Locus coeruleus-noradrenergic modulation of trigeminal pain: Implications for trigeminal neuralgia and psychiatric comorbidities

Donertas-Ayaz, Basak; Caudle, Robert M.

doi:10.1016/j.ynpai.2023.100124

Cited by 6 publications

(5 citation statements)

References 161 publications

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“…Our experiments found that LC noradrenergic neurons have an important function in the interaction between ASD and NTG-induced migraine-like headache. This observation supports the hypotheses posited in a earlier literature review in which the LC acts as a shared pathway linking pain and sleep, thus potentially assuming a critical role in the reciprocal relationship between the two [ 7 – 9 , 31 – 38 ].…”

Section: Discussionsupporting

confidence: 90%

“…For each experiment, we conducted essential verification steps to separately validate the role of LC noradrenergic neurons in headache and sleep. The involvement of LC noradrenergic neurons in these processes has been consistently demonstrated in previous studies [ 9 , 38 , 40 ]. When examining the role of LC noradrenergic neurons in ASD-induced pain facilitation, we employed both pharmacological and chemical genetic approaches to confirm their contributions and found that the LC was an important mediator rather than an antagonist of this process.…”

Section: Discussionsupporting

confidence: 71%

“…Additionally, studies have observed heightened activity of LC-prefrontal cortex (PFC) noradrenergic neurons in mice [ 42 ] and found that chemogenetic activation of these neurons exacerbated spontaneous foot-lifts in rats with tibial nerve injury [ 42 ]. These observations suggest that overactivation of the LC induced by neuropathic pain may contribute, at least partially, to the sleep disturbances associated with chronic pain [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

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The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache

Li,

Cao,

Yuan

et al. 2024

J Headache Pain

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Background Both epidemiological and clinical studies have indicated that headache and sleep disturbances share a complex relationship. Although headache and sleep share common neurophysiological and anatomical foundations, the mechanism underlying their interaction remains poorly understood. The structures of the diencephalon and brainstem, particularly the locus coeruleus (LC), are the primary sites where the sleep and headache pathways intersect. To better understand the intricate nature of the relationship between headache and sleep, our study focused on investigating the role and function of noradrenergic neurons in the LC during acute headache and acute sleep disturbance. Method To explore the relationship between acute headache and acute sleep disturbance, we primarily employed nitroglycerin (NTG)-induced migraine-like headache and acute sleep deprivation (ASD) models. Initially, we conducted experiments to confirm that ASD enhances headache and that acute headache can lead to acute sleep disturbance. Subsequently, we examined the separate roles of the LC in sleep and headache. We observed the effects of drug-induced activation and inhibition and chemogenetic manipulation of LC noradrenergic neurons on ASD-induced headache facilitation and acute headache-related sleep disturbance. This approach enabled us to demonstrate the bidirectional function of LC noradrenergic neurons. Results Our findings indicate that ASD facilitated the development of NTG-induced migraine-like headache, while acute headache affected sleep quality. Furthermore, activating the LC reduced the headache threshold and increased sleep latency, whereas inhibiting the LC had the opposite effect. Additional investigations demonstrated that activating LC noradrenergic neurons further intensified pain facilitation from ASD, while inhibiting these neurons reduced this pain facilitation. Moreover, activating LC noradrenergic neurons exacerbated the impact of acute headache on sleep quality, while inhibiting them alleviated this influence. Conclusion The LC serves as a significant anatomical and functional region in the interaction between acute sleep disturbance and acute headache. The involvement of LC noradrenergic neurons is pivotal in facilitating headache triggered by ASD and influencing the effects of headache on sleep quality.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache

Li,

Cao,

Yuan

et al. 2024

J Headache Pain

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“…The synergistic and enhanced antinociception driven by Cocktail A and Cocktail B, respectively, each which contain a MOR agonist, provides a route for reduced opioid use by leveraging the modular interaction in LC-NE system with other receptor ligands. Considering the prevalence of comorbid anxiodepressive disorders and sleep dysfunction during the chronification and maintenance of chronic pain 116 – 118 , the LC-NE system could be an excellent target for pain therapeutics due to its contribution to cognitive function, stress processing, and pain regulation 35 , 49 , 50 , 117 , 118 . Previous studies have shown decreased mRNA expression and faster desensitization of MOR in LC during the development of neuropathic pain 119 , 120 , and selective antagonism of alpha1/2 adrenergic receptors reversed neuropathic pain-induced depression 121 .…”

