Genetic Enhancement of Behavioral Itch Responses in Mice Lacking Phosphoinositide 3-Kinase-γ (PI3Kγ)

Lee, Bolam; Descalzi, Giannina; Baek, Jong Hwan; Kim, Jae‐Ick; Lee, Hye Ryeon; Lee, Kyungmin; Kaang, Bong‐Kiun; Zhuo, Min

doi:10.1186/1744-8069-7-96

Cited by 6 publications

(4 citation statements)

References 31 publications

(62 reference statements)

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“…Phosphatidylinositol signaling is a second messenger cascade involving the sequential phosphorylation of phosphatidylinositol 4-phosphate (PIP) to generate phosphatidylinositol 4,5-bisphosphate (PIP2) via PIP5' kinases (phosphatidylinositol-5-OH kinase; PIP5K), and then phosphorylation of PIP2 via PI3 kinases (phosphatidylinositol-3-OH kinase; PI3K) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). In mammalian systems phospholipid signaling has been implicated in regulating pain perception [11]–[13], TRPV1 function [14]–[21], and itch [22], but how phosphatidylinositol signaling is involved in mammalian nociception is controversial, with data suggesting for example that PIP2 may either increase or decrease TRPV1 function [23], [24]. Based on the suggested involvement of phospholipid signaling in our conserved functional pain network, and in context of the controversial role for phosphatidylinositol signaling in pain perception, we employed genetic approaches to evaluate the role of phosphatidylinositol signaling in mammalian nociception.…”

Section: Introductionmentioning

confidence: 99%

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

Neely

Costigan

et al. 2012

PLoS Genet

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The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species.

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Section: Introductionmentioning

confidence: 99%

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

Neely

Costigan

et al. 2012

PLoS Genet

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“…Two cameras were placed at two neighbor sides of the cage between the iPad and the cage wall. The itching demonstrator mouse was chosen randomly and 500 μg histamine (Sigma, USA) dissolved in 50 μl saline was injected subcutaneously to the nape of its neck [1, 4, 11, 12]. The typical scratching activity was recorded and looped on the iPads (Apple, USA).…”

Section: Methodsmentioning

confidence: 99%

Contagious itch can be induced in humans but not in rodents

Chen

Zhou

et al. 2019

Mol Brain

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Itch contagion has been reported in human when people watch someone scratching in a video. The basic mechanism of contagious itch induced by scratching video is still being investigated. A recent study has reported that adult mice showed itch like responses after watching itch-like video or mice showing itching responses. However, such contagious itch behaviors failed to be reproduced by another study by repeating the same experiments of viewing itching mice. It is unclear if contagious itch induced by seeing itching video may be reproducible. In the present study, we used a four-iPad paradigm to repeat these experiments, and found that mice showed no significant itch-like responses after watching itching video of mice. To test if mice actually can see the video, we placed mirrors at the same location. Interestingly, mice showed altered activities in the open field with the mirrors. Finally, in healthy subjects, we found that viewing human itch video did cause itch sensation or responses. Our results indicate that the mouse model may not appropriate for studying contagious itch in humans.

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“…However (unlike the PIRT, PLCβ3, TrpV1 and TrpA1) loss of PI3Kγ in mice gives rise to more, not less itch. Furthermore, though PI3Kγ-deficient mice show significantly elevated scratching behavior in response to PAR-2 and histamine, they show normal responses in assays for acute pain (Lee et al, 2011). Thus, loss of PI3Kγ appears to be relatively specific to itch.…”

Section: Ngf Signaling Is Required For the Survival Of Pruritoceptorsmentioning

confidence: 97%

A Counterpart to Pain

Kardon

Ross

2013

Pain Genetics

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Pain is not the only defense mechanism that alerts us to a physical hazard -the other is itch, an unpleasant sensation that is distinct from pain because it provokes the desire to scratch. Although pain and itch feel different, these two sensations share many qualities. Both are aversive sensations that evolved to protect us. Moreover, both can become pathological, developing into chronic debilitating conditions that ruin one's quality of life.Itch, in particular, represents the most common reason that a patient sees a dermatologist. It is estimated that ~10% of the general population and 30% of the elderly suffer from pruritis (the medical term for itch), which negatively affects sleep, mood, and quality of life, thereby presenting an enormous health burden (Weisshaar and Dalgard, 2009;Yosipovitch, 2008). Despite this prevalence, itch has received little attention, and the genetic underpinnings of itch sensitivity are virtually unknown. Here we discuss the limited number of genetic mutations in humans and in mice that have been found to affect itch sensitivity -either heightening or reducing it -and what such mutations tells us about how itch is detected and encoded in the nervous system. Why do we scratch?Scratching in response to a noxious agent is seen across vertebrates, who use this strategy to remove potential threats from the skin's surface, thereby minimizing exposure to harm. Even fish scratch, typically using tail fins or by rubbing against abrasive rocks (Stein, 1983). The highly conserved nature of this scratching response suggests that itch, like pain, confers an important evolutionary advantage. The basics of itchThe key difference between itch and pain is that itch is triggered by noxious stimuli at the very outermost aspect of the skin, whereas pain can be elicited from all cutaneous layers, ranging from superficial to deep, as well as most other regions of the body (Ross, 2011). Thus, the primary sensory neurons that detect pruritic stimuli are postulated to be a subset of dorsal root ganglia (DRG) and trigeminal neurons (perhaps 5%) that selectively innervate the dermis. Most itch fibers are likely to be a subset of unmyelinated, slowly conducting C-fibers, though recent studies suggest that some Aδ fibers may also be involved mediating itch (Ringkamp et al., 2011).What is the identity of these fibers? Remarkably, we do not yet know which sensory fibers mediate itch. Moreover, whether this subset of sensory neurons is specific for itch remains highly controversial. The best evidence that there exists a dedicated subset of peripheral sensory neurons that are selectively tuned to convey itch rather than nociception comes from experiments performing microneurography in humans. Using this technique, it is possible to isolate the activity of individual nerve fibers and identify those that respond to itch-inducing chemicals. Such experiments led to the discovery of C-fibers that are activated by pruritogens and whose activity corresponds to the sensation of itch in humans (Schmelz et al., 1997). Furt...

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Genetic Enhancement of Behavioral Itch Responses in Mice Lacking Phosphoinositide 3-Kinase-γ (PI3Kγ)

Cited by 6 publications

References 31 publications

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

Contagious itch can be induced in humans but not in rodents

A Counterpart to Pain

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