Journal club 2012-09-20

JCI45414    JCI45414sd

J Clin Invest. 2012 Jun 1;122(6):2195-207. doi: 10.1172/JCI45414. Epub 2012 May 8.

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

Liu T, Berta T, Xu ZZ, Park CK, Zhang L, Lü N, Liu Q, Liu Y, Gao YJ, Liu YC, Ma
Q, Dong X, Ji RR.

Sensory Plasticity Laboratory, Pain Research Center, Department of
Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

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.

PMCID: PMC3366391
PMID: 22565312 [PubMed – indexed for MEDLINE]

Journal club 2012-09-13

ncb2529

ncb2529-s1

Direct inhibition of the cold-activated TRPM8 ion channel by Gα(q).

Source

Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.

Abstract

Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit Gα(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of Gα(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a Gα(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated Gα(q) protein, but not Gβγ, potently inhibits TRPM8 in excised patches. We conclude that Gα(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.

PMID:

 22750945

[PubMed – in process] PMCID:

PMC3428855 [Available on 2013/2/1]

Journal club 2012-09-06

11330.full

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms

  1. Noritaka Imamachia,1,
  2. Goon Ho Parkb,
  3. Hyosang Leec,
  4. David J. Andersonc,
  5. Melvin I. Simonc,2,
  6. Allan I. Basbaumaand
  7. Sang-Kyou Hanb,3

+ Author Affiliations


  1. aDepartment of Anatomy, University of California, San Francisco, CA 94143;

  2. bDepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92093; and

  3. cDivision of Biology, California Institute of Technology, Pasadena, CA 91125
  1. Contributed by Melvin I. Simon, May 20, 2009 (received for review May 4, 2009)

Abstract

The mechanisms that generate itch are poorly understood at both the molecular and cellular levels despite its clinical importance. To explore the peripheral neuronal mechanisms underlying itch, we assessed the behavioral responses (scratching) produced by s.c. injection of various pruritogens in PLCβ3- or TRPV1-deficient mice. We provide evidence that at least 3 different molecular pathways contribute to the transduction of itch responses to different pruritogens: 1) histamine requires the function of both PLCβ3 and the TRPV1 channel; 2) serotonin, or a selective agonist, α-methyl-serotonin (α-Me-5-HT), requires the presence of PLCβ3 but not TRPV1, and 3) endothelin-1 (ET-1) does not require either PLCβ3 or TRPV1. To determine whether the activity of these molecules is represented in a particular subpopulation of sensory neurons, we examined the behavioral consequences of selectively eliminating 2 nonoverlapping subsets of nociceptors. The genetic ablation of MrgprD+ neurons that represent ≈90% of cutaneous nonpeptidergic neurons did not affect the scratching responses to a number of pruritogens. In contrast, chemical ablation of the central branch of TRPV1+ nociceptors led to a significant behavioral deficit for pruritogens, including α-Me-5-HT and ET-1, that is, the TRPV1-expressing nociceptor was required, whether or not TRPV1 itself was essential. Thus, TRPV1 neurons are equipped with multiple signaling mechanisms that respond to different pruritogens. Some of these require TRPV1 function; others use alternate signal transduction pathways.

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