12th May 15:47
5-HT3 receptor antagonists for pain and inflammation (anxiety migraine systemic sclerosis lymphocytes irritable bowel)
Eur J Pharmacol. 2007 Mar 29;560(1):1-8. Epub 2007 Jan 30.
The neuronal 5-HT3 receptor network after 20 years of research--evolving
concepts in management of pain and inflammation.
Faerber L, Drechsler S, Ladenburger S, Gschaidmeier H, Fischer W.
Department of Pharmacology, Regensburg Medical School, Universitaetsstr.
31, 93053 Regensburg, Germany.
The 5-HT3 receptor is a pentameric ligand-gated cation channel which is
found in the central and peripheral nervous system and on extraneuronal
locations like lymphocytes, monocytes and fetal tissue. Five monomer
subtypes, the 5-HT(3A-E) subunits, have been identified which show
differences in the amino-terminal and the transmembrane region. The
functional relevance of different receptor compositions is not yet
clarified. 5-HT3 receptors are located predominantly in CNS regions that
are involved in the integration of the vomiting reflex, pain processing,
the reward system and anxiety control. The preferential localization on
nerve endings is consistent with a physiological role of 5-HT3 receptors
in the control of neurotransmitter release such as dopamine,
cholecystokinin, glutamate, acetylcholine, GABA, substance P, or
serotonin itself. 5-HT3-receptor agonists cause unpleasant effects like
nausea and anxiety, and no clinical use has been considered. In
contrast, the introduction of 5-HT3-receptor antagonists for
chemotherapy-induced vomiting was extremely successful. After
development of other gastrointestinal indications like postoperative
vomiting and diarrhea-predominant irritable bowel syndrome recent
research focuses on rheumatological indications such as fibromyalgia,
rheumatoid arthritis and tendinopathies. Positive effects have also been
observed for pain syndromes such as chronic neuropathic pain and
migraine. These effects seem to be related to substance P-mediated
inflammation and hyperalgesia. Furthermore, antiinflammatory and
immunomodulatory properties have been observed for 5-HT3-receptor
antagonists which might explain promising findings in systemic sclerosis
and other immunological conditions. For all of these innovative
indications the optimal dosing schedule is a crucial issue, since a
bell-shaped dose-response curve has been observed repeatedly for
5-HT3-receptor antagonists, particularly in CNS effects.
* Research Support, Non-U.S. Gov't