Section: Discussionmentioning

confidence: 99%

Neural circuit-selective, multiplexed pharmacological targeting of prefrontal cortex-projecting locus coeruleus neurons drives antinociception

Kuo,

McCall

2024

Preprint

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Selective manipulation of neural circuits using optogenetics and chemogenetics holds great translational potential but requires genetic access to neurons. Here, we demonstrate a general framework for identifying genetic tool-independent, pharmacological strategies for neural circuit-selective modulation. We developed an economically accessible calcium imaging-based approach for large-scale pharmacological scans of endogenous receptor-mediated neural activity. As a testbed for this approach, we used the mouse locus coeruleus due to the combination of its widespread, modular efferent neural circuitry and its wide variety of endogenously expressed GPCRs. Using machine learning-based action potential deconvolution and retrograde tracing, we identified an agonist cocktail that selectively inhibits medial prefrontal cortex-projecting locus coeruleus neurons.In vivo, this cocktail produces synergistic antinociception, consistent with selective pharmacological blunting of this neural circuit. This framework has broad utility for selective targeting of other neural circuits under different physiological and pathological states, facilitating non-genetic translational applications arising from cell type-selective discoveries.

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“…The LC neurons are implicated in a variety of brain functions, including sleep–wake control, sensory perception, attention, and learning. The descending noradrenergic (NA) inhibitory system is one of the main pathways in endogenous pain modulation (Yaksh, 1989 ; Millan, 2002 ; Pertovaara, 2006 ; Donertas-Ayaz and Caudle, 2023 ). Patients with trigeminal neuropathy had altered LC functional connectivity with increased connectivity between the rostral ventromedial medulla and decreased connectivity between the ventrolateral periaqueductal gray matter (Mills et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Locus coeruleus inhibition of vibrissal responses in the trigeminal subnucleus caudalis are reduced in a diabetic mouse model

Mesa-Lombardo

García-Magro

Núñez

et al. 2023

Front. Cell. Neurosci.

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Diabetic neuropathy is the loss of sensory function beginning distally in the lower extremities, which is also characterized by pain and substantial morbidity. Furthermore, the locus coeruleus (LC) nucleus has been proposed to play an important role in descending pain control through the activation of α2-noradrenergic (NA) receptors in the spinal dorsal horn. We studied, on control and diabetic mice, the effect of electrical stimulation of the LC nucleus on the tactile responses in the caudalis division of the spinal trigeminal nucleus (Sp5C), which is involved in the relay of orofacial nociceptive information. Diabetes was induced in young adult C57BL/6J mice with one intraperitoneal injection of streptozotocin (50 mg/kg) daily for 5 days. The diabetic animals showed pain in the orofacial area because they had a decrease in the withdrawal threshold to the mechanical stimulation in the vibrissal pad. LC electrical stimulation induced the inhibition of vibrissal responses in the Sp5C neurons when applied at 50 and 100 ms before vibrissal stimulation in the control mice; however, the inhibition was reduced in the diabetic mice. These effects may be due to a reduction in the tyrosine hydroxylase positive (TH+) fibers in the Sp5C, as was observed in diabetic mice. LC-evoked inhibition was decreased by an intraperitoneal injection of the antagonist of the α2-NA receptors, yohimbine, indicating that it was due to the activation of α2-NA receptors. The decrease in the LC-evoked inhibition in the diabetic mice was partially recovered when clonidine, a non-selective α2-agonist, was injected intraperitoneally. These findings suggest that in diabetes, there is a reduction in the NA inputs from the LC in the Sp5C that may favor the development of chronic pain.

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Locus coeruleus-noradrenergic modulation of trigeminal pain: Implications for trigeminal neuralgia and psychiatric comorbidities

Cited by 6 publications

References 161 publications

The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache

The crucial role of locus coeruleus noradrenergic neurons in the interaction between acute sleep disturbance and headache

Neural circuit-selective, multiplexed pharmacological targeting of prefrontal cortex-projecting locus coeruleus neurons drives antinociception

Locus coeruleus inhibition of vibrissal responses in the trigeminal subnucleus caudalis are reduced in a diabetic mouse model

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