Roles for substance P and gastrin-releasing peptide as neurotransmitters released by primary afferent pruriceptors

Akiyama, Tasuku; Tominaga, Mitsutoshi; Davoodi, Auva; Nagamine, Masaki; Blansit, Kevin; Horwitz, Alexander; Carstens, Mirela Iodi; Carstens, Earl

doi:10.1152/jn.00539.2012

Cited by 54 publications

(44 citation statements)

References 34 publications

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“…For example, it was recently reported that GRP antagonists would inhibit nonhistaminergic itch, but not that elicited by histamine, and that histamine responses at the H1 receptor on C-fibers were unique in requiring phospholipase Cb as an intracellular mediator. 1,13,42 In conclusion, the data presented here provide, for the first time, evidence that the mTORC1 signaling pathway regulates both histamine-dependent and histamine-independent itch. Together with our previous studies on the role of mTORC1 in pain, 9,18,30,31 this result may suggest that a subpopulation of P-mTOR-positive A-fibers may also be crucial for the full response to pruritic stimuli and therefore may underline the importance of the mTORC1 pathway in the regulation of homeostatic primary afferent functions such as pain and itch.…”

Section: Metformin As An Antipruritic Agentsupporting

confidence: 57%

Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice

Obara

Medrano

Signoret-Genest

et al. 2015

Pain

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Activated mammalian target of rapamycin (P-mTOR) has been shown to maintain the sensitivity of subsets of small-diameter primary afferent A-nociceptors. Local or systemic inhibition of the mTOR complex 1 (mTORC1) pathway reduced punctate mechanical and cold sensitivity in neuropathic pain and therefore offered a new approach to chronic pain control. In this study, we have investigated the effects of the rapamycin analog temsirolimus (CCI-779) on itch. Bouts of scratching induced by the histamine-dependent pruritogenic compound 48/80 and histamine-independent pruritogens, chloroquine and SLIGRL-NH2, injected intradermally were significantly reduced by local (intradermal) or systemic (intraperitoneal, i.p.) pretreatment with CCI-779. We also investigated the action of metformin, a drug taken to control type 2 diabetes and recently shown to inhibit mTORC1 in vivo. Although the response to nonhistaminergic stimuli was reduced at all of the time points tested, scratching to compound 48/80 was modified by metformin only when the drug was injected 24 hours before this pruritogen. We also examined the colocalization of P-mTOR with gastrin-releasing peptide, a putative marker for some itch-sensitive primary afferents, and found that P-mTOR was coexpressed in less than 5% of gastrin-releasing peptide-positive fibers in the mouse skin. Taken together, the data highlight the role that P-mTOR-positive A-fibers play in itch signaling and underline the importance of the mTORC1 pathway in the regulation of homeostatic primary afferent functions such as pain and itch. The actions of the antidiabetic drug metformin in ameliorating nonhistamine-mediated itch also suggest a new therapeutic route for the control of this category of pruritus.

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Section: Metformin As An Antipruritic Agentsupporting

confidence: 57%

Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice

Obara

Medrano

Signoret-Genest

et al. 2015

Pain

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“…A majority of GRP immunopositive fibers in dorsal root ganglion (DRG) cells express SP, CGRP, and TRPV1 (31,32). A recent in vivo study demonstrated that SP, glutamate, and GRP each partially contributes to histamine-independent itch (33). Patch clamp recordings using slices of spinal cord from rats and mice revealed that a portion of dorsal horn neurons receiving input from PANs showed an increased firing frequency of action potential in response to GRP application (34).…”

Section: Tks and Itchmentioning

confidence: 99%

Tachykinin: recent developments and novel roles in health and disease

Onaga

2014

Biomolecular Concepts

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Over 80 years has passed since the discovery of substance P (SP), and a variety of peptides of the tachykinin (TK) family have been found and investigated. SP, neurokinin A (NKA), and neurokinin B (NKB) are representative peptides in mammalian species. SP and NKA are major excitatory neurotransmitters in the peripheral nervous system, while NKB is primarily involved in the central nervous system (CNS). Moreover, TK peptides play roles not only as neurotransmitters but also as local factors and are involved in almost all aspects of the regulation of physiological functions and pathophysiological processes. The role of SP as a mediator of pain processing and inflammation in peripheral tissues in coordination with transient receptor potential channels is well established, while novel aspects of TKs in relation to hematopoiesis, venous thromboembolism, tendinopathy, and taste perception have been clarified. In the CNS, the NKB signaling system in the hypothalamus has been shown to play a crucial role in the regulation of gonadotropin hormone secretion and the onset of puberty, and molecular biological studies have elucidated novel prophylaxic activities of TKs against neurogenic movement disorders based on their molecular structure. This review provides an overview of the novel aspects of TKs reported around the world in the last 5 years, with particular focus on nociception, inflammation, hemopoiesis, gonadotropin secretion, and CNS diseases.

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“…Histaminergic and non-histaminergic itch require TRPV1 and TRPA1, respectively [18; 33]. In the spinal cord, glutamate as well as neuropeptides including substance P, gastrin releasing peptide (GRP), neuromedin B, and natriuretic polypeptide B (Nppb) are involved in the transmission of itch signals [6; 8; 21; 27; 36]. Neurons expressing the substance P neurokinin-1 receptor (NK1R) represent the majority of ascending somatosensory projection neurons from the spinal and medullary dorsal horn, and are implicated in acute itch [14; 29].…”

Section: Introductionmentioning

confidence: 99%

A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch

Akiyama

Nguyen

Curtis

et al. 2015

Pain

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We investigated roles for spinal neurons expressing the neurokinin-1 receptor (NK1R) and/or gastrin releasing peptide receptor (GRPR) in a mouse model of ovalbumin (OVA)-induced chronic atopic dermatitis (AD). Mice receiving repeated topical application of OVA exhibited atopic-like skin lesions and behavioral signs of chronic itch including spontaneous scratching, touch-evoked scratching (alloknesis), and enhancement of chloroquine-evoked scratching (hyperknesis). Substance P-saporin (SP-SAP) and bombesin-saporin (BB-SAP) were intrathecally injected into OVA-sensitized mice to neurotoxically ablate NK1R- or GRPR-expressing spinal neurons, respectively. SP-SAP diminished the expression of NK1R in the superficial spinal dorsal horn, and significantly attenuated all behavioral signs of chronic itch. BB-SAP reduced the spinal dorsal horn expression of GRPR and significantly attenuated hyperknesis, with no effect on spontaneous scratching or alloknesis. To investigate whether NK1R-expressing spinal neurons project in ascending somatosensory pathways, we performed a double-label study. The retrograde tracer, Fluorogold (FG), was injected into either the somatosensory thalamus or lateral parabrachial nucleus. In the upper cervical (C1-2) spinal cord, most neurons retrogradely labeled with FG were located in the dorsomedial aspect of the superficial dorsal horn. Of FG-labeled spinal neurons, 89-94% were double-labeled for NK1R. These results indicate that NK1R-expressing spinal neurons play a major role in the expression of symptoms of chronic itch, and give rise to ascending somatosensory projections. GRPR-expressing spinal neurons contribute to hyperknesis but not alloknesis or ongoing itch. NK1R-expressing spinal neurons represent a potential target to treat chronic itch.

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Roles for substance P and gastrin-releasing peptide as neurotransmitters released by primary afferent pruriceptors

Cited by 54 publications

References 34 publications

Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice

Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice

Tachykinin: recent developments and novel roles in health and disease

A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch

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