Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation

Gao, Zhengrun; Chen, Wenzhen; Liu, Mingzhe; Chen, Xiaojun; Wan, Li; Zhang, Xinyan; Yuan, Lei; Lin, Jun-Kai; Wang, Meng; Zhou, Li; Xu, Xiaohong; Sun, Yan-Gang

doi:10.1016/j.neuron.2018.11.010

Cited by 95 publications

(94 citation statements)

References 77 publications

(132 reference statements)

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“…This includes pacemakers for gait initiation, speed regulation, and their descending targets in the pontine reticular formation of mammals, including humans (Kozlov et al, 2014;Brownstone and Chopek, 2018). In mice, an activation of brainstem interneurons by periventricular glutamatergic neurons that were active by itch and modify the scratching patterns was observed (Gao et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…It is important to emphasize that the scratching phenomenon in fictive motor preparations has not been deeply investigated to establish the afferent and descendent pathway producing FS in cats. A relevant work was made in a mice model, which exhibits the pathways related to itch and their relationship to periaqueductal gray glutamatergic neurons (Gao et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Fictive Scratching Patterns in Brain Cortex-Ablated, Midcollicular Decerebrate, and Spinal Cats

Garcia

Dueñas‐Jiménez

Castillo

et al. 2020

Front. Neural Circuits

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fictive Scratching Patterns in Brain Cortex-Ablated, Midcollicular Decerebrate, and Spinal Cats

Garcia

Dueñas‐Jiménez

Castillo

et al. 2020

Front. Neural Circuits

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“…proportions of retrogradely labeled spinothalamic and spinoparabrachial neurons that co-express the activity marker, c-fos, following intradermal injection of histamine, chloroquine or capsaicin (36). Finally, the spinal itch-signaling circuitry is very likely under descending modulatory influences from the brainstem, although this has only begun to be experimentally addressed (37,38).…”

Section: Overview Of Itch Pathwaymentioning

confidence: 99%

The Challenge of Basic Itch Research

2020

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This paper reviews the basic mechanisms and pathways of itch signaling, emphasizing the progress to date as well as remaining challenges in translating current knowledge to the clinical treatment of chronic itch. Major questions that are addressed include: is itch signaled by a labeled-line pathway separate from that for pain; can alternative theories explain the ability to distinguish between itch and pain; are there specific markers of itch (such as gastrin releasing peptide and its receptor); are there histaminergic and nonhistaminergic itch-signaling pathways? We also address challenges in understanding touch-evoked itch (alloknesis) as a symptom of chronic itch. Basic mechanisms and pathways of itch signaling are reviewed, with an emphasis on the progress to date as well as remaining challenges in translating current knowledge to the clinical treatment of chronic itch. Recent studies reveal 3 subsets of pruriceptive sensory neurons highly expressing itch-related genes. Their fibers project into the spinal cord to activate neurons expressing gastrin releasing peptide (GRP) and its receptor (GRPR), which connect to neurons that express the substance P (NK-1) receptor and project to the parabrachial nucleus and thalamus. Spinal inhibitory interneurons release GABA, glycine and dynorphin to modulate segmental itch transmission. However, nearly all pruriceptive neurons also respond to algogens such as capsaicin. Alternative theories of itch-pain discrimination, such as intensity or spatial contrast, are based on the observation that focal stimulation of nociceptive nerve endings elicits itch while more widespread stimulation elicits pain. These findings cloud the issue of a labeled line for itch-a long-debated but currently unresolved challenge. In higher primates there is a dichotomy of histaminergic and non-histaminergic itch-signaling pathways which is less demarcated in rodents, suggesting species differences. A cardinal symptom of chronic itch is alloknesis, i.e., mechanical or touch-evoked itch. Recent evidence indicates that low-threshold mechanosensory afferents can access the spinal itch pathway, but are normally kept in check by inhibitory interneurons expressing neuropeptide Y (NPY). In chronic itch, NPY-mediated inhibition is reduced, allowing touch to excite itch-signaling pathways. These recent advances provide novel targets for development of therapeutic strategies to relieve chronic itch.

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“…SP and the NK1 receptor are also widely expressed centrally and have a role in transmission of the peripheral itch signal via the spinal superficial dorsal horn to higher brain centres for processing 20. In rodents scratching behaviour can be blocked by neurotoxic destruction of spinal NK1 receptor-expressing neurons,21 22 and Tac1 (the gene encoding SP)-expressing spinal neurons have also been linked to the promotion of scratching behaviour 23. Intradermal injection of SP in humans causes pruritus, erythema and oedema 24–26.…”

Section: Introductionmentioning

confidence: 99%

Neurokinin-1 antagonist orvepitant for EGFRI-induced pruritus in patients with cancer: a randomised, placebo-controlled phase II trial

et al. 2020

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ObjectiveTo evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus.DesignRandomised, double-blind, placebo-controlled clinical trial.Setting15 hospitals in Italy and five hospitals in the UK.Participants44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment.Intervention30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1).Primary and secondary outcome measuresThe primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus.ResultsThe trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was −2.78 (SD: 2.64) points in the 30 mg group, −3.04 (SD: 3.06) points in the 10 mg group and −3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity.ConclusionsOrvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible.Trial registration numberEudraCT2013-002763-25.

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Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation

Cited by 95 publications

References 77 publications

Fictive Scratching Patterns in Brain Cortex-Ablated, Midcollicular Decerebrate, and Spinal Cats

Fictive Scratching Patterns in Brain Cortex-Ablated, Midcollicular Decerebrate, and Spinal Cats

The Challenge of Basic Itch Research

Neurokinin-1 antagonist orvepitant for EGFRI-induced pruritus in patients with cancer: a randomised, placebo-controlled phase II trial

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