Hemokinin-1 mediates pruriceptive processing in the rat spinal cord

Funahashi, Hideki; Naono-Nakayama, Rumi; Ebihara, Kosuke; Koganemaru, Go; Kuramashi, Aki; Ikeda, Tetsuya; Nishimori, Toshikazu; Ishida, Yoshiteru

doi:10.1016/j.neuroscience.2014.07.001

Cited by 11 publications

(6 citation statements)

References 44 publications

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“…As noted earlier, the presence of HK-1 was a potential experimental confound because HK-1 has recently been implicated in nociception or itch (Funahashi et al, 2014) and in adjuvant-induced chronic arthritis (Borbely et al, 2013). It is also upregulated in glia by inflammatory stimuli (Morteau et al, 2001; Duffy et al, 2003; Fu et al, 2005; Endo et al, 2006; Matsumura et al, 2008).…”

Section: Discussionmentioning

confidence: 97%

“…The amino acid sequences for SubP and HK-1 are 55% identical, and both proteins bind the NK1R with similar high affinity (Morteau et al, 2001; Camarda et al, 2002; Duffy et al, 2003; Berger and Paige, 2005). The potential presence of HK-1 was a confound not only for the specificity of the EIA, but also because HK-1 is upregulated in glia by inflammatory stimuli (Morteau et al, 2001; Duffy et al, 2003; Fu et al, 2005; Endo et al, 2006; Matsumura et al, 2008) and has recently been implicated in nociception or itch (Funahashi et al, 2014) and in CFA-induced chronic arthritis (Borbely et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

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Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

et al. 2016

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This study examined whether peripheral inflammatory injury increases the levels or changes the disposition of substance P (SubP) in the rostral ventromedial medulla (RVM), which serves as a central relay in bulbospinal pathways of pain modulation. Enzyme immunoassay and reverse transcriptase quantitative polymerase chain reaction were used to measure SubP protein and transcript, respectively, in tissue homogenates prepared from the RVM and the periaqueductal gray and cuneiform nuclei of rats that had received an intraplantar injection of saline or complete Freund's adjuvant (CFA). Matrix Assisted Laser Desorption/Ionization Time of Flight analysis confirmed that the RVM does not contain hemokinin-1, which can confound measurements of SubP because it is recognized equally well by commercial antibodies for SubP. Levels of SubP protein in the RVM were unchanged four hours, four days and two weeks after injection of CFA. Tac1 transcripts were similarly unchanged in the RVM four days or two weeks after CFA. In contrast, the density of SubP immunoreactive processes in the RVM increased 2-fold within four hours and 2.7-fold four days after CFA injection; it was unchanged at two weeks. SubP-immunoreactive processes in the RVM include axon terminals of neurons located in the periaqueductal gray and cuneiform nucleus. Substance P content in homogenates of the periaqueductal gray and cuneiform nucleus was significantly increased four days after CFA, but not at four hours or two weeks. Tac1 transcripts in homogenates of these nuclei were unchanged four days and two weeks after CFA. These findings suggest that there is an increased mobilization of SubP within processes in the RVM shortly after injury accompanied by an increased synthesis of SubP in neurons that project to the RVM. These findings are consonant with the hypothesis that an increase in SubP release in the RVM contributes to the hyperalgesia that develops after peripheral inflammatory injury.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

et al. 2016

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“…Here, in vivo, the efficacy of 3’-O-methylorobol on itch relief in histaminergic itching induced by compound 48/80 was evaluated, an evaluation in which the spontaneous scratching bouts of mice were remarkably reduced. C-fos expression in the nuclei of neurons can be rapidly enhanced following pruritic agent stimulation (compound 48/80, 5-hydroxytryptamine) in the spinal dorsal horn, and it has therefore been used as a marker in pruriceptive processing [36,37,38]. Consistent with the efficacy in reducing the scratching bouts, 3’-O-methylorobol suppressed c-fos expression to a degree that was comparable to that of cyproheptadine.…”

Section: Discussionmentioning

confidence: 99%

3’-O-Methylorobol Inhibits the Voltage-Gated Sodium Channel Nav1.7 with Anti-Itch Efficacy in A Histamine-Dependent Itch Mouse Model

