title: Dissecting the functional significance of endothelin A receptors in peripheral nociceptors in vivo via conditional gene deletion.
abstract: The peptide endothelin-1 (ET1), which was originally identified as a vasoconstrictor, has emerged as a critical regulator of a number of painful conditions, including inflammatory pain and tumor-associated pain. There is considerable pharmacological evidence supporting a role for endothelin A receptors (ET(A)) in mediating ET1-induced pro-algesic functions. ET(A) receptors are expressed in small-diameter nociceptive neurons, but also found in a variety of other cell types in peripheral tissues, including immune cells, keratinocytes, endothelial cells, which have the potential to modulate nociception. To elucidate the functional contribution of ET(A) receptors expressed in sensory neurons towards the functions of the ET1 axis in pathological pain states, we undertook a conditional gene deletion approach to selectively deplete expression of ET(A) in sensory nerves, preserving expression in non-neural peripheral tissues; the expression of ET(B) remained unchanged. Behavioural and pharmacological experiments showed that only late nociceptive hypersensitivity caused by ET1 is abrogated upon a loss of ET(A) receptors on nociceptors and further suggest that ET1-induced early nociceptive hypersensitivity involves activation of ET(A) as well as ET(B) receptors in non-neural peripheral cells. Furthermore, in the context of alleviation of cancer pain and chronic inflammatory pain by ET(A) receptor antagonists, we observed in corresponding mouse models that the contribution of ET(A) receptors expressed in nociceptors is most significant. These results help understand the role of ET(A) receptors in complex biological processes and peripheral cell-cell interactions involved in inflammatory and tumor-associated pain.
authors.affiliation: Institute for Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg 69120, Germany Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stösser
authors.forename: Nitin
authors.initials: N
authors.lastname: Agarwal
authors.forename: Anke
authors.initials: A
authors.lastname: Tappe-Theodor
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002277:Carcinoma / Q000150:complications; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D008175:Lung Neoplasms / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009619:Nociceptors / Q000502:physiology*; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D010456:Peptides, Cyclic / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D062559:NAV1.8 Voltage-Gated Sodium Channel; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; C568318:Scn10a protein, mouse; D015222:Sodium Channels; D014404:Tubulin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)