Agonists and positive allosteric modulators (PAMs) of α7
nicotinic acetylcholine receptors (nAChRs) are currently being considered as novel therapeutic approaches for managing cognitive deficits in
schizophrenia and
Alzheimer's disease. Though α7 agonists were recently found to possess antinociceptive and anti-inflammatory properties in rodent models of chronic
neuropathic pain and
inflammation, the effects of α7 nAChRs PAMs on
chronic pain and
inflammation remain largely unknown. The present study investigated whether PAMs, by increasing endogenous
cholinergic tone, potentiate α7 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 α7 nAChR antagonist MLA reversed PNU-120596's effects, suggesting the involvement of central and peripheral α7 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 α7 nAChRs PAM
PNU-120596, but not the type I α7 nAChRs PAM
NS1738, shows significant anti-edematous and anti-allodynic effects in inflammatory and CCI
pain models in mice.