Augmenting the antinociceptive effects of nicotinic acetylcholine receptor activity through lynx1 modulation

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) of the cholinergic system have been linked to antinociception, and therefore could be an alternative target for pain alleviation. nAChR activity has been shown to be regulated by the nicotinic modulator, lynx1, which forms stable complexes with nAChRs and has a negative allosteric action on their function. The objective in this study was to investigate the contribution of lynx1 to nicotine-mediated antinociception. Lynx1 contribution was investigated by mRNA expression analysis and electrophysiological responses to nicotine in the dorsal raphe nucleus (DRN), a part of the pain signaling pathway. In vivo antinociception was investigated in a test of nociception, the hot-plate analgesia assay with behavioral pharmacology. Lynx1/α4β2 nAChR interactions were investigated using molecular dynamics computational modeling. Nicotine evoked responses in serotonergic and GABAergic neurons in the DRN are augmented in slices lacking lynx1 (lynx1KO). The antinociceptive effect of nicotine and epibatidine is enhanced in lynx1KO mice and blocked by mecamylamine and DHβE. Computer simulations predict preferential binding affinity of lynx1 to the α:α interface that exists in the stoichiometry of the low sensitivity (α4)3(β2)2 nAChRs. Taken together, these data point to a role of lynx1 in mediating pain signaling in the DRN through preferential affinity to the low sensitivity α4β2 nAChRs. This study suggests that lynx1 is a possible alternative avenue for nociceptive modulation outside of opioid-based strategies.

Lynx Prototoxins: Roles of Endogenous Mammalian Neurotoxin-Like Proteins in Modulating Nicotinic Acetylcholine Receptor Function to Influence Complex Biological Processes

“…Computational models of lynx1 interaction with nicotinic receptor subunits. (A) Co-model of ws-lynx1 and α4: α4 nAChR interface (Nissen et al, 2018). (B) Co-model of ws-lynx1 and α7 nAChRs (Lyukmanova et al, 2011).…”

“…Contextual memory (assessed using the Morris Water Maze, passive avoidance conditioning, and contextual fear conditioning) does not significantly differ between wild-type and lynx1KO mice, suggesting a specific role of lynx1 in associative learning. To further investigate phenotypic specificity, lynx1KO mice were tested for pain sensitivity (Nissen et al, 2018). Since the fear conditioning paradigm involves shock/tone pairing, this would serve as an important control test for the specificity of the learning phenotype.…”

“…Since the fear conditioning paradigm involves shock/tone pairing, this would serve as an important control test for the specificity of the learning phenotype. In one test of nociceptive signaling, the hot-plate test, lynx1KO mice exhibited no significant differences in performance when compared to their wild-type counterparts (Nissen et al, 2018). Indeed, nicotine administration reduced nociceptive behavior in lynx1KO mice (Nissen et al, 2018), suggesting a possible link between lynx1 and analgesia.…”

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence

“…Results suggest that lynx proteins can modulate nAChR function in the brain with important consequences for cholinergic-dependent synaptic plasticity (reviewed in Miwa et al 2011;Miwa and Walz 2012;Thomsen and Mikkelsen 2012). Recently, Nissen and colleagues reported that the antinociceptive effect of nicotine and epibatidine in acute thermal pain tests is enhanced in Lynx1 knockout mice (Nissen et al 2018). Further, computer simulations predict preferential binding affinity of Lynx1 to the α:α interface that exists in the stoichiometry of the low sensitivity (α4)3(β2)2 nAChRs.…”

Lynx1 modulates the activity of nAChRs to slow NMJ and muscle fiber degeneration during aging

“…However it has also been proposed to promote the translocation of nAChR pentamers with lower sensitivity to ACh ( 23 ) via preferentially binding of nAChR subunit interfaces in the endoplasmic reticulum ( 24 ). In the brain, Lynx1 regulation of synaptic plasticity ( 25 – 27 ) has been demonstrated to impact motor learning ( 28 ), nicotine addiction ( 29 ), nociception ( 30 ), neuronal survival ( 31 ), and pathologies caused by aging ( 32 ) and Alzheimer’s disease ( 33 ). Thus, Lynx1 is a promising candidate for modulating nAChRs at NMJs during development, adulthood, and under stressed conditions such as aging and in Amyotrophic Lateral Sclerosis (ALS).…”