Narcolepsy has long been viewed as a disease of REM sleep. This is because cataplexy, its most striking symptom seems physiologically similar to the muscle tone suppression of REM sleep46–48
. The discovery that loss of cells containing the peptide orexin/hypocretin (two names for the same peptide) underlies most cases of narcolepsy49, 50
has provided a key insight into the sleepiness and cataplexy that define this disorder. Sinton14
takes on the Herculean task of integrating the more than 2,000 publications on orexin/hypocretin since the discovery of this peptide in 199814
. Key issues that are explored include the nature of the triggering of REM sleep and the relation of REM sleep signs to symptoms of narcolepsy. Although it has been speculated that offset of activity in orexin/hypocretin neurons is responsible for sleep or REM sleep onset, recordings of the activity of these neurons indicate a more complex process. In normal rats orexin/hypocretin neurons can be silent for long periods of time in waking51
that are not followed by sleep. In sleep, activity is minimal in nonREM sleep with only a relatively small further decrement in activity in REM and without marked changes at the nonREM-REM transition. This is in keeping with other evidence suggesting a gradual transition between these two sleep states. The gradual transition between nonREM and REM sleep contrasts with the abrupt transition between either of these sleep states and waking whose substrates can be identified in unit recordings28
The link between REM sleep and cataplexy can be seen in unit activity recording in other cell groups. For example the cells in the medulla that are though to be responsible for the motor inhibition by GABA and glycine seen in REM sleep are maximally active only during REM sleep and cataplexy47
. Conversely the noradrenergic cells that facilitate muscle tone in waking and to a lesser extent in nonREM sleep are inactive during REM sleep and cataplexy46
. Serotonergic cells of the dorsal raphe show a similar slowing in cataplexy, but to a lesser extent than locus coeruleus cells52
. On the other hand, most cells in the brainstem tegmentum that are active during REM sleep are inactive during cataplexy53
. Thus at the neuronal level we see aspects of REM sleep occurring during cataplexy, supporting the concept of REM sleep intrusion. However, just as cataplexy differs from REM sleep in its maintenance of consciousness and tracking eye movement, the neuronal activity that accompanies it also differs, most interestingly in the maintenance of activity in histamine cells in cataplexy54
. We hypothesized that this activity is responsible for the maintenance of consciousness in cataplexy, a key aspect distinguishing it from REM sleep.
Presumably it is the loss of orexin/hypocretin signaling that is responsible for the dyscoordination of REM sleep signs that produces cataplexy. But it seems unlikely that this is a direct effect, since as mentioned above, long duration cessation of neuronal activity and orexin/hypocretin release in waking is a normal phenomenon, not liked to narcolepsy. However, the death of orexin/hypocretin cells presumably removes trophic effects on other brain systems normally receiving projections from these neurons. The anatomical and physiological changes that result from this produce the symptoms of narcolepsy.
Sinton integrates the sleep pathology caused by orexin/hypocretin cell loss with the larger issue of the adaptive role of the orexin/hypocretin cells. He reviews evidence indicating that these cells are activated and appear to drive adaptive responses to need for food and associated changes in autonomic function.
The maladaptive changes in CNS structures normally innervated by orexin/hypocretin neurons may be responsible for some aspects of the autonomic changes reviewed by Plazzi et al. in narcoleptics13
. Plazzi et al. explain the reduction in pupil diameter and increase in low frequency oscillation in pupil diameter in narcolepsy by the loss of the projection of these neurons to the ciliary ganglion. They cite evidence that reduced cardiovascular reflexes occur in narcolepsy and are not due to the chronic use of stimulants. This finding is in accord with data from orexin/hypocretin KO mice55
. Similarly, obesity occurs not only in human narcolepsy but also in KO mice, despite reduced food intake, and this effect is sex dependent56–58
. Sexual disorders tend to occur many years after the loss of orexin/hypocretin cells and are of uncertain etiology. Plazzi et al. document several other disputed claims of altered autonomic function in narcolepsy. Parallel studies in animal models may help resolve these disputes.
There have been publications claiming a role for orexin/hypocretin in thermoregulation, but the evidence for this stems from injections of large amounts of the peptide into the cerebral ventricles or into relatively small brain regions. Orexin/hypocretin is an excitatory peptide and like glutamate or other excitatory neurotransmitters the effects seen from nonspecific administration have questionable relevance to normal function.