The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α represents a new antinociceptive signaling pathway in mice

Abstract

Recently, α7 nicotinic acetylcholine receptors (nAChRs), primarily activated by binding of orthosteric agonists, represent a target for anti-inflammatory and analgesic drug development. These receptors may also be modulated by positive allosteric modulators (PAMs), ago-allosteric ligands (ago-PAMs), and α7-silent agonists. Activation of α7 nAChRs has been reported to increase the brain levels of endogenous ligands for nuclear peroxisome proliferator-activated receptors type-α (PPAR-α), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in a Ca2+-dependent manner. Here, we investigated potential crosstalk between α7 nAChR and PPAR-α, using the formalin test, a mouse model of tonic pain. Using pharmacological and genetic approaches, we found that PNU282987, a full α7 agonist, attenuated formalin-induced nociceptive behavior in α7-dependent manner. Interestingly, the selective PPAR-α antagonist GW6471 blocked the antinociceptive effects of PNU282987, but did not alter the antinociceptive responses evoked by the α7 nAChR PAM PNU120596, ago-PAM GAT107, and silent agonist NS6740. Moreover, GW6471 administered systemically or spinally, but not via the intraplantar surface of the formalin-injected paw blocked PNU282987-induced antinociception. Conversely, exogenous administration of the naturally occurring PPAR-α agonist PEA potentiated the antinociceptive effects of PNU282987. In contrast, the cannabinoid CB1 antagonist rimonabant and the CB2 antagonist SR144528 failed to reverse the antinociceptive effects of PNU282987. These findings suggest that PPAR-α plays a key role in a putative antinociceptive α7 nicotinic signaling pathway.

Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone

“…Our results suggest that endogenous signalling at PPARα, PPARβ/δ and PPARγ does not mediate or modulate formalin-evoked nociceptive behaviour. Our findings are in accordance with Donvito et al [50] who demonstrated that intraperitoneal administration of the PPARα antagonist GW6471 did not affect formalin-evoked nociceptive behaviour in mice. Previous reports have shown that systemic administration of PPARα [25,28,51] and PPARβ/δ [52] agonists attenuated acute inflammatory pain behaviour, which indicates an antinociceptive effect of PPARα and PPARβ/δ activation by exogenously administered agonists (for review, see [11]).…”

Allosterically Potentiated α7 Nicotinic Acetylcholine Receptors: Reduced Calcium Permeability and Current-Independent Control of Intracellular Calcium

“…The impact a single such burst would have on the calcium concentration of a small (25 µm) cell, if the receptor had significant calcium permeability would be enormous. The fact that PAMs and ago-PAMs have been successfully used for in vivo preclinical studies without overt cytotoxic effects (Bagdas et al, 2016;Donvito et al, 2017;Freitas et al, 2013;Munro et al, 2012) is consistent with our data that indicate PAM-potentiated a7 currents have reduced calcium permeability and therefore are not likely to produce excitotoxicity related to channel-mediated calcium influx. Another important factor that may limit any potential excitotoxic effects of a7…”

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.…”