The Antinociceptive Effects of Nicotinic Receptors α7-Positive Allosteric Modulators in Murine Acute and Tonic Pain Models

Abstract

The a7 nicotinic acetylcholine receptor (nAChR) subtype is abundantly expressed in the central nervous system and in the periphery. Recent evidence suggests that a7 nAChR subtypes, which can be activated by an endogenous cholinergic tone, comprising acetylcholine and the a7 nAChR agonist choline, play an important role in subchronic pain and inflammation. This study's objective was to test whether a7 nAChR positive allosteric modulators (PAMs) produce antinociception in in vivo mouse models of acute and persistent pain.nAChR PAMs in acute and persistent pain, we found that, although neither reduced acute thermal pain, only PNU-120596 dose-dependently attenuated paw-licking behavior in the formalin test. The long-acting effect of PNU-120596 in this test was in discordance with its pharmacokinetic profile in mice, which suggests the involvement of postreceptor signaling mechanisms. Our results with selective mitogen-activated protein kinase kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene monoethanolate (U0126) argues for an important role of extracellular signal-regulated kinase-1/2 pathways activation in PNU-120596's antinociceptive effects. The a7 antagonist MLA, administered intrathecally, reversed PNU-120596's effects, confirming PNU-120596's action, in part, through central a7 nAChRs. Importantly, tolerance to PNU-120596 was not developed after subchronic treatment of the drug. Surprisingly, PNU-120596's antinociceptive effects were blocked by NS1738. Our results indicate that type II a7 nAChR PAM PNU-120596, but not type I a7 nAChR PAM NS1738, shows significant antinociception effects in persistent 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.…”

The Minimal Pharmacophore for Silent Agonism of the α7 Nicotinic Acetylcholine Receptor

“…Some recent studies (Freitas et al, 2013) demonstrating analgetic effects of PNU-120596 suggest that this may be the case. However, the ubiquitous presence of choline in all in vivo and most in vitro experiments makes it impossible to conclude that such effects are due to the activity of the PAM alone.…”

1,3-Diphenylpropan-1-Ones as Allosteric Modulators of α7 Nach Receptors with Analgesic and Antioxidant Properties

“…For instance, PNU-120596 induced analgesic activity by its own or combined with choline in the formalin pain test, and showed anti-allodynic effects in the CCI neuropathic pain model [33][34][35]. On the other hand, it is reported that different dietary polyphenols, like chlorogenic acid (CGA), resveratrol and quercetin derivatives, have antinociceptive effects on acute, inflammatory and neuropathic pain models [36][37][38], although their mechanisms of action are not totally understood.…”