Opioids depress breathing through two small brainstem sites

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose—opioid respiratory depression. Here, we identify two primary changes to breathing after administering opioids. These changes implicate the brainstem’s breathing circuitry which we confirm by locally eliminating the μ-Opiate receptor. We find the critical brain site is the origin of the breathing rhythm, the preBötzinger Complex, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

A novel mechanism in control of human pigmentation by β-melanocyte-stimulating hormone and 7-tetrahydrobiopterin

The human skin holds the full machinery for pro-opiomelanocortin processing. The α-melanocyte-stimulating hormone (α-MSH)/melanocortin-1-receptor cascade has been implicated as a major player via the cAMP signal in the control of melanogenesis. Only very recently the β-endorphin/μ-opiate receptor signal has been added to the list of regulators of melanocyte dendricity and melanin formation. In this context it was reported that (6R)-l-erythro-5,6,7,8-tetrahydrobiopterin (6BH4) can act as an allosteric inhibitor of tyrosinase, the key enzyme in melanogenesis, and this inhibition is reversible by both α- and β-MSH. It was also shown earlier that 7BH4, the isomer of 6BH4, is twice as active in this inhibition reaction. However, as yet it is not known whether 7BH4 is indeed present in loco in the melanosome. We here provide evidence that this isomer is present in this organelle in a concentration range up to 50 × 10−6 M. Determination of β-MSH in melanosomal extracts yielded 10 pg/mg protein. Moreover, we demonstrate reactivation of the 7BH4/tyrosinase inhibitor complex by β-MSH, whereas α-MSH failed to do so. Furthermore, we show intra-melanosomal l-dopa formation from dopachrome by 7BH4 in a concentration range up to 134 × 10−6 M. Based on these results, we propose a new receptor-independent mechanism in the control of tyrosinase/melanogenesis by β-MSH and the pterin 7BH4.