In vivo pharmacological interactions between a type II positive allosteric modulator of alpha7 nicotinic ACh receptors and nicotinic agonists in a murine tonic pain model

Abstract

Background and Purpose
The alpha7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that ala7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the alpha7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II alpha7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model.

Experimental Approach
We 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 alpha7 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 Results
We 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 alpha7 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 alpha7 nAChRs.

Conclusions and Implications
Our results demonstrate that type II alpha7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous alpha7 agonist choline.