Differential release of peptide and classic transmitters from the same cell has been observed in various types of neurons due to differences in vesicle storage. Nonpeptide vesicles, located near the active zones, can be rapidly released (<1 msec) in response to single action potentials, facilitated by localized influx of Ca++. Consequently, low-frequency stimulation of the cell results in the release of nonpeptide transmitter alone. Conversely, higher-frequency stimulation of the presynaptic neuron leads to a global increase in [Ca++] throughout the nerve terminal, causing the release of neuropeptide as well as neurotransmitter.

The co-release of neuropeptides with other transmitters can have synergistic or antagonistic effects. For instance, in the spinal cord, tachykinins and calcitonin gene–related peptide (CGRP) work synergistically with glutamate and substance P to enhance the action of serotonin. On the other hand, tachykinins and CGRP oppose the action of norepinephrine at other synapses. However, the interactions are not simply one-to-one synergism or antagonism at a specific synapse due to the temporal and spatial differences between the actions of peptides and classic transmitters. Neuropeptides, with their slower release and lack of rapid reuptake, can have long-lasting effects, diffuse over a region of brain tissue, and impact all cells in that region (that possess the appropriate receptors). This is in contrast to classic transmitters that primarily act at the specific synapse from which they were released. Studies have shown a spatial mismatch between presynaptic terminals containing a specific neuropeptide and the sites of receptors for that peptide. In summary, peptides released from a particular synapse likely influence the entire local neuronal population, while co-released classic transmitters act in a more localized manner.

Opiates are drugs derived from the opium poppy's juice. Compounds that are not opium-derived but still bind to opiate receptors and produce direct effects are referred to as opioids. Opioids form a clinically and functionally significant class of neuropeptides. Operationally, opioids are defined as compounds whose effects are specifically antagonized by a morphine derivative known as naloxone.

Mammals possess three major classes of endogenous opioid peptides: enkephalins, endorphins, and dynorphins. Enkephalins are the simplest opioids, consisting of pentapeptides. Dynorphins and endorphins are slightly longer peptides that contain an enkephalin sequence at their N-terminal ends.

Opioid peptides are widely distributed in the CNS's neurons and the intrinsic neurons of the gastrointestinal tract. Endorphins are specifically localized in certain CNS structures, while enkephalins and dynorphins are more widely distributed. Opioids inhibit neurons in the brain that are involved in pain perception. In fact, opioid peptides are extremely potent analgesic compounds and are used therapeutically as powerful pain relievers. Their analgesic effects are exerted through binding to specific opiate receptors.

Substance P is an 11-amino acid peptide present in specific brain neurons, primary sensory neurons, and plexus neurons in the gastrointestinal tract wall. The gastrointestinal tract wall is abundantly innervated by neurons that form networks or plexuses. The intrinsic plexuses of the gastrointestinal tract primarily control its motor and secretory activities. These enteric neurons contain numerous neuropeptides, including substance P, which are also found in the brain and spinal column. Substance P plays a role in pain transmission and exerts a strong effect on smooth muscle.
In fact, differential release of peptide and classic transmitters from the same cell has been demonstrated for several types of neurons and is probably a result of the differences in vesicle storage described earlier. Because of their proximity to the active zones, nonpeptide vesicles can be released rapidly (<1 msec) in response to single action potentials • BOX 6.1 Some Neuroactive Peptides as a result of localized influx of Ca++ . Thus, low-frequency stimulation of the cell causes just the release of nonpeptide transmitter. In contrast, with higher-frequency stimulation of the presynaptic neuron, there is a more global increase in [Ca++] throughout the nerve terminal that leads to release of neuropeptide as well as neurotransmitter.
When neuropeptides are co-released with other transmitters, they may act synergistically or antagonistically. For example, in the spinal cord, tachykinins and calcitonin gene–related peptide (CGRP) act synergistically with glutamate and with substance P to enhance the action of serotonin. Conversely, tachykinins and CGRP antagonize norepinephrine’s action at other synapses. The interactions, however, are not simply a one-to-one synergism or antagonism at a particular synapse because of the differing temporal and spatial profiles of the action of peptides versus classic transmitters. In particular, the slower release and lack of rapid reuptake mean that neuropeptides can act for long durations, diffuse over a region of brain tissue, and affect all cells in that region (that have the appropriate receptors) rather than just acting at the specific synapse at which it was released. In fact, studies have shown that there is often a spatial mismatch between the presynaptic terminals that contain a particular neuropeptide and the sites of the receptors for that peptide. In sum, peptides released from a particular synapse probably affect the local neuronal population as a whole, whereas the co-released classic transmitters act in more of a point-to-point manner.
Opiates are drugs derived from the juice of the opium poppy. Compounds that are not derived from the opium poppy but that exert direct effects by binding to opiate receptors are called opioids and form a clinically and functionally important class of neuropeptides. Operationally, opioids are defined as compounds whose effects are stereospecifically antagonized by a morphine derivative called naloxone.
The three major classes of endogenous opioid peptides in mammals are enkephalins, endorphins, and dynorphins. Enkephalins are the simplest opioids; they are pentapeptides. Dynorphins and endorphins are somewhat longer peptides that contain one or the other of the enkephalin sequences at their N-terminal ends.
Opioid peptides are widely distributed in neurons of the CNS and intrinsic neurons of the gastrointestinal tract. The endorphins are discretely localized in particular structures of the CNS, whereas the enkephalins and dynorphins are more widely distributed. Opioids inhibit neurons in the brain involved in the perception of pain. Indeed, opioid peptides are among the most potent analgesic (pain-relieving) compounds known, and opiates are used therapeutically as powerful analgesics. They exert their analgesic effect by binding to specific opiate receptors.
Substance P is a peptide consisting of 11 amino acids. It is present in specific neurons in the brain, in primary sensory neurons, and in plexus neurons in the wall of the gastrointestinal tract. The wall of the gastrointestinal tract is richly innervated with neurons that form networks or plexuses (see also ). The intrinsic plexuses of the gastrointestinal tract exert primary control over its motor and secretory activities. These enteric neurons contain many of the neuropeptides, including substance P, that are found in the brain and spinal column. Substance P is involved in pain transmission and has a powerful effect on smooth muscle.