New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on α7 nAChRs

Abstract

BackgroundNicotine and nicotinic acetylcholine receptors (nAChRs) have been explored for the past three decades as targets for pain control. The aim of this review is to introduce readers particularly to α7 nAChRs in a perspective of pain and its modulation.MethodsDevelopments for α7 nAChR modulators and recent animal studies related to pain are reviewed.ResultsAccumulating evidences suggest that selective ligands for α7 nAChRs hold promise in the treatment of chronic pain conditions as they lack many of side effects associated with other nicotinic receptor types.ConclusionThis review provides the reader recent insights on α7 nAChRs from structure and function to the latest findings on the pharmacology and therapeutic targeting of these receptors for the treatment of pain and inflammation.

NS6740, an α7 nicotinic acetylcholine receptor silent agonist, disrupts hippocampal synaptic plasticity

“…NS6740 then appears as a key to altering the modality of α7-mediated signaling. The activity of GTS-21, NS6740, other α7 silent agonists, and allosteric modulators [1,15,17,32,34,56] in models of inflammatory disease and neuropathic pain appear to be independent of ion channel activation and, rather, depend on activation and modulation of intracellular signal transduction pathways [4,14,26,49,54]. In the case of the α7-mediated control of CAP, the cellular mediators of activity are themselves not even competent for generating nAChR channel currents, and so we must consider the complete receptor protein [50], multiple conformational states, and the complete receptor interactome [29,42] as mediators of the activity.…”

“…Drugs targeting α7 have also been identified as effective at reducing inflammation and asso-ciated pain [43,47]. While α7 channel activation appears to be im-portant for cognitive effects [8], it does not seem to be important for the modulation of inflammation [4,26,49,54]. In fact, NS6740, which is a compound with good activity in models of inflammation and pain, is an extremely weak partial agonist of α7 and is otherwise a strong de-sensitizer of α7 channel activity [32].…”

Nicotinic acetylcholine receptors in neuropathic and inflammatory pain

“…For further review of the involvement of α7 nAChRs in pain and inflammation and therapeutic strategies for targeting them see Bagdas et al . .…”

“…A summary is presented in Table 2 of the ligands discussed above and the effects of a7 nAChR stimulation on the target cell population. For further review of the involvement of a7 nAChRs in pain and inflammation and therapeutic strategies for targeting them see Bagdas et al [122]. a9 nAChRs in neuropathic pain and inflammation…”

Effect of nicotine and alpha‐7 nicotinic modulators on visceral pain‐induced conditioned place aversion in mice

“…However, several recent developments have potentially opened new windows of opportunity in the use of nicotinic agents for analgesia. Accumulating evidences suggest that agonists and modulators for α7 nAChRs hold a lot of promise in the treatment of pain conditions (Bagdas et al., ). Therefore, in this study, we evaluated the pharmacological modulation of AA stimulus‐induced stretching and CPA in mice by α7 nAChRs ligands and compared it to that of nicotine, a prototypical nicotinic agonist.…”