The endogenous peptide endothelin-1 (ET-1) is essential for pain and the sensitization of pain fibers to non-noxious stimuli after nerve injury, incision, inflammation and in cancer. In this proposal we seek to understand the relationship between the elevation of ET-1 in skin after injury and inflammation and the ensuing pain. Recent work suggests that ET-1 causes elevated pain in the periphery by acting on tissues that surround nerve endings, rather than directly on nerves;ET-1 and its cognate, GPC receptors ETA and ETB are elevated in conditions of hyperalgesia and allodynia. Antagonists of the ET receptors are able to prevent or reverse these pains, testifying to an important role for endogenous ET-1 in driving chronic pain states. Current evidence indicates that ET-1's actions during cutaneous injury/inflammation is closely linked to three other molecules/ receptors;TRPV1 (the receptor for hot peppers that is also activated by heat and by a H+), glutamate, and CGRP. TRPV1's participation in cutaneous pain from ET-1 or CFA injection into the rat's paw is evident within a very short time and immunocytochemical staining of TRPV1 in cutaneous nerve fibers increases 5-10-fold. In ~30 min after ET-1 or CFA injection, glutamate and CGRP contribute to ET-1's pain sensitizing effects;these substances are also released by cultured sensory neurons in a way that is potentiated by ET-1. This proposal contains 4 Specific Aims to address the processes underlying these changes: 1. To determine the mechanism for the rapid increase in TRPV1 in epidermal nociceptors following injection of ET-1 and local inflammation. 2. To investigate the temporal relationship between the rapid changes in ETA receptor distribution in skin (after inflammation and ET- 1 delivery) and the resulting desensitization of responses to local ET-1. 3. To determine if the ET receptors in skin cells are able to modulate keratinocye TRPV1, and other TRP channels (TRPV3, TRPV4). 4. To evaluate the role of ET-1-induced release of cutaneous glutamate, CGRP and ATP in ET-1- induced algesia and allodynia. Experiments will integrate the results from behavioral, immunocytochemical, biochemical and cell physiological techniques, for determining the importance of different pathways and substances for ET-1-induced pain, for quantitating ET-1-induced changes in TRPV receptors and ET receptors in skin, for establishing the ability of ET-Rs in keratinocytes to modulate TRPV receptors in those cells, and for examining ET-1's ability to stimulate release of pain-inducing substances from the skin.

Public Health Relevance

The results of this research will lead to a better understanding of the role of endothelin and its receptors in elevated pain from nerve injury, from incision (trauma) and from cancer, situations where it is known to contribute substantially. This understanding will provide a basis for designing new drugs and new interventional procedures to reduce or abolish such pain, and so to lessen suffering and improve the quality of life for millions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080153-13
Application #
8466288
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Woodhouse, Elizabeth
Project Start
1999-07-16
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2013
Total Cost
$394,182
Indirect Cost
$173,352
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Barr, Travis P; Hrnjic, Alen; Khodorova, Alla et al. (2014) Sensitization of cutaneous neuronal purinergic receptors contributes to endothelin-1-induced mechanical hypersensitivity. Pain 155:1091-101
Barr, Travis P; Albrecht, Phillip J; Hou, Quanzhi et al. (2013) Air-stimulated ATP release from keratinocytes occurs through connexin hemichannels. PLoS One 8:e56744
Barreveld, Antje; Witte, Jurgen; Chahal, Harkirat et al. (2013) Preventive analgesia by local anesthetics: the reduction of postoperative pain by peripheral nerve blocks and intravenous drugs. Anesth Analg 116:1141-61
Barr, Travis P; Kam, Sarah; Khodorova, Alla et al. (2011) New perspectives on the endothelin axis in pain. Pharmacol Res 63:532-40
Ji, Ru-Rong; Xu, Zhen-Zhong; Strichartz, Gary et al. (2011) Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci 34:599-609
Huang, Liang; Gao, Yong-Jing; Wang, Jeffrey et al. (2011) Shifts in cell-type expression accompany a diminishing role of spinal p38-mapkinase activation over time during prolonged postoperative pain. Anesthesiology 115:1281-90
Khodorova, Alla; Strichartz, Gary R (2010) Remarkably long-lasting tachyphylaxis of pain responses to ET-1: evidence against central nervous system involvement. Can J Physiol Pharmacol 88:668-75
Khodorova, A; Strichartz, G R (2010) Contralateral paw sensitization following injection of endothelin-1: effects of local anesthetics differentiate peripheral and central processes. Neuroscience 165:553-60
Khodorova, Alla; Montmayeur, Jean-Pierre; Strichartz, Gary (2009) Endothelin receptors and pain. J Pain 10:4-28
Feng, Bihua; Strichartz, Gary (2009) Endothelin-1 raises excitability and reduces potassium currents in sensory neurons. Brain Res Bull 79:345-50

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