2 Neuroscience2.5 Neurochemistry and neurophysiology
2.5.2.5 Neuropeptides, the endocannabinoid system and orexins
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Written by Resident Doctor Committee · Published
How neuropeptides differ from classical transmitters
Neuropeptides are the large-molecule transmitters, chains of amino acids, whereas classical transmitters are small molecules.
Feature | Small-molecule transmitter | Neuropeptide | Endocannabinoid |
|---|---|---|---|
Where made | At the terminal, and recycled there | Precursor in the cell body | Membrane lipid, made on demand |
Storage | Synaptic vesicles | Dense core vesicles | Not stored in vesicles |
Receptors | Ionotropic or metabotropic | Mainly G-protein-coupled | Cannabinoid receptors |
How the signal ends | Reuptake, metabolism and diffusion | Peptidases and diffusion | Enzyme breakdown |
Opioid peptides
Precursor | Peptide | Preferred receptor |
|---|---|---|
Proenkephalin | Met- and leu-enkephalin | Delta, with mu activity |
Pro-opiomelanocortin | Beta-endorphin | Mu and delta |
Prodynorphin | Dynorphin | Kappa |
Dynorphin is released by stress, and kappa activation causes dysphoria and anhedonia, so kappa antagonists have been studied in depression.
Substance P
Substance P is a tachykinin that binds the neurokinin-1 (NK1) receptor with highest affinity.
NK1 blockade was tried as an antidepressant, with disappointing trials, and the NK1 antagonist aprepitant is now used as an antiemetic.
Vasopressin and oxytocin
Vasopressin (antidiuretic hormone) is made in the supraoptic and paraventricular nuclei and released from the posterior pituitary.
At renal V2 receptors it moves aquaporin-2 channels into the collecting duct, so the kidney retains water.
Oxytocin is a nonapeptide that differs from vasopressin at two amino acids.
Both peptides act as central neurotransmitters released by neurones and as hormones secreted into the blood.
Orexins
Orexin-A and orexin-B (hypocretin-1 and hypocretin-2) are made only by lateral hypothalamic neurones and couple arousal to appetite and energy state.
Narcolepsy type 1 follows loss of orexin cells and shows cataplexy and low cerebrospinal fluid orexin.
Orexin receptor antagonists such as daridorexant treat insomnia.
Endocannabinoids
Anandamide and 2-arachidonoylglycerol are released by the postsynaptic cell and act backwards on presynaptic CB1 receptors to reduce gamma-aminobutyric acid or glutamate release.
CB1 is widespread in memory, movement and reward circuits, whereas CB2 is mainly involved in immune signalling.