The Distinct Roles of Two GPCRs, MrgprC11 and PAR2, in Itch and Hyperalgesia

Liu, Qin; Weng, Han‐Rong; Patel, Krishna; Tang, Zongxiang; Bai, Haibo; Steinhoff, Martin; Dong, Xinzhong

doi:10.1126/scisignal.2001925

Cited by 192 publications

(214 citation statements)

References 21 publications

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“…Scratching elicited by these pruritogens was significantly reduced in Tlr3 −/− mice (Supplemental Figure 1, B-D; P < 0.05, 2-way repeated-measures ANOVA). Further, scratching induced by endothelin-1 and serotonin, as well as nonhistaminergic pruritogens SLIGRL-NH2 (PAR2 agonist) (21,22) and trypsin, was abrogated in Tlr3 −/− mice (Supplemental Figure 1, E-H; P < 0.05, 2-way repeated-measures ANOVA). Finally, we tested scratching by using a low concentration of formalin (0.6%) (23) and the TLR7 agonist imiquimod, which was shown to induce robust itch in mice (13,24).…”

Section: Resultsmentioning

confidence: 99%

“…As previously reported (28), GRP is expressed in primary afferent axons and terminals in the superficial dorsal horn of WT mice, but this expression was reduced in Tlr3 −/− mice (Supplemental Figure 8, A and B; P < 0.05, Student's t test). Of interest, spinal administration of GRP [18][19][20][21][22][23][24][25][26][27] rescued the itch deficits in Tlr3 −/− mice and elicited comparable scratching in Tlr3 −/− and WT mice (Supplemental Figure 8C), indicating that the ascending itch pathway from the secondary order spinal neurons to the brain is still intact in Tlr3 −/− mice. Therefore, itch deficiency in Tlr3 −/− mice may be attributed to impairment in the TRPV1-and GRP-mediated neurotransmission in the spinal cord.…”

Section: Tlr3 Agonist Poly (I:c) Induces Inward Currents and Action Pmentioning

confidence: 94%

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TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

Liu¹,

Berta²,

Xu³

et al. 2012

J. Clin. Invest.

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144

169

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Itch, also known as pruritus, is a common, intractable symptom of several skin diseases, such as atopic dermatitis and xerosis. TLRs mediate innate immunity and regulate neuropathic pain, but their roles in pruritus are elusive. Here, we report that scratching behaviors induced by histamine-dependent and -independent pruritogens are markedly reduced in mice lacking the Tlr3 gene. TLR3 is expressed mainly by small-sized primary sensory neurons in dorsal root ganglions (DRGs) that coexpress the itch signaling pathway components transient receptor potential subtype V1 and gastrin-releasing peptide. Notably, we found that treatment with a TLR3 agonist induces inward currents and action potentials in DRG neurons and elicited scratching in WT mice but not Tlr3 −/− mice. Furthermore, excitatory synaptic transmission in spinal cord slices and long-term potentiation in the intact spinal cord were impaired in Tlr3 −/− mice but not Tlr7 −/− mice. Consequently, central sensitization-driven pain hypersensitivity, but not acute pain, was impaired in Tlr3 −/− mice. In addition, TLR3 knockdown in DRGs also attenuated pruritus in WT mice. Finally, chronic itch in a dry skin condition was substantially reduced in Tlr3 −/− mice. Our findings demonstrate a critical role of TLR3 in regulating sensory neuronal excitability, spinal cord synaptic transmission, and central sensitization. TLR3 may serve as a new target for developing anti-itch treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Tlr3 Agonist Poly (I:c) Induces Inward Currents and Action Pmentioning

confidence: 94%

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

Liu¹,

Berta²,

Xu³

et al. 2012

J. Clin. Invest.

Self Cite

144

169

View full text Add to dashboard Cite

show abstract

“…A plethora of studies over the past decade have implicated Mrgprs in nociception and inflammation (27)(28)(29)(30). While the expression of most Mrgprs is restricted to sensory dorsal root ganglion neurons, human MRGPRX2 and the mouse ortholog MrgprB2, are expressed on mast cells (8,31).…”

Section: Discussionmentioning

confidence: 99%

Dual action of neurokinin-1 antagonists on Mas-related GPCRs

Azimi¹,

Reddy²,

Shade³

et al. 2016

JCI Insight

124

135

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“…Histamine activates H1 and H4 receptors (de Esch et al 2005), and the cysteine protease in cowhage activates protease-activated receptors 2 and 4 (Reddy et al 2008) or may generate products such as a hexapeptide that activates the MrgprC11 receptors (Liu et al 2011). These are G protein-coupled receptors (GPCRs) that typically signal via G q proteins to phospholipase C activation and various intracellular signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans

Nie

et al. 2012

Journal of Neurophysiology

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Ma C, Nie H, Gu Q, Sikand P, LaMotte RH. In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans. J Neurophysiol 107: 357-363, 2012. First published October 12, 2011 10.1152/jn.00801.2011.-Native cowhage spicules, and heat-inactivated spicules containing histamine or capsaicin, evoke similar sensations of itch and nociceptive sensations in humans. In ongoing studies of the peripheral neural mechanisms of chemical itch and pain in the mouse, extracellular electrophysiological recordings were obtained, in vivo, from the cell bodies of mechanosensitive nociceptive neurons in response to spicule stimuli delivered to their cutaneous receptive fields (RFs) on the distal hindlimb. A total of 43 mechanosensitive, cutaneous, nociceptive neurons with axonal conduction velocities in the C-fiber range (C-nociceptors) were classified as CM if responsive to noxious mechanical stimuli, such as pinch, or CMH if responsive to noxious mechanical and heat stimuli (51°C, 5 s). The tips of native cowhage spicules, or heat-inactivated spicules containing histamine or capsaicin, were applied to the RF. Heat-inactivated spicules containing no chemical produced only a transient response occurring during insertion. Of the 43 mechanosensitive nociceptors recorded, 20 of the 25 CMHs responded to capsaicin, and of these, 13 also responded to cowhage and/or histamine. In contrast, none of the 18 CMs responded to any of the chemical stimuli. The time course of the mean discharge rate of CMHs was similar in response to each type of spicule and generally similar, although reaching a peak earlier, to the temporal profiles of itch and nociceptive sensations evoked by the same stimuli in humans. These findings are consistent with the hypothesis that the itch and nociceptive sensations evoked by these punctuate chemical stimuli are mediated at least in part by the activity of mechanoheat-sensitive C-nociceptors. In contrast, activity in mechanosensitive C-nociceptors that do not respond to heat or to pruritic chemicals is hypothesized as contributing to pain but not to itch.

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The Distinct Roles of Two GPCRs, MrgprC11 and PAR2, in Itch and Hyperalgesia

Cited by 192 publications

References 21 publications

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice

Dual action of neurokinin-1 antagonists on Mas-related GPCRs

In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans

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