Ganglionic Pharmacology

Ganglia serve far more complex functions than that of a simple connection between the nerve process of one cell and the cell body of its next connection. Integrative and processing functions may contribute to the subtlety of response and organization of the ANS. The electrophysiology of ganglionic stimulation is complex, with at least four different types of responses to electrical stimulation ^{[161] [162]} ( Table 16-7 ).

The central event at the ganglion is the excitatory postsynaptic potential (EPSP) when acetylcholine interacts with a nicotinic receptor to rapidly depolarize the postsynaptic membrane. Depolarization results primarily from the influx of sodium ions through the nicotinic receptor channel, and it is sensitive to nondepolarizing nicotinic blocking drugs such as hexamethonium. The other changes in electrical potential are related to secondary

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Secondary pathways are indicated by the following changes in potential elicited by electrical stimulation of the ganglia: (1) slow EPSP, (2) late slow EPSP, and (3) inhibitory postsynaptic potential (IPSP).

The slow EPSP is slower in onset than the EPSP and lasts 30 to 60 seconds because of a decrease in potassium ion conductance. The interaction of acetylcholine with nicotinic receptors leads to closing of a potassium channel (i.e., M channel). The slow EPSP is associated with the reduction or suppression of a potassium current through this channel. This wave is initiated by muscarinic receptor agonists and can be blocked by atropine and the selective M₁ -muscarinic antagonists.

Like the slow EPSP, the late slow EPSP is caused by a decrease in potassium ion conductance. It lasts for several minutes after being initiated by peptides in specialized ganglia. Peptides have special properties as neurotransmitters, showing prolonged stability and extending their influence to other postsynaptic sites, not just those in the immediate vicinity of the nerve ending. Depolarization of the membrane activates the potassium channel; the conductance of potassium ion has been labeled the M current and appears to act to regulate the cell's response to repetitive fast depolarizations.

The IPSP is inhibitory because the membrane is hyperpolarized and therefore resistant to depolarization. The slow IPSP seems to be mediated by the activation of an interneuron interposed between the preganglionic fiber and the ganglionic cell. The preganglionic nerve ending releases acetylcholine, which stimulates the catecholamine-containing interneurons to release dopamine and norepinephrine. Catecholamine released by the interneuron then hyperpolarizes the ganglion cell membrane, causing an IPSP. M₂ receptors appear to be involved, as are small, intensely fluorescent (SIF) cells. IPSP and catecholamine-induced hyperpolarization are blocked by adrenergic blocking drugs. IPSP is not affected by classic nicotinic blocking agents but is frequently sensitive to block by atropine.

The impact of the secondary pathways on the initial EPSP and the identity of the involved neurotransmitter vary among ganglia and differ between the parasympathetic and sympathetic ganglia. Many peptides identified in the ganglia are released on stimulation of preganglionic nerves, including gonadotropin-releasing hormone, substance P, angiotensin, VIP, NPY, and the enkephalins. The peptides are associated primarily with the late slow EPSP and inhibition of the M current; 5-HT and γ-aminobutyric acid (GABA) modify ganglionic transmission.

Autonomic ganglia may be stimulated by two groups of drugs, the nicotinic and muscarinic agonists. Nicotinic agonists cause the rapid onset of excitatory effects, mimic the initial EPSP, and are blocked by classic nondepolarizing ganglionic blocking drugs. Muscarinic agonists delay onset of excitatory effects, are blocked by atropine, and mimic the slow EPSP.

Blockade of ganglionic transmission results primarily from action at the nicotinic receptor to stop or inhibit transmission. Two groups of drugs block ganglionic transmission. The first group is classically represented by nicotine and initially stimulates the receptor but then blocks it. This action is similar to the action of persistent depolarization. The second group causes no prior stimulation of the ganglia or change in ganglionic potentials and includes the drugs hexamethonium, trimethaphan, and mecamylamine. Trimethaphan acts by competing with acetylcholine at the cholinergic receptor sites on the ganglia; hexamethonium blocks the channel when it is open. Either mechanism blocks the initial EPSP and ganglionic transmission.

Muscarinic antagonists or α-agonists are incapable of completely blocking transmission, but they may inhibit normal modulation of the nerve impulse. β-Adrenergic stimulation facilitates nicotinic and muscarinic transmission, whereas α-adrenergic stimulation inhibits it. 5-HT is mostly facilitative, but it can be inhibitory in certain areas. Dopamine may also be inhibitory through stimulation of the IPSP. The adrenal medulla is a specialized ganglionic synapse and is therefore under influences similar to those arising on the autonomic ganglia.