Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain. | LitMetric
Department of Neuroscience, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA Department of Protein Sciences, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA Department of Lead Discovery, Amgen, Inc., Josef-Engert-St. 11, D-93053 Regensburg, Germany Department of Inflammation, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA Department of Chemistry Research and Development, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA.
Published: April 2010
AI Article Synopsis
Article Abstract
Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha4beta2 or for alpha7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective alpha4beta2 agonist ispronicline and a novel alpha4beta2-selective potentiator did not appear to produce analgesia in either model. alpha7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective alpha7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by alpha4beta2 and only minimally by alpha7 subtypes. Taken with previous studies, the results suggest that agonism of alpha4beta2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia.
