Substance P is an example of a peptide that acts as a primary transmitter at synapses, specifically those formed by primary sensory neurons in the dorsal root ganglia and spinal interneurons in the dorsal horn of the spinal column. Enkephalins, on the other hand, decrease the release of substance P at these synapses, inhibiting the pain sensation pathway at the first synapse.

Gas neurotransmitters, a new category of neurotransmitter, do not follow the traditional definition of synaptic transmission. They are not packaged into synaptic vesicles or released by exocytosis. Instead, gas neurotransmitters are highly permeable and diffuse from synaptic terminals to neighboring cells after synthesis, which is triggered by depolarization of the nerve terminal. Unlike other neurotransmitters, gas neurotransmitters do not have specific reuptake mechanisms or undergo enzymatic destruction. Instead, their action is typically ended by diffusion or binding to superoxide anions or scavenger proteins. Examples of gas neurotransmitters include nitric oxide (NO) and carbon monoxide (CO). NO acts as a transmitter at synapses between inhibitory motor neurons of the enteric nervous system and gastrointestinal smooth muscle cells. It also functions as a neurotransmitter in the central nervous system (CNS). The synthesis of NO is catalyzed by the enzyme NO synthase, which is stimulated by an increase in cytosolic calcium.

In addition to its role as a neurotransmitter, NO also acts as a cellular signal transduction molecule in both neurons and nonneuronal cells such as vascular smooth muscle. One way NO functions as a signal transduction molecule is by regulating guanylyl cyclase, an enzyme that produces cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). NO binds to a heme group in soluble guanylyl cyclase, stimulating the enzyme and leading to an elevation in cGMP levels in the target cell. This increase in cGMP can then influence various cellular processes.

The nervous system utilizes a multitude of neurotransmitters to establish a specific and flexible interneuronal communication system. Each neurotransmitter has a variety of receptors, further enhancing the system's capabilities. Traditionally, receptors for a specific neurotransmitter were classified based on their sensitivity to particular agonists and antagonists. However, this classification scheme has limitations, as some receptors do not respond to agonists and it fails to uncover all the receptor subtypes for a given neurotransmitter. Molecular biological approaches have been employed to identify and sequence receptor genes for many known neurotransmitters, resulting in a relatively comprehensive catalog of these genes. This research has unveiled a vast diversity of actual and potential receptor subtypes within the nervous system. Moreover, knowledge of the gene sequences has provided insights into the relationship between different receptor proteins and other important proteins, thanks to biochemical, crystallographic, and other types of studies. As a result, a deeper understanding of the structural and functional mechanisms of receptor proteins has been achieved. Receptors can now be grouped into families based on their gene sequences, and members of each family share various structural and functional characteristics.
Substance P is probably the transmitter used at synapses made by primary sensory neurons (their cell bodies are in the dorsal root ganglia) with spinal interneurons in the dorsal horn of the spinal column, and thus it is an example of a peptide acting as a primary transmitter at a synapse.
Enkephalins act to decrease the release of substance P at these synapses and thereby inhibit the pathway for pain sensation at the first synapse in the pathway.
This is the newest category of neurotransmitter to be defined and stretches the usual definition of synaptic transmission even further than neuropeptides do. Gas neurotransmitters are neither packaged into synaptic vesicles nor released by exocytosis. Instead, gas neurotransmitters are highly permeant and simply diffuse from synaptic terminals to neighboring cells after synthesis, their synthesis being triggered by depolarization of the nerve terminal (the influx of Ca++ activates synthetic enzymes). Moreover, there are no specific reuptake mechanisms, nor do they undergo enzymatic destruction, so their action appears to be ended by diffusion or binding to superoxide anions or various scavenger proteins. Both nitric oxide (NO) and carbon monoxide (CO) are examples of gaseous neurotransmitters. NO is a transmitter at synapses between inhibitory motor neurons of the enteric nervous system and gastrointestinal smooth muscle cells (see ). NO also functions as a neurotransmitter in the CNS. The enzyme NO synthase catalyzes the production of NO as a product of the oxidation of arginine to citrulline. This enzyme is stimulated by an increase in cytosolic [Ca++].
In addition to serving as a neurotransmitter, NO functions as a cellular signal transduction molecule both in neurons and in nonneuronal cells (e.g., vascular smooth muscle; see
Chapter 14).
One way that NO functions as a signal transduction molecule is by regulating guanylyl cyclase, the enzyme that produces cGMP from GTP. NO binds to a heme group in soluble guanylyl cyclase and potently stimulates the enzyme. Stimulation of this enzyme leads to an elevation in cGMP in the target cell. The cGMP can then influence multiple cellular processes.
The multitude of neurotransmitters used in the nervous system provides it with a specific and flexible interneuronal communications system. These characteristics are even further enhanced by the variety of receptors for each neurotransmitter. Receptors for a particular neurotransmitter were traditionally distinguished primarily by pharmacological differences in their sensitivity to particular agonists and antagonists. For example, acetylcholine receptors were split into muscarinic and nicotinic classes, depending on whether they bind muscarine or nicotine. Similarly, glutamate receptors were split into three main groups according to their sensitivity to the agonists NMDA, kainic acid, or AMPA. Though useful, this classification scheme has several limitations: some receptors fail to be activated by agonists, and it fails to disclose all the various receptor subtypes for a particular transmitter. Over the past 15 years or so, molecular biological approaches have been used to identify and sequence the receptor genes for many of the known neurotransmitters. It is thought that we now have a relatively complete catalog of the genes for these receptors. What this work has revealed is that there is a tremendous diversity of actual and potential receptor subtypes that are or could be used by the nervous system. Moreover, knowledge of the gene sequences has enabled an understanding of the relationship of different receptor proteins to each other and to other important proteins. This knowledge, combined with the results of biochemical, crystallographic, and other types of studies, has led to a much deeper understanding of the structural and functional workings of receptor proteins. In particular, various receptors can be grouped into families based on gene sequences, and members of each family share various structural and functional features.