Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy

Abstract

The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.

The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand

“…In Experiment 1, high motivation (low demand elasticity) animals had greater LH orexin expression than low motivation animals (high demand elasticity) animals. In Experiment 2, the number of remaining LH orexin cells following orexin-A morpholino antisense Although other studies reported that chronic exposure to drugs of abuse upregulated numbers of LH orexin-expressing cells (James, Stopper, Zimmer et al, 2018;Lawrence, Cowen, Yang et al, 2006;Thannickal, John, Shan et al, 2018), to our knowledge our results are the first to show a relationship between the endogenous number of LH orexin cells and baseline addiction propensity. Taken together, these results are consistent with our hypothesis that orexin signaling is particularly important in highly motivated individuals , and that the number of LH orexin neurons could serve as a biomarker of addiction susceptibility.…”

“…We reported that the persistent IntA-induced addiction phenotype was associated with higher numbers of orexin-expressing neurons in LH but not Pef/DMH (James, Stopper, Zimmer et al, 2018). Another recent study found that postmortem tissue from heroin addicts contains higher numbers of orexin-expressing neurons compared to healthy controls, and mice exposed to chronic non-contingent morphine injections had increases in the number of orexin neurons particularly in LH (Thannickal, John, Shan et al, 2018). These studies are consistent with an earlier study that reported that chronic alcohol consumption increased the area of prepro-orexin mRNA expression preferentially in LH of alcohol-preferring rats (Lawrence, Cowen, Yang et al, 2006).…”

“…Our results are consistent with several studies from our lab and others indicating that individual differences in the LH orexin system are associated with reward/motivation levels. LH orexin neurons and mRNA expression is upregulated in animals with high motivation for drug (James, Stopper, Zimmer et al, 2018;Lawrence, Cowen, Yang et al, 2006;Thannickal, John, Shan et al, 2018). In addition, Fos expression specifically in LH orexin cells correlates with preference for both morphine and cocaine (Harris, Wimmer & Aston-Jones, 2005;Harris, Wimmer, Randall-Thompson et al, 2007;Lasheras, Laorden, Milanes et al, 2015;Richardson & Aston-Jones, 2012;.…”

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin‐1 receptor antagonist in rats

“…Indeed, we recently reported that the number and activity of orexin‐expressing neurons is higher in animals that exhibit high demand for cocaine following IntA (James et al ., ). Similarly, enhanced orexin expression has been reported in brains of human heroin addicts (Thannickal et al ., ) and in alcohol‐preferring rats following chronic alcohol intake (Lawrence et al ., ). Differences in orexin system function in high demand animals might also be associated with greater receptor densities in key reward regions or enhanced receptor binding; further studies are required to test these possibilities.…”

Striking cessation of cataplexy by opioids

“…Impact on the noradrenergic and/or serotonergic system could possibly explain this. However, a recent finding from Thannickal et al (2018) shed new light on the mode of action of opiates in narcolepsy. They discovered that human heroin addicts have, on average, 54% more hypocretinproducing cells than controls.…”