Overview of Neuropeptides: Awakening the Senses?

Abstract

Humans have a diverse collection of neuropeptides that can influence a multitude of activities. There are now over 100 known neuropeptides and probably many more yet to be identified from the over 1000 predicted peptides encoded in the genome. While diverse, peptides generally share three common characteristics: (1) post-translational processing and release from vesicles, (2) activation of cell-surface receptors over a relatively large distance, and (3) modulation of target cells that are often in the brain and periphery. Within the brain, neuropeptides can modulate the activity of co-released neurotransmitters to either increase or decrease the strength of synaptic signaling. Within the periphery, neuropeptides can function similar to peptide hormones and modulate nearly all bodily functions. Given the clear involvement of the neuropeptide CGRP in migraine and the emerging evidence for other peptides, it seems likely that neuropeptides may help "awaken" the senses and contribute to the heightened sensory state of migraine.

Keywords: CGRP; neuromodulation; neuropeptide.

Figure 1. Neuropeptide activation requires multiple processing steps in the cell

A representative neuropeptide is shown with sequential processing steps within the neuron beginning in the endoplasmic reticulum, followed by endoproteolytic cleavages in the trans-Golgi network (TGN) or secretory vesicles. Further processing in the vesicles at the C-terminus removes amino acids and adds a C-terminal amide group. The vesicles are transported down the axon and are stored at varicosities (not shown) and near the synapse. Neuropeptides are stored in dense core vesicles, which are larger and functionally distinct from the small, clear synaptic vesicles.

Figure 2. Neuropeptides broadly diffuse and act beyond the synapse

Distinguishing features of fast synaptic transmission versus neuropeptide transmission are shown. Classical small molecule transmitters, such as glutamate, are stored in clear synaptic vesicles, while peptides are stored in dense core vesicles. The synaptic vesicles are rapidly recycled and refilled with neurotransmitter close to the synaptic cleft. Once released, neuropeptides are not taken back up into the neuron, so dense core vesicles are not regenerated at the synapse. Instead, dense core vesicles are replenished by axonal transport of new vesicles from the cell body. In addition, dense core vesicles are released from non-synaptic sites as indicated. Once released, classical neurotransmitters bind to ion channel receptors (ionotropic receptors), while nearly all neuropeptides bind to G-protein coupled receptors. A major feature of neuropeptides is their ability to act by volume transmission due to diffusion over a relatively large distance from the point of release to act on targets far from the synapse.

Figure 3. Enhancement of neural activity by neuropeptides acting via peripheral and central mechanisms

An example of peripheral actions of the neuropeptide CGRP to alter the microenvironment of the trigeminovasculature is shown. The release of inflammatory and pro-inflammatory molecules from mast cells, glia, and vascular cells can lead to sensitization of the trigeminal nerve. An example of central neuromodulation by CGRP to enhance glutamatergic signaling by cAMP-induced phosphorylation of glutamate receptors is shown. A conceptual link between peripheral and central CGRP actions is indicated by the arrow.

Figure 4. Neuromodulation by neuropeptides in the central nervous system

A) Schematic representation of three neurons (1–3) and a post-synaptic neuron with stimulating and recording electrodes. B) Representation of an action potential triggered in neuron 1, a glutamate releasing neuron, which produces a typical fast excitatory postsynaptic potential (EPSP). C) Representations of two consequences following an action potential triggered in neurons 2 and 3 that release neuropeptides, which produce either a slow onset and long-duration EPSP (top) or does not produce an EPSP (bottom). D) Neuromodulation by prior release or co-release of a neuropeptide and a neurotransmitter. In this scenario, the neuropeptide from neuron 3 has enhanced the EPSP caused by the neurotransmitter from neuron 1. The non-modulated EPSP from neuron 1 alone is shown as a solid line and the EPSP following stimulation of neurons 1 and 3 is shown as the dashed line. A similar enhancement of the EPSP might also be observed following stimulation of neurons 1 and 2 or if a neuropeptide was co-released from the same neuron with a transmitter (not shown).

Figure 4. Neuromodulation by neuropeptides in the central nervous system

A) Schematic representation of three neurons (1–3) and a post-synaptic neuron with stimulating and recording electrodes. B) Representation of an action potential triggered in neuron 1, a glutamate releasing neuron, which produces a typical fast excitatory postsynaptic potential (EPSP). C) Representations of two consequences following an action potential triggered in neurons 2 and 3 that release neuropeptides, which produce either a slow onset and long-duration EPSP (top) or does not produce an EPSP (bottom). D) Neuromodulation by prior release or co-release of a neuropeptide and a neurotransmitter. In this scenario, the neuropeptide from neuron 3 has enhanced the EPSP caused by the neurotransmitter from neuron 1. The non-modulated EPSP from neuron 1 alone is shown as a solid line and the EPSP following stimulation of neurons 1 and 3 is shown as the dashed line. A similar enhancement of the EPSP might also be observed following stimulation of neurons 1 and 2 or if a neuropeptide was co-released from the same neuron with a transmitter (not shown).

Figure 5. Perivascular convergence of neurotransmitters and neuropeptides in the periphery

The vasculature is innervated by sensory, parasympathetic, and sympathetic autonomic nerves. Nerve fibers from sensory ganglia release CGRP, PACAP, nociceptin, and substance P-neurokinin A. Fibers from parasympathetic ganglia release PACAP, VIP, nitric oxide (NO) and the neurotransmitter acetylcholine (ACh). Fibers from sympathetic ganglia release neuropeptide Y (NPY), and the neurotransmitters noradrenaline (NA) and adenosine triphosphate (ATP).

Figure 6. Model of neuropeptide induction of a heightened sensory state in migraine

The senses of sight, smell, taste, hearing, and touch are indicated, with transmission of their sensory information to the CNS represented as arrows. Neuropeptides are predicted to enhance the perception of these sensory signals and in the case of migraine, the signals are suggested to reach a threshold that triggers a pain response.