levels before synapsing with one or more postganglionic neurons. Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology Instructor: Dr. Carl RosowHST-151 2 2. Prevertebral: The celiac, superior mesenteric and inferior mesenteric ganglia. Sometimes called collateral ganglia. 3. Adrenal Medulla: This is also derived from neural crest tissue and functions in much the same way as a ganglion, although the output is circulating epinephrine and norepinephrine. The parasympathetic or CRANIOSACRAL division has its origin in the nuclei of cranial nerves III, VII, IX, and X as well as the S2-4 nerve roots. The preganglionic fibers travel almost to the end-organ before synapsing in the ganglion: 1. III goes from the Edinger Westphal nucleus to the ciliary ganglion, and the postganglionic nerves continue to the eye. 2. VII innervates the pterygopalatine and submandibular ganglia which control lacrimal and salivary glands, respectively. 3. IX innervates the otic ganglion which controls the parotid 4. X innervates the heart, lung, GI tract, and other splanchnic viscera. The postganglionic cell bodies are contained in specialized tissue within the heart (e.g. AV nodal tissue), GI tract (e.g. Auerbach's plexus). 5. S2-4 preganglionic nerves originate in the sacral parasympathetic nucleus and leave the cord by way of the pelvic splanchnic and pudendal nerves. They innervate the distal GI tract, bladder, and genitalia. We will not specifically discuss the enteric nervous system – often treated as a third division of the ANS. It consists of complex networks of interconnected ganglia and nerve fibers, largely contained with the myenteric (Auerbach’s) and submucosal (Meissner’s) plexuses. This system exerts local control over GI secretion, motility, blood vessel tone,, and fluid transport. It is subject to control by sympathetic, parasympathetic, and CNS iinputs. If we look at the sympathetic and parasympathetic divisions schematically, it is easy to see how the sympathetic division is suited to "flight or fright" responses. The stimulation of one preganglionic neuron can lead to widespread activation of postganglionic neurons and to the liberation of stress hormones like epinephrine. The parasympathetic division is often called a "vegetative" system, and it is well suited to controlling discrete parts of the body. Sympathetic α1,α2 β1,β2 (Dopamine) (ACh)HST-151 3 ACh Parasympathetic ACh (Muscarinic) ACh There are some differences between the somatic and autonomic systems that are worth remembering. AUTONOMIC Synapses in periphery Nerve plexuses Organs, glands, sm. muscle have activity without nerves Symp and Parasymp afferent and efferent nerves overlap in terminal retinaculum Sm. muscle has protoplasmic bridges, so stimulating one can depolarize 100 others. Cholinergic neurotransmission SOMATIC Synapses in CNS No plexuses Skeletal muscle atrophies without nerve Nerves end in discrete motor end plates on muscle fibers Muscle fiber depolarized discretely Fig 6-3 and 6-4 in Katzung schematize the cholinergic and adrenergic nerve terminals. Cholinergic receptors are generally categorized as follows: Nicotinic motor end plate autonomic ganglia Muscarinic autonomic ganglia parasympathetic postganglionicHST-151 4 All nicotinic receptors are, by definition, stimulated by the alkaloid nicotine. We know that the two types of nicotinic receptor differ because they are differentially affected by various agonists and antagonists Agonists Antagonists Motor End Plate phenyltrimethylammonium decamethonium (PTMA) bungarotoxin Ganglion dimethylphenylpiperazinium (DMPP) hexamethonium Muscarinic receptors are those stimulated by the alkaloid muscarine, which comes from the mushroom Amanita muscaria. At this writing there are 5 postulated subtypes of muscarinic receptors (see table) although not much is known about the last two. Muscarinic Receptor Subtypes M1 M2 M3 M4 M5 Antagonists atropine + + + + + pirenzipine M1>M3>>M 2 AFDX-116 M2>M1>>M3 4-DAMP M3>>M1>M2 Location Neural Heart Sm. Musc. Neural Endocrine Sm Musc. Neural Striatum Amino Acids 460 466 589/590 478/479 531/532HST-151 6 Cholinergic Signal Transduction The nicotinic response of skeletal muscle