301 Therapeutic Potential of Opioids in Narcolepsy Type 1 Introduction Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin (orexin) transmission leading to excessive daytime sleepiness and cataplexy. Hypocretin is a neuropeptide normally produced in the hypothalamus and is essential in maintaining wakefulness. In people with narcolepsy type 1 roughly 90% of hypocretin-producing neurons are lost, most likely resulting from a combined genetic predisposition, environmental factors and immunological triggers leading to a hypothalamic autoimmune reaction [4]. In addition to sleep-wake management, hypocretin is also involved in regulation of reward and addiction [347]. Hypocretin-producing neurons in the hypothalamus have strong projections to the ventral tegmental area [348] and are essential for the modulation of reward circuits within the ventral tegmental area [349]. Recent studies have suggested that opioid use, and heroin addiction in particular, are associated with increased postmortem hypothalamic hypocretin-producing neuron counts in humans [125]. There is a clinical impression, however, that people with hypocretin-deficient narcolepsy type 1 have a lower susceptibility to drug abuse and addiction, despite the highly addictive medication that is regularly prescribed to them (for example sodium oxybate, methylphenidate and amphetamines) [350, 351]. This decreased susceptibility to drug abuse has been confirmed by studies using hypocretin-deficient animal models [352-354]. This leads us to ask whether opioids can increase hypocretin signalling in people with hypocretin deficiency to a (close to) normal level and thereby potentially serve as new therapeutic agents to treat people with narcolepsy type 1 without leading to addiction. Pharmacology of opioids and the effects on hypocretin transmission Opioids provide analgesic effects by reducing conduction of central nervous system action potentials after ligand-binding at the μ (mu), κ (kappa), and/ or δ (delta) receptors. The effect strength of different types of opioids varies largely. Tramadol and codeine are examples of weak-acting opioids (with non-specific and low receptor affinity), and their main analgesic effects come through conversion to strong-acting opioids, whereas morphine, oxycodone, and fentanyl are considered strong-acting opioids (predominantly through μ receptor but also some κ receptor binding) [355]. As well as the analgesic effects, μ receptor binding is known to disinhibit the ventral tegmental area and thereby increase dopaminergic signalling of this reward hub that is well connected with the hypothalamus [356]. 10
RkJQdWJsaXNoZXIy MjY0ODMw