RTI uses cookies to offer you the best experience online. By clicking “accept” on this website, you opt in and you agree to the use of cookies. If you would like to know more about how RTI uses cookies and how to manage them please view our Privacy Policy here. You can “opt out” or change your mind by visiting: http://optout.aboutads.info/. Click “accept” to agree.
Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models
Freitas, K., Ghosh, S., Carroll, F. I., Lichtman, A. H., & Damaj, M. I. (2013). Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models. Neuropharmacology, 65, 156-164. https://doi.org/10.1016/j.neuropharm.2012.08.022
Agonists and positive allosteric modulators (PAMs) of alpha 7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as novel therapeutic approaches for managing cognitive deficits in schizophrenia and Alzheimer's disease. Though alpha 7 agonists were recently found to possess antinociceptive and anti-inflammatory properties in rodent models of chronic neuropathic pain and inflammation, the effects of alpha 7 nAChRs PAMs on chronic pain and inflammation remain largely unknown. The present study investigated whether PAMs, by increasing endogenous cholinergic tone, potentiate alpha 7 nAChRs function to attenuate inflammatory and chronic neuropathic pain in mice. We tested two types of PAMS, type I (NS1738) and type II (PNU-120596) in carrageenan-induced inflammatory pain and chronic constriction injury (CCI) neuropathic pain models. We found that both NS1738 and PNU-120596 significantly reduced thermal hyperalgesia, while only PNU-120596 significantly reduced edema caused by a hind paw infusion of carrageenan. Importantly, PNU-120596 reversed established thermal hyperalgesia and edema induced by carrageenan. In the CCI model, PNU-120596 had long-lasting (up to 6 h), dose-dependent anti-hyperalgesic and anti-allodynic effects after a single injection, while NS1738 was inactive. Systemic administration of the alpha 7 nAChR antagonist MLA reversed PNU-120596's effects, suggesting the involvement of central and peripheral alpha 7 nAChRs. Furthermore, PNU-120596 enhanced an ineffective dose of selective agonist PHA-543613 to produce anti-allodynic effects in the CCI model. Our results indicate that the type II alpha 7 nAChRs PAM PNU-120596, but not the type I alpha 7 nAChRs PAM NS1738, shows significant anti-edematous and anti-allodynic effects in inflammatory and CCI pain models in mice. (C) 2012 Elsevier Ltd. All rights reserved