Zhang

Xue

et al. 2019

IJMS

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An itch is a clinical complication that affects millions of patients. However, few treatment options are available. The voltage-gated sodium channel Nav1.7 is predominantly expressed in peripheral sensory neurons and is responsible for the rising phase of action potentials, thereby mediating nociceptive conduction. A gain-of-function mutation of Nav1.7 results in the hyperexcitability of sensory neurons and causes the inherited paroxysmal itch. Conversely, a monoclonal antibody that selectively inhibits Nav1.7 is able to effectively suppress the histamine-dependent itch in mice. Therefore, Nav1.7 inhibitors may possess the potential to relieve the itch. In the present study, using whole-cell voltage-clamp recordings, we demonstrated that 3’-O-methylorobol inhibited Na+ currents in Nav1.7-CHO cells and tetrodotoxin-sensitive Na+ currents in mouse dorsal root ganglion (DRG) neurons with IC50 (half-maximal inhibitory concentration) values of 3.46 and 6.60 μM, respectively. 3’-O-methylorobol also suppressed the tetrodotoxin-resistant Na+ currents in DRG neurons, though with reduced potency (~43% inhibition at 30 µM). 3’-O-methylorobol (10 µM) affected the Nav1.7 by shifting the half-maximal voltage (V1/2) of activation to a depolarizing direction by ~6.76 mV, and it shifted the V1/2 of inactivation to a hyperpolarizing direction by ~16.79 mV. An analysis of 3’-O-methylorobol activity toward an array of itch targets revealed that 3’-O-methylorobol was without effect on histamine H1 receptor, TRPV1, TRPV3, TRPV4, TRPC4 and TRPM8. The intrathecal administration of 3’-O-methylorobol significantly attenuated compound 48/80-induced histamine-dependent spontaneous scratching bouts and the expression level of c-fos in the nuclei of spinal dorsal horn neurons with a comparable efficacy to that of cyproheptadine. Our data illustrated the therapeutic potential for 3’-O-methylorobol for histamine-dependent itching, and the small molecule inhibition of Nav1.7 may represent a useful strategy to develop novel therapeutics for itching.

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“…Recent studies suggest that nociception and pruritus are likely to be mediated by modality-selective signaling molecules or receptors/channels (Bautista et al, 2014; Davidson and Giesler, 2010; Han et al, 2013; Ikoma et al, 2006; Kardon et al, 2014; McNeil et al, 2015; Wilson et al, 2011). In this respect, several peptides including gastrin-releasing peptide (GRP), natriuretic polypeptide B (NPPB), neuromedin B (NMB), and hemokinin-1, have been suggested as endogenous pruritogens (Funahashi et al, 2014; Mishra and Hoon, 2013; Su and Ko, 2011; Sun and Chen, 2007). Utilizing the bioinformatics algorithm from information provided by the Genome Projects, two secreted, highly conserved peptides, PNX-14 and PNX-20, with no known biological functions, were isolated and identified in neural and non-neural tissues (Lyu et al, 2013; Yosten et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Phoenixin: A candidate pruritogen in the mouse

Cowan

Lyu²,

Chen

et al. 2015

Neuroscience

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Phoenixin (PNX) is a 14-amino acid amidated peptide (PNX-14) or an N-terminal extended 20-residue amidated peptide (PNX-20) recently identified in neural and non-neural tissue. Mass spectrometry analysis identified a major peak corresponding to PNX-14, with negligible PNX-20, in mouse spinal cord extracts. Using a previously characterized antiserum that recognized both PNX-14 and PNX-20, PNX-immunoreactivity (irPNX) was detected in a population of dorsal root ganglion (DRG) cells and in cell processes densely distributed to the superficial layers of the dorsal horn; irPNX cell processes were also detected in the skin. The retrograde tracer, Fluorogold, injected subcutaneously (s.c.) to the back of the cervical and thoracic spinal cord of mice, labeled a population of DRG, some of which were also irPNX. PNX-14 (2, 4 and 8 mg/kg) injected s.c.to the nape of the neck provoked dose-dependent repetitive scratching bouts directed to the back of the neck with the hindpaws. The number of scratching bouts varied from 16–95 in 30 min, commencing within 5 min post-injection and lasted 10–15 min. Pretreatment of mice at −20 min with nalfurafine (20 µg/kg, s.c.), the kappa opioid receptor agonist, significantly reduced the number of bouts induced by PNX-14 (4 mg/kg) compared with that of saline-pretreated mice. Our results suggest that the peptide, PNX-14, serves as one of the endogenous signal molecules transducing itch sensation in the mouse.

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Hemokinin-1 mediates pruriceptive processing in the rat spinal cord

Cited by 11 publications

References 44 publications

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

Changes in the disposition of substance P in the rostral ventromedial medulla after inflammatory injury in the rat

3’-O-Methylorobol Inhibits the Voltage-Gated Sodium Channel Nav1.7 with Anti-Itch Efficacy in A Histamine-Dependent Itch Mouse Model

Phoenixin: A candidate pruritogen in the mouse

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