In vivo pharmacological interactions between a type II positive allosteric modulator of α7 nicotinic ACh receptors and nicotinic agonists in a murine tonic pain model

Abstract

BACKGROUND AND PURPOSEThe a7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that a7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the a7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II a7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model. EXPERIMENTAL APPROACHWe assessed the effects of PNU-120596 and choline and the nature of their interactions in the formalin test using an isobolographic analysis. In addition, we evaluated the interaction of PNU-120596 with PHA-54613, an exogenous selective a7 nAChR agonist, in the formalin test. Finally, we assessed the interaction between PNU-120596 and nicotine using acute thermal pain, locomotor activity, body temperature and convulsing activity tests in mice. KEY RESULTSWe found that PNU-120596 dose-dependently attenuated nociceptive behaviour in the formalin test after systemic administration in mice. In addition, mixtures of PNU-120596 and choline synergistically reduced formalin-induced pain. PNU-120596 enhanced the effects of nicotine and a7 agonist PHA-543613 in the same test. In contrast, PNU-120596 failed to enhance nicotine-induced convulsions, hypomotility and antinociception in acute pain models. Surprisingly, it enhanced nicotine-induced hypothermia via activation of a7 nAChRs. CONCLUSIONS AND IMPLICATIONSOur results demonstrate that type II a7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous a7 agonist choline. Abbreviations%MPE, percent maximum possible effect; i.pl

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

“…The decreased locomotor activity could be related to the microdialysis results showing that PAM-2 potentiates nicotine-induced neurotransmitter (i.e., glutamate, dopamine, and serotonin) levels in the rat striatum (Arias, 2013), a brain area involved in the coordination of body movements. On the contrary, PNU-120596 (type II PAM) did not change the observed nicotine-induced locomotor activity in mice (Freitas et al, 2013c), although these experiments were performed with a higher dose of nicotine (0.5 mg/kg) than that in our experiments (0.2 mg/kg).…”

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.…”

Nicotinic ACh receptors as therapeutic targets in CNS disorders

“…For instance the α7 nAChR PAM PNU-120596 caused a significant reduction in mechanical hyperalgesia in rats [182]. 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].…”