Locus Coeruleus Acid-Sensing Ion Channels Modulate Sleep–Wakefulness and State Transition from NREM to REM Sleep in the Rat

Mir, Fayaz Ahmad; Jha, Sushil K.

doi:10.1007/s12264-020-00625-0

Cited by 13 publications

(12 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It was reported that the mechanisms of bone cancer pain include tumor cells-induced nerve injury, central sensitization, tumor cells themselves, osteoclast-mediated osteolysis as well as acidic environment of bone tissue ( Nagae et al, 2007 ; Mantyh, 2014 ; Romero-Morelos et al, 2021 ). The Acid-sensitive ion channels (ASICs) is one of the most sensitive ion channels in detecting changes in pH ( Mir and Jha, 2021 ). ASIC3 has the highest content in dorsal root ganglions (DRGs) and is sensitive to extracellular acidification.…”

Section: Introductionmentioning

confidence: 99%

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Qian

Zhou

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Bone cancer pain (BCP) is a common pathologic pain associated with destruction of bone and pathological reconstruction of nervous system. Current treatment strategies in clinical is inadequate and have unacceptable side effects due to the unclear pathology mechanism. In the present study, we showed that transplantation of Walker 256 cells aggravated mechanical allodynia of BCP rats (**p < 0.01 vs. Sham), and the expression of ASIC3 (Acid-sensitive ion channel 3) and TRPV1 was obviously enhanced in L4-6 dorsal root ganglions (DRGs) of BCP rats (**p < 0.01 vs. Sham). ASIC3 and TRPV1 was mainly expressed in CGRP and IB4 positive neurons of L4-6 DRGs. While, TRPV1 but not ASIC3 was markedly upregulated in L4-6 spinal dorsal horn (SDH) of BCP rats (**p < 0.01 vs. Sham). Importantly, intrathecal injection of CPZ (a TRPV1 inhibitor) or Amiloride (an ASICs antagonist) markedly increased the paw withdraw threshold (PWT) of BCP rats response to Von Frey filaments (**p < 0.01 vs. BCP + NS). What’s more, intraperitoneally injection of Metformin or Vinorelbine markedly elevated the PWT of BCP rats, but reduced the expression of TRPV1 and ASIC3 in L4-6 DRGs and decreased the TRPV1 expression in SDH (*p < 0.05, **p < 0.01 vs. BCP + NS). Collectively, these results suggest an effective analgesic effect of Metformin on mechanical allodynia of BCP rats, which may be mediated by the downregulation of ASIC3 and TRPV1.

show abstract

Section: Introductionmentioning

confidence: 99%

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Qian

Zhou

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…10,14 We have recently shown that ASICs in the LC modulate hypercapnia-mediated sleep-state transitions from NREM to REM sleep. 23 It is likely that the increased proton concentration during NREM sleep may be facilitating REM sleep generation (Figure 6). Therefore, REM sleep may be playing a crucial role in the maintenance of the proton concentration and bodily pH within the physiological limit.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…18−22 Acid-sensing ion channels (ASICs) in the LC modulate the hypercapnia-dependent NREM−REM sleep state transition as well as regulate REM sleep generation. 23 Blocking ASICs in the LC with amiloride (universal ASIC blocker) as well as with APETx2 (a specific inhibitor of ASIC-2/3) decreased REM sleep but increased NREM sleep. In addition, ASIC inhibition in the LC abolished the hypercapnia-mediated increase in the REM sleep frequency, suggesting that LC chemosensory machinery is intricately involved in REM sleep modulation.…”

Section: ■ Introductionmentioning

confidence: 99%

“…This chemosensory signaling-dependent modulation of REM sleep involves several ion channels in the LC, such as ASICs, proton pumps, and so forth. 23,24 The LC plays an essential role in the regulation of sleep−wakefulness (S−W). The LC neurons remain highly active during wake but decrease their activity in NREM sleep and become silent during REM sleep.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The locus coeruleus (LC) neurons are intrinsically chemosensitive, and they respond to a drop in the extracellular pH by increasing their firing rate and concomitantly elevating the breathing frequency. − Acid-sensing ion channels (ASICs) in the LC modulate the hypercapnia-dependent NREM–REM sleep state transition as well as regulate REM sleep generation . Blocking ASICs in the LC with amiloride (universal ASIC blocker) as well as with APETx2 (a specific inhibitor of ASIC-2/3) decreased REM sleep but increased NREM sleep.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Proton Pump Inhibitor “Lansoprazole” Inhibits Locus Coeruleus’s Neuronal Activity and Increases Rapid Eye Movement Sleep

