GABAA Receptors in the Central Nucleus of the Amygdala Are Involved in Pain- and Itch-Related Responses

Chen, Long; Wang, Wei; Tan, Tao; Han, Hyounkoo; Dong, Zhifang

doi:10.1016/j.jpain.2015.10.008

Cited by 28 publications

(29 citation statements)

References 31 publications

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“…Given that baclofen and muscimol were administered systemically, it remains to be determined whether their site of action is spinal and/or supraspinal. Interestingly, a recent study reported that direct microinjection of muscimol into the central nucleus of the amygdala has anti-pruritic effects against both acute (serotonin) and chronic (dry skin model) itch 37 . As supraspinal antinociceptive actions of GABA receptor agonists have been reported 38 , it is likely that systemic administration of GABA agonists has concurrent spinal and supraspinal actions.…”

Section: Discussionmentioning

confidence: 99%

Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis

Cevikbas

Bráz²,

Wang³

et al. 2017

Journal of Allergy and Clinical Immunology

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Background Despite recent insights into the pathophysiology of acute and chronic itch, chronic itch remains an often intractable condition. Among major contributors to chronic itch is dysfunction of spinal cord GABAergic inhibitory controls. Objective To test the hypothesis that selective GABA agonists as well as cell transplant-derived GABA are antipruritic against acute itch and in a transgenic mouse model of atopic dermatitis produced by overexpression of the TH2 cell-associated cytokine, IL-31 (IL-31Tg mice). Methods We injected wild-type and IL-31Tg mice with combinations of GABA-A (muscimol) or GABA-B (baclofen) receptor agonists 15–20 min prior to injection of various pruritogens (histamine, chloroquine or endothelin-1) and recorded spontaneous scratching before and after drug administration. We also tested the antipruritic properties of intraspinal transplantation of precursors of GABAergic interneurons in the IL-31Tg mice. Results Systemic muscimol or baclofen are antipruritic against both histamine-dependent and independent pruritogens, but the therapeutic window using either ligand alone was very small. In contrast, combined subthreshold doses of baclofen and muscimol produced a significant synergistic antipruritic effect, with no sedation. Finally, transplant-mediated long term enhancement of GABAergic signaling not only reduced spontaneous scratching in the IL-31Tg mice but also dramatically resolved the associated skin lesions. Conclusion Although additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis.

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Section: Discussionmentioning

confidence: 99%

Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis

Cevikbas

Bráz²,

Wang³

et al. 2017

Journal of Allergy and Clinical Immunology

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“…Activation of the amygdala has been observed in most studies of itch, suggesting that memory of previous itch experiences may be a significant factor in itch‐related emotional aspects. GABA A receptors in the CeA were reported to be involved in attenuating and enhancing acute and chronic itch in mice . Thus, aspects of learning and memory in the hippocampus and amygdala may play important roles in reward regulation.…”

Section: Clinical and Neurobiological Similarities Between Addiction mentioning

confidence: 99%

Addiction and the itch‐scratch cycle. What do they have in common?

Ishiuji

2019

Experimental Dermatology

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Itch is a multidimensional experience involving various brain regions associated with sensory perception and emotion, as well as an urge to scratch employing the motor system. Scratch temporarily relieves itch sensation in healthy subjects. However, in patients with chronic itch, rather than inhibit, scratch may aggravate itch. Patients with chronic itch, such as those with atopic dermatitis, experience severe itch and a strong desire to scratch. This urge to scratch is the driving force underlying the formation of the itch‐scratch‐cycle, an addictive and vicious cycle in chronic itch patients. This vicious itch‐scratch behaviour and various types of addiction (henceforth, including recreational drug use) were shown to share common sensory mechanisms. Abnormalities have been observed in central neural circuits, including the reward, motivation/drive, control and learning/memory circuits, as well as other brain systems. Reward systems, including the ventral tegmental area (VTA), nucleus accumbens (NAc) and striatum, are important for brain processing of both addiction and itch. In addition to reward, addicted individuals can experience severe disruptions in motor control, cognitive awareness, executive function, learning/memory and even emotional functions. Findings showing that addiction and itch share a common neurobiological foundation could have important mechanistic and therapeutic implications. Here we propose that similar neuroadaptations exist in addiction and chronic itch patients.

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“…The amygdala, the major center for generation of anxiety and fear, was activated by both histamine-dependent and -independent itch stimuli but deactivated by scratching (Papoiu et al, 2012(Papoiu et al, , 2013Vierow et al, 2015). Additionally, it has been reported that injection of a GABA A agonist into the central amygdala (CeA) suppressed acute and chronic itch in rats (Chen et al, 2016). Recent studies have identified populations of amygdala neurons that respond to other emotionally valent (appetitive or aversive) sensory stimuli, such as olfactory and taste cues (Xiu et al, 2014;Kim et al, 2016Kim et al, , 2017, and the amygdala is known to mediate the affective processing of pain (Neugebauer, 2015).…”

Section: Introductionmentioning

confidence: 99%

A Subpopulation of Amygdala Neurons Mediates the Affective Component of Itch

et al. 2019

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Itch consists of both sensory and affective components. For chronic itch patients, the affective component of itch affects both quality of life (leading to psychological comorbidities) and disease prognosis (by promoting scratching of itchy skin). We found that acute itch stimuli, such as histamine, induced anxiety-like behavior and increased activity (c-Fos expression) in the amygdala in adult male C57BL/6 mice. Itch stimuli also increased activity in projection areas to the amygdala, suggesting that these regions form a circuit for affective itch processing. Electrophysiological characterization of histamine-responsive amygdala neurons showed that this population was active on a behaviorally relevant timescale and partially overlapped with pain signaling. Selective optogenetic activation of histamine-responsive amygdala neurons in adult male and female Fos:CreER T2 ;R26 Ai14 mice using the Targeted Recombination in Active Populations system enhanced both scratching and anxiety-like behavior. These results highlight the importance of itch-responsive amygdala neurons in modulating itch-related affect and behavior.The sensation of itch includes an affective component that leads to stress and anxiety in chronic itch patients. We investigated the neuronal basis of affective itch in mice, with a focus on the amygdala, the key brain region for the generation of anxiety. A subpopulation of amygdala neurons responded to itch stimuli such as histamine. Optogenetic activation of histamine-responsive amygdala neurons affected both scratching and anxiety-like behavior. Therefore, this population appears to be important for mediating the affective component of itch.

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GABAA Receptors in the Central Nucleus of the Amygdala Are Involved in Pain- and Itch-Related Responses

Cited by 28 publications

References 31 publications

Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis

Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis

Addiction and the itch‐scratch cycle. What do they have in common?

A Subpopulation of Amygdala Neurons Mediates the Affective Component of Itch

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