Peptides tend to be involved in amplifying or damping down signals rather than transmitting signals. Many are involved in inflammation and are released from the peripheral ends of neurones as well as the central ends. They tend to diffuse away from the cells that produce them to affect all the surrounding cells, so they can have a wide range of effects. Peptides such as substance P enhance pain signals leading to hypersensitivity (more later). Encephalins such as β endorphin or endomorphin usually have the opposite effect, although others such as nociceptin, and possibly dynorphin also enhance pain signals. Morphine (and codeine in invertebrates) are possibly also endogenous neurotransmitters, as well as analgesic drugs. Neuropeptide Y is the most abundant neuromodulator in the mammalian brain. It is involved in pain and appetite, among other things. A variety of cytokines and growth factors also act as neuromodulators, as do a number of peptides first isolated from the gut such as cholecystokinin and vasoactive intestinal peptide. The list is getting longer all the time. Numerous drugs interact with one or more of these, usually to produce CNS side effects. There are also a number of anomalies - for instance, capsaicin, the hot substance in chillies, acts at specific receptors in the spinal cord and the periphery to increase the release of substance P, but no endogenous ligands for these receptors have yet been found. This area is likely to get even more complicated in the future, and there is plenty of scope for drugs which interact with neuromodulators.
Nitric oxide and carbon monoxide are also implicated in neuromodulation. Nitric oxide usually increases excitability, the effects of carbon monoxide are thought to be similar. These gases are produced as needed and rapidly diffuse away. They can be altered by manipulating the enzymes that make them, but appear to be so widely used in the body that increasing or reducing their production causes a vast range of effects.
Arachidonic acid may act as a neuromodulator in its own right, although it is difficult to distinguish its effects from those of its metabolites, the prostaglandins and leukotrienes. PGF2a may be an important neuromodulator in the brain. A variety of commonly used drugs affect arachidonic acid, including corticosteroids and aspirin type drugs.