Mir

Jha

2021

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

Alteration of the bodily CO2 concentration and proton pump activity affects the sleep architecture. The brainstem locus coeruleus (LC) area plays an essential role in rapid eye movement (REM) sleep generation and chemoregulation. Previously, we reported that lansoprazole injections (intraperitoneal) increased REM sleep in the rats. However, it is not known if proton pumps in the LC influence REM sleep. Here, we studied the effects of lansoprazole in the LC on the neuronal activity and REM sleep expression. Male Wistar rats (250–300 g) were surgically prepared for sleep recording and drug microinjections into the LC. We determined the localization of proton pumps and expression levels of cFOS in the LC neurons immunohistochemically. Sleep–wake was recorded before and after the microinjections of drugs/vehicles. Our results demonstrate (i) the presence of proton pumps in the LC neurons, (ii) that the microinjection of lansoprazole into the LC reduced the number of cFOS+ve–TH+ve double-labeled neurons in the LC by 52.6% (p < 0.001) compared to the vehicle and (iii) that low and high doses of lansoprazole significantly increased REM sleep by 32% (p < 0.001) and 60% (p < 0.001), respectively, compared to the vehicle. Our results suggest that the proton pumps modulate the LC’s noradrenergic (NE-ergic) neuronal activity and REM sleep. The increased amount of REM sleep can be attributed to the inhibition of the LC NE-ergic activity. Further, the REM sleep amount increased after the lansoprazole microinjections into the LC with a significant increase in the REM sleep episode numbers. Overall, our results suggest that proton pumps in the LC may be involved in REM sleep generation.

show abstract

Homeostatic Shrinkage of Dendritic Spines Requires Melatonin Type 3 Receptor Activation During Sleep

Li,

et al. 2024

Advanced Science

View full text Add to dashboard Cite

High‐frequency oscillatory activity in cognition‐related neural circuits during wakefulness consistently induces the growth of dendritic spines and axonal terminals. Although these structural changes are essential for cognitive functions, it is hypothesized that if these newly expanded structures fail to establish functional connections, they may become superfluous. Sleep is believed to facilitate the reduction of such redundant structures to maintain neural homeostasis. However, the mechanisms underlying this pruning process during sleep remain poorly understood. In this study, that melatonin type 3 receptors (MT3Rs) are selectively expressed in the stellate neurons of the medial entorhinal cortex (MEC) is demonstrated, an area where high melatonin levels are detected during sleep. Activation of MT3Rs during sleep initiates the shrinkage of dendritic spines in stellate neurons by downregulating neural network activity and dephosphorylating synaptic proteins in the MEC. This process is disrupted when MT3R expression is knocked down or when MT3Rs are blocked during sleep. Notably, interference with MT3Rs in the MEC during sleep impairs the acquisition of spatial memory but does not affect object memory acquisition following sleep. These findings reveal novel molecular mechanisms involving melatonin and MT3Rs in the regulation of dendritic spine shrinkage during sleep, which is crucial for the acquisition and consolidation of spatial memory.

show abstract

Locus Coeruleus Acid-Sensing Ion Channels Modulate Sleep–Wakefulness and State Transition from NREM to REM Sleep in the Rat

Cited by 13 publications

References 84 publications

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression

Proton Pump Inhibitor “Lansoprazole” Inhibits Locus Coeruleus’s Neuronal Activity and Increases Rapid Eye Movement Sleep

Homeostatic Shrinkage of Dendritic Spines Requires Melatonin Type 3 Receptor Activation During Sleep

Contact Info

Product

Resources

About