Conclusions And Therapeutic Opportunities For The Future

There is a growing consensus among researchers in the field that the orexins play a pivotal role in orchestrating the complex behavioural and physiologic responses underpinning the complementary homeostatic processes of feeding and sleep-wakefulness. Emerging genetic and pharmacological data are now beginning to elucidate the orexin receptor subtype(s) mediating these varied effects of the orexins (Table 5) and highlight a number of exciting therapeutic possibilities for agents that selectively modulate this novel system. The dramatic loss of orexin peptides in many narcolepsy sufferers (see Section 3.2.1) suggests that orexin receptor agonists may be of benefit as replacement therapy in this disabilitating neurological disorder. Indeed, ICV administration of OxA rescues the narcolepsy-cataplexy phenotype of orexin neuron-ablated mice.68 Furthermore, modafinil, which has been approved and marketed for narcolepsy, promotes wakefulness in rats in association with activation of orexin neurones.69 Importantly, hcrt1/OxA-induced arousal in animals is not followed by periods of rebound sleep,49,50 often a confounding factor in therapies for excessive daytime sleepiness based on classical psychostimulants. Pre-clinical studies also suggest that OX1R agonists may be of value in circumstances where acute injury and pain may be present, such as post-operatively, and in conditions such as arthritis and neuropathic pain where hyperalgesia is a significant factor.13 However, a major challenge to delivering this therapeutic promise remains the development of small molecule orexin receptor agonists that are bioavailable and CNS penetrant.

In order for orexin receptor antagonists to be of therapeutic benefit it is implicit that there must be a degree of endogenous orexinergic tone at the orexin receptors. It is already evident that orexin receptor antagonists do not always produce the opposite effect as exogenously administered orexin peptides. For example, OxA elevates blood pressure and heart rate in rats but the OX1R selective antagonist SB-334867 has no haemodynamic effects in its own right.65 The most striking evidence that orexin receptor antagonists can be pharmacologically active when given by themselves comes from experiments showing that SB-334867 reduces food intake and body weight gain while increasing energy expenditure in rodents (see Section 3.1). This suggests that OX1R antagonists may have potential in the treatment of obesity and metabolic disorders. Counter to the envisaged role for orexin receptor agonist to promote arousal in narcoleptics, the most exciting therapeutic prospect for orexin receptor antagonists is predicted to be in the treatment of insomnia. Studies to determine whether OX1R and/or OX2R antagonists can induce physiologically balanced sleep have not yet been reported but are eagerly awaited. However, of some interest in this regard is the observation that in contrast to clinically used hypnotic benzodiazepines, SB-334867 is not overtly sedating in circumstances when rats are normally active.14,54,35,38 This at least suggests that orexin receptor antagonists should be devoid of the unwanted hangover effects classically associated with benzodiazepines.

Hopefully, the rapidity with which we have come to understand the unique physiological and pathophysiological roles fulfilled by the orexin peptides and receptors will now be matched by the emergence of novel orexin system therapeutics over the next decade.

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