Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models

Abstract

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 hrs), 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.

The antidepressant-like activity of nicotine, but not of 3-furan-2-yl- N - p -tolyl-acrylamide, is regulated by the nicotinic receptor β4 subunit

“…Additional results using type I (e.g., NS1738) and type II (e.g., PNU-120596) PAMs also indicate that α7 PAMs do not produce unspecific stimulation (Freitas et al, 2013a(Freitas et al, , 2013b. The current results indicate that co-administration of nicotine and PAM-2 also induces antidepressant-like activity.…”

Nicotinic ACh receptors as therapeutic targets in CNS disorders

“…Additionally, PNU-120596 is able to decrease formalin-induced pain by itself, and in combination with the α7 nAChR agonists choline, nicotine and PHA-543613 [183]. PNU-120596 is also able to reduce edema induced by a hind paw infusion of carrageenan in mice [184]. Another α7 nAChR PAM, NS-1738, has also been tested for its effects on pain.…”

Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection

“…Particularly, the a7 nAChR PAM PNU-120596 caused a significant reduction in mechanical hyperalgesia in rats [75] and decreased formalin-induced pain. Both, NS-1738 and PNU-120596 have demonstrated to reduce heat-induced hyperalgesia [76], and, PNU-120596 offered anti-hyperalgesic anti-allodynic effect in a chronic constriction injury model for neurophatic pain [32,76].…”