an expanded list of authors' affiliations.....
Broad modulation of neuropathic pain states by a selective estrogen receptor beta agonist
Fabrice Piua, Cindy Cheeversc, Lene Hyldtoftb, Luis R. Gardella, Andria L. Del Tredicia, Carsten B. Andersena, Luke C. Fairbairna, Birgitte W. Lundb, Magnus Gustafssonb, Hans H. Schiffera, John E. Donelloc, Roger Olssonb, Daniel W. Gilc and Mark R. Branna
aACADIA Pharmaceuticals Inc, San Diego, CA, USA
bACADIA Pharmaceuticals AB, Malmo, Sweden
cAllergan Inc, Irvine, CA, USA
Abstract
The effects of estrogens on pain perception remain controversial. In animal models, both beneficial and detrimental effects of non-selective estrogens have been reported. ERb-131 a non-steroidal estrogen receptor beta ligand was evaluated in several pain animal models involving nerve injury or sensitization. Using functional and binding assays, ERb-131 was characterized as a potent and selective estrogen receptor beta agonist. In vivo, ERb-131 was devoid of estrogen receptor alpha activity as assessed in a rat uterotrophic assay. ERb-131 alleviated tactile hyperalgesia induced by capsaicin, and reversed tactile allodynia caused by spinal nerve ligation and various chemical insults. Moreover, ERb-131 did not influence the pain threshold of normal healthy animals. Thus, estrogen receptor beta agonism is a critical effector in attenuating a broad range of anti-nociceptive states.
and this is new....
Eur J Pharmacol. 2008 May 20. [Epub ahead of print]
The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation.
Hansen JL, Aplin M, Hansen JT, Christensen GL, Bonde MM, Schneider M, Haunsø S, Schiffer HH, Burstein ES, Weiner DM, Sheikh SP.
Laboratory for Molecular Cardiology, The Danish National Research Foundation Centre for Cardiac Arrhythmia, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Juliane Mariesvej 20, section 9302, DK-2100 Copenhagen, Denmark; Laboratory for Molecular Cardiology, Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark; ACADIA Pharmaceuticals Inc., San Diego, California, United States.
The angiotensin AT(1) receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms in recombinant expression systems, primary cells and in vivo. The in vivo work clearly demonstrates profoundly different cellular consequences of angiotensin AT(1) receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of angiotensin AT(1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1) receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT(1) receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the human angiotensin AT(1) receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes. |
