Acute nociceptive stimuli rapidly induce the activity of serotonin and noradrenalin neurons in the brain stem of awake mice

Abstract

Nociception is an important type of perception that has major influence on daily human life. There are some descending pathways related to pain management and modulation, which are collectively known as the descending antinociceptive system (DAS). Noradrenalin (NA) in the locus coeruleus (LC) and serotonin (5-HT) in the rostral ventromedial medulla (RVM) are components of the DAS. Most 5-HT neurons in the dorsal raphe (DR) have ascending projections rather than descending projections, and they project to the thalamus that modulates nociception. Both the DAS and the DR are believed to be involved in pain-emotion symptoms. In this study, we utilized a fiber photometry system to specifically examine the activity of LC NA neurons and RVM/DR 5-HT neurons using mice carrying tetracycline-controlled transactivator transgene (tTA) under the control of either a dopamine β-hydroxylase promoter or a tryptophan hydroxylase-2 promoter and site-specific infection of an adeno-associated virus carrying a TetO G-CaMP6 gene. After confirmation of specific expression of G-CaMP6 in the target populations, changes in green fluorescent signal intensity were recorded in awake mice upon exposure to acute nociceptive stimulation consisting of a pinch and application of heat (55 °C) to the tail. Both stimuli resulted in rapid and transient (<15 s) increases in the activity of LC NA neurons and RVM/DR 5-HT neurons while the control stimuli did not induce any changes. The present results clearly indicate that acute nociceptive stimuli increase the activity of LC NA neurons and RVM/DR 5 H T neurons and suggest a possible therapeutic target for pain treatment.

Involvement of supralemniscal nucleus (B9) 5-HT neuronal system in nociceptive processing: a fiber photometry study

“…The tryptophan hydroxylase-2 tetracycline-controlled transactivator (TPH2-tTA) transgenic mice were used [18,23,24] (Fig. 1a).…”

“…We showed fiber photometry system in previous reports [17,18,25,26]. In this study, we adopted the fiber photometry system with two channels (Fig.…”

“…We applied two types of acute stress test showed in previous reports [17,18]. We applied acute tail pinch stimulus using a pinch meter (PM-201, Soshin-Medic, Chiba, Japan) and acute heat stimulus using a heating probe (5R7-570, Oven Industries, Inc., Mechanicsburg, PA, USA).…”

“…Also, ventral tegmental area (VTA) DA neurons play roles in regulating nociceptive information [12,15,16]. We recently certified that acute nociceptive stimuli rapidly increased the activities of LC noradrenalin (NA) neurons and RVM 5-HT neurons and VTA DA neurons in awake mice by using fiber photometry system [17,18].…”

“…In this study, we focused on the possible contribution of B9 5-HT system in pain processing because B9 5-HT cells project to LC and VTA [22], which are important nuclei in pain processing (see above). We have demonstrated fiber photometry system [17,18] for evaluating real time and cell type specific neuronal activity in awake mice with G-CaMP6 as a detector of Ca 2+ concentration in the neuron of interest. This system has high temporal resolution (< sec) and unaffected by metabolism as in microdialysis, a different character from other electrophysiological and chemical methods.…”