In the CNS, nitric oxide has an array of functions, such as the regulation of synaptic plasticity, the sleepwake cycle

and hormone secretion. Particularly interesting is the role of nitric oxide as a Janus molecule in the cell death or survival mechanisms in brain cells. In fact, physiological amounts of this gas are neuroprotective, whereas higher concentrations are clearly neurotoxic.

NO may contribute to synaptic plasticity as a retrograde mediator that is released by postsynaptic NMDA-receptor activation. Microglia contains membrane-bound inducible iNOS that may be important in host defence function. Glia and pericytes surrounding the blood vessels contain GC that is stimulated by NO released from endothelium and nerve endings. Excessive production of highly reactive NO may be responsible for the neurotoxicity mediated by NMDA receptors that contributes to the symptomatology of strokes and neurodegenerative diseases. Moreover, after initial stimulation by cytokines, large amounts of NO produced by iNOS in the microglia (brain-based macrophages) may cause cellular damage.
Peptides A great many CNS peptides have been discovered that produce dramatic effects both on animal behavior and on the activity of individual neurons. Many of the peptides have been mapped with immunohistochemical techniques and include opioid peptides (enkephalins, endorphins, etc), neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone. As in the peripheral autonomic nervous system, peptides often coexist with a conventional nonpeptide transmitter in the same neuron. A good example of the approaches used to define the role of these peptides in the central nervous system comes from studies on substance P and its association with sensory fibers. Substance P is contained in and released from small unmyelinated primary sensory neurons of the spinal cord and brain stem and causes a slow EPSP in target neurons. These sensory fibers are known to transmit noxious stimuli, and it is therefore surprising thatwhile substance P receptor antagonists can modify responses to certain types of painthey do not block the response. Glutamate, which is released with substance P from these synapses, presumably plays an important role in transmitting pain stimuli. Substance P is certainly involved in many other functions, since it is found in many areas of the central nervous system that are unrelated to pain pathways. Many of these peptides are also found in peripheral structures, including peripheral synapses. They are described in Chapter 6: Introduction to Autonomic Pharmacology and Chapter 17: Vasoactive Peptides. Nitric Oxide The CNS contains a substantial amount of nitric oxide synthase (NOS), which is found within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide. While a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial.