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Altered anti-allodynic potency and efficacy of nicotine in Chrna6 mutant mice. (A to H) Dose-response relationships for the ability of systemic [intraperitoneal (i.p.); A and B], intracerebroventricular (i.c.v.; C and D), intrathecal (i.t.; E and F), and peripheral [intraplantar (i.pl.); G and H] nicotine to reverse already developed (and maximal) mechanical allodynia produced by SNI (day 7 after surgery; A, C, E, and G) and CFA (day 3 after injection; B, D, F, and H). Symbols (n = 4 to 8 mice per dose per genotype) represent mean ± SEM percentage of maximum possible anti-allodynia, based on the pre-SNI/CFA and post-SNI/CFA withdrawal thresholds of each mouse (see Materials and Methods). Statistical analyses are shown in table S3.
Source publication
Chronic pain is a highly prevalent and poorly managed human health problem. We used microarray-based expression genomics in 25 inbred mouse strains to identify dorsal root ganglion (DRG)-expressed genetic contributors to mechanical allodynia, a prominent symptom of chronic pain. We identified expression levels of Chrna6, which encodes the α6 subuni...
Contexts in source publication
Context 1
... = 0.01 and t 16 = 2.2, P < 0.05, respectively). There were no significant genotype × sex interactions ob- served in any data set. In an experiment performed independently, in a different laboratory, using Chrna6 KO mice and another neuropathic assay [chronic constriction injury (CCI)], the increased mechanical allodynia of KO mice was confirmed ( fig. S4A). A separate head-to-head exper- iment using CCI and CFA in Chrna6 and Chrna4 KO mice confirmed the significantly increased allodynia in Chrna6 KOs, but revealed no differences between Chrna4 KOs and their WT controls ( fig. S4, B and C). The a6 subunit appears to play a highly specific role in the modulation of mechanical allodynia ...
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... neuropathic assay [chronic constriction injury (CCI)], the increased mechanical allodynia of KO mice was confirmed ( fig. S4A). A separate head-to-head exper- iment using CCI and CFA in Chrna6 and Chrna4 KO mice confirmed the significantly increased allodynia in Chrna6 KOs, but revealed no differences between Chrna4 KOs and their WT controls ( fig. S4, B and C). The a6 subunit appears to play a highly specific role in the modulation of mechanical allodynia because Chrna6 KO mice showed statistically equivalent responses to WT mice on a battery of acute and tonic nociceptive assays ( fig. ...
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... intrathecal, and peripheral (intraplantar) (−)-nico- tine to reverse mechanical allodynia produced by either SNI or CFA in WT, KO, and L9′S mice. Although potency and efficacy varied by route of administration, nicotine was significantly and dose-dependently ef- fective against both types of allodynia in WT mice by all injection routes ( Fig. 4 and table S3). Gain-of-function L9′S mutants showed similar or significantly increased efficacy, but Chrna6 KO mice dis- played no significant nicotine-induced anti-allodynia in either assay by any route. We then performed a head-to-head comparison of supra- spinal, spinal, and peripheral nicotine-induced anti-allodynia (25 mg, ...
Context 4
... (n = 5 to 12 mice per genotype) represent mean ± SEM paw withdrawal threshold (g) on each testing day; bars represent mean ± SEM percentage of maximum possible allodynia (see Materials and Methods). *P < 0.05, **P < 0.01, ***P < 0.001 compared to other genotype. A replication of the KO data, using a different neuropathic assay, can be found in fig. S4. at any concentration. We found as well that P2X2, P2X3, or P2X2/3 currents were not affected by ACh (100 mM). In four of the six cases where we could study dose-response relations, we found only minor (less than two-fold) changes in the EC 50 (median effective concentra- tion) values, and insignificant changes in the Hill coefficient, ...
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... to von Frey fiber stimulation measured before (−14, −7 days) and after (1,4,7,14,21, and 28 days) SNI surgery. Fig. S2. Sex differences in Chrna6 DRG mRNA expression in SM mice and their correlation with sex differences in mechanical allodynia. Fig. S3. Down-regulation of Chrna6 by nerve injury and correlation with mechanical allodynia. Fig. S4. Increased ipsilateral mechanical allodynia in Chrna6 (a6 KO) but not Chrna4 null mu- tants (a4 KO). Fig. S5. No altered sensitivity of Chrna6 KO mice in a battery of acute and tonic nociceptive assays. Fig. S6. Physical contacts between P2X3 and a6b4* nAChRs revealed by FLIM. Table S1. Affymetrix gene expression data of all Chrn* ...
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Citations
... α6-containing (α6*) nAChRs are expressed throughout the peripheral and central nervous systems [14][15][16]. α6β4 nAChR is concentrated in rat dorsal medullary ganglion neurons, which are associated with chronic pain and have become an expected therapeutic target [17,18]. Overall, the distributions of α3β4 and α6β4 nAChRs overlap in some tissues, and the extra-cellular domains (ECDs) of 2 of 14 the two receptors are highly homologous. ...
α4/6-conotoxin TxID, which was identified from Conus textile, simultaneously blocks rat (r) α3β4 and rα6/α3β4 nicotinic acetylcholine receptors (nAChRs) with IC50 values of 3.6 nM and 33.9 nM, respectively. In order to identify the effects of loop2 size on the potency of TxID, alanine (Ala) insertion and truncation mutants were designed and synthesized in this study. An electrophysiological assay was used to evaluate the activity of TxID and its loop2-modified mutants. The results showed that the inhibition of 4/7-subfamily mutants [+9A]TxID, [+10A]TxID, [+14A]TxID, and all the 4/5-subfamily mutants against rα3β4 and rα6/α3β4 nAChRs decreased. Overall, ala-insertion or truncation of the 9th, 10th, and 11th amino acid results in a loss of inhibition and the truncation of loop2 has more obvious impacts on its functions. Our findings have strengthened the understanding of α-conotoxin, provided guidance for further modifications, and offered a perspective for future studies on the molecular mechanism of the interaction between α-conotoxins and nAChRs.
... Moreover, rat dorsal root ganglion (DRG) neurons express mRNAs of the α6 subunit and putatively form functional nAChRs that include the β4 subunit [74]. Furthermore, the α6 subunit protein has also been detected in a subpopulation of mouse DRG neurons positive for isolectin B4 (IB 4 ), calcitonin gene-related peptide and neurofilament-200 [75], in the thalamus region [76,77] particularly in a subpopulation of the parafascicular neurons [78] and the terminal locus of mouse catecholaminergic neurons [79]. The α6 subunit has also been immunopurified from the chick retina and rat optic nerve [67,80] and the subunit is expressed in the mouse visual system including retinal ganglion cells, visual thalamus, and superior colliculus [81]. ...
... Expression levels of CHNRA6 encoding the α6 subunit in mouse DRG neurons show a correlation with mechanical allodynia in 25 mouse strains, and compared to wild-type animals, α6 KO and α6L9'S mice Table 1 α-Conotoxins with therapeutic potential selectively targeting α3β4, α6-containing, α7, and α9α10 nAChRs. 132-595 [187][188][189][190] • Paclitaxel-loaded ImI-micelles had greater cytotoxic and apoptotic effects on cultured human MCF-7 breast cancer cells, and supressed MCFtumour growth in nude mice with enhanced efficacy [191] • Docetaxel-loaded ImI-micelles were more cytotoxic on cultured human A549 (continued on next page) demonstrate higher and lower paw withdrawal thresholds, respectively [75]. In addition, the CHNRA6 TT polymorphism in humans was linked to an increased risk of chronic pain [75]. ...
... 132-595 [187][188][189][190] • Paclitaxel-loaded ImI-micelles had greater cytotoxic and apoptotic effects on cultured human MCF-7 breast cancer cells, and supressed MCFtumour growth in nude mice with enhanced efficacy [191] • Docetaxel-loaded ImI-micelles were more cytotoxic on cultured human A549 (continued on next page) demonstrate higher and lower paw withdrawal thresholds, respectively [75]. In addition, the CHNRA6 TT polymorphism in humans was linked to an increased risk of chronic pain [75]. Analgesia was proposed to involve activation of α6-containing nAChRs and subsequently, direct contact-inhibition of P2X2/3 receptors [75,94], which themselves are implicated in pain and expressed in IB 4 -positive DRG neurons [95]. ...
The pentameric nicotinic acetylcholine receptors (nAChRs) are typically classed as muscle- or neuronal-type, however, the latter has also been reported in non-neuronal cells. Given their broad distribution, nAChRs mediate numerous physiological and pathological processes including synaptic transmission, presynaptic modulation of transmitter release, neuropathic pain, inflammation, and cancer. There are 17 different nAChR subunits and combinations of these subunits produce subtypes with diverse pharmacological properties. The expression and role of some nAChR subtypes have been extensively deciphered with the aid of knock-out models. Many nAChR subtypes expressed in heterologous systems are selectively targeted by the disulfide-rich α-conotoxins. α-Conotoxins are small peptides isolated from the venom of cone snails, and a number of them have potential pharmaceutical value.
... Additionally, a clinical study revealed a sex-treatment interaction for rs230497, with a twofold greater abstinence in the bupropion arm in males versus females by end of treatment, although not surpassing Bonferroni corrections (33). Sex heterogeneity has been observed as a critical factor to be considered with α6 nAChRs, the CHRNA6 gene and the CHRNA6 3 -UTR SNP in nicotine addiction and other neurological diseases (33,(42)(43)(44)(45). The CHRNA6 3 -UTR SNP has been associated with nicotine dependence in males (46). ...
Rationale
Large-scale human candidate gene studies have indicated that a genetic variant (rs2304297) in the alpha(α)6 nicotinic acetylcholine receptor (nAChR) subunit, encoded by the CHRNA 6 gene, may play a key role in adolescent nicotine addictive behavior. We hypothesized that the polymorphism selectively enhances nicotine + cue-primed reinstatement, but not nicotine- or cue-reinstatement in α6 GG (risk) vs. α6 CC (non-risk) allele carriers, without having baseline effects on natural rewards.
Methods
Using CRISPR-Cas9 genomic engineering, we developed a humanized rat line with the human gene variant of the CHRNA 6 3′-UTR C ¹²³ G polymorphism in Sprague-Dawley rats. Genetically modified adolescent male and female rats were food trained under a fixed-ratio (FR)1 schedule of reinforcement and progressively increased to FR5. Animals were implanted with catheters and began nicotine self-administration (15 μg/kg/infusion) at FR5. Upon reaching stable responding, reinforced behavior was extinguished by removal of drug and cues. Reinstatement testing began for cue only, nicotine only, and nicotine + cue in a Latin Square Design. Animals were returned to extinction conditions for 2 days minimum between testing.
Results
For natural food rewards, nicotine self-administration, progressive ratio, and extinction, adolescent male and female (α6 GG and α6 CC ) rats exhibited equivalent behaviors. Male α6 GG rats show enhanced nicotine + cue-primed reinstatement when compared with male α6 CC rats. This genotype effect on reinstatement was not seen in female rats.
Conclusion
Our findings support the in vivo functional role of the human CHRNA 6 3′-UTR SNP genetic variant in sex-dependently enhancing nicotine seeking behavior in adolescent rats. Overall, the findings support clinical and preclinical data highlighting a role of α6 nAChRs mediating sex heterogeneity in substance use and related phenotypes.
... We found that three genes coding subunits for nicotinic acetylcholine receptors, chrna1, chrna2b, and chrna6, are down-regulated in enteric neurons in the absence of chd8. Mutations in CHRNA1 and CHRNA6 have been implicated in fast-channel congenital myasthenic syndrome (MIM#608930) characterized by early-onset progressive muscle weakness and chronic pain (Wieskopf et al, 2015;Natera-de Benito et al, 2017). Of note, a decrease in cholinergic signaling in individuals with duplication of CHRFAM7A, that encodes a dominant negative α7-nAChR inhibitor, is associated with IBD (Baird et al, 2016;Rueda Ruzafa et al, 2021). ...
Individuals with mutations in CHD8 present with gastrointestinal complaints, yet the underlying mechanisms are understudied. Here, using a stable constitutive chd8 mutant zebrafish model, we found that the loss of chd8 leads to a reduced number of vagal neural crest cells (NCCs), enteric neural and glial progenitors, emigrating from the neural tube, and that their early migration capability was altered. At later stages, although the intestinal colonization by NCCs was complete, we found the decreased numbers of both serotonin-producing enterochromaffin cells and NCC-derived serotonergic neurons, suggesting an intestinal hyposerotonemia in the absence of chd8 . Furthermore, transcriptomic analyses revealed an altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. The tissue examination of chd8 mutants revealed a thinner intestinal epithelium accompanied by an accumulation of neutrophils and the decreased numbers of goblet cells and eosinophils. Last, single-cell sequencing of whole intestines showed a global disruption of the immune balance with a perturbed expression of inflammatory interleukins and changes in immune cell clusters. Our findings propose a causal developmental link between chd8 , NCC development, intestinal homeostasis, and autism-associated gastrointestinal complaints.
... Given that heat-response genes function to relieve stress and regulate ATPase to protect proteins from unfolding (17,18), they are important for determining the critical thermal maximum of organisms. The other set of gradually up-regulated genes found in N. parkeri, such as ADCYAP1, SSTR2 and CHRNA6, are relevant to regulation of the peripheral nervous system (the neuropeptide signaling pathway and neurotransmitter biosynthesis) (40,41,42; Supplementary Data 6). This nding is in accord with the abundant number of neurotransmitter metabolites identi ed in N. parkeri ( Fig. 1c and Supplementary Data 2). ...
Defense against increasing ultraviolet radiation (UV) exposure is essential for survival, especially in high-elevation species. Although some specific genes involved in UV response have been reported, the full view of UV-defense mechanisms remains largely unexplored. Herein, we analyzed UV responses in the highest-elevation frog, Nanorana parkeri , using integrated approaches. We show less damage and more efficient antioxidant activity in skin of this frog than those of its lower-elevation relatives after UV exposure. Our study revealed new UV-defense systems. Genomic and metabolomic analysis along with large-scale transcriptomic and microRNA profiling revealed a time-dependent coordinated defense mechanism in N. parkeri . Both gene mutations and expression shifts contribute to such UV adaptation. We found that microRNAs play important regulatory roles, especially in decreasing the expression levels of cell-cycle genes. Moreover, multiple defense genes (i.e., TYR for melanogenesis) exhibit positive selection with function-enhancing substitutions. Our work demonstrates a genetic framework for evolution of UV-defense in a natural environment.
... Previous research has reported this receptor regulating exocytosis in human adrenal chromaffin cells [11,12]. Besides, α6β4* nAChRs are highly expressed in dorsal root ganglia neurons, which are involved in pain [13][14][15]. Therefore, α6β4* nAChR has the potential to be developed as an attractive non-opioid therapeutic target for pain. ...
... α3β2 nAChRs were found in the dorsal root ganglia, which is associated with regulating pain awareness [24]. α6β4* is another type of nAChR also highly expressed by the dorsal root ganglia, which is an attractive target for treating neuropathic pain [13,15,25]. Furthermore, α6β4* nAChR is also found in the hippocampus regulating the secretion of norepinephrine, which is closely related to learning and memory [15,26]. ...
α6β4 nAChR is expressed in the peripheral and central nervous systems and is associated with pain, addiction, and movement disorders. Natural α-conotoxins (α-CTxs) can effectively block different nAChR subtypes with higher efficacy and selectivity. However, the research on α6β4 nAChR is relatively poor, partly because of the lack of available target-specific α-CTxs. In this study, we synthesized a novel α-4/7 conotoxin QuIA that was found from Conus quercinus. We investigated the efficacy of this peptide to different nAChR subtypes using a two-electrode voltage-clamp technique. Remarkably, we found α-QuIA inhibited the neuronal α3β2 and α6/α3β4 nAChR subtypes with significantly high affinity (IC50 was 55.7 nM and 90.68 nM, respectively), and did not block other nAChR subtypes even at a high concentration of 10 μM. In contrast, most α-CTxs have been determined so far to effectively block the α6/α3β4 nAChR subtype while also maintaining a similar higher efficacy against the closely related α6β2β3 and/or α3β4 subtypes, which are different from QuIA. In conclusion, α-QuIA is a novel α4/7-CTx, which has the potential to develop as an effective neuropharmacology tool to detect the function of α6β4 nAChR.
... The upregulation of Chrna6 is unexpected because its overexpression is protective against tactile allodynia associated with inflammatory injuries. 60 The downregulation of Grik1 and Ntrk1 was also unpredicted because Grik1 deletion reduces inflammatory pain 27 and NGF acts as a mediator of inflammatory pain. 2,12,54 However, the deregulation of Trpm8 may play a role in the observed hypersensitivity of icKO mice. ...
Prdm12 is a conserved epigenetic transcriptional regulator that displays restricted expression in nociceptors of the developing peripheral nervous system. In mice, Prdm12 is required for the development of the entire nociceptive lineage. In humans, PRDM12 mutations cause congenital insensitivity to pain, likely because of the loss of nociceptors. Prdm12 expression is maintained in mature nociceptors suggesting a yet-to-be explored functional role in adults. Using Prdm12 inducible conditional knockout mouse models, we report that in adult nociceptors Prdm12 is no longer required for cell survival but continues to play a role in the transcriptional control of a network of genes, many of them encoding ion channels and receptors. We found that disruption of Prdm12 alters the excitability of dorsal root ganglion neurons in culture. Phenotypically, we observed that mice lacking Prdm12 exhibit normal responses to thermal and mechanical nociceptive stimuli but a reduced response to capsaicin and hypersensitivity to formalin-induced inflammatory pain. Together, our data indicate that Prdm12 regulates pain-related behavior in a complex way by modulating gene expression in adult nociceptors and controlling their excitability. The results encourage further studies to assess the potential of Prdm12 as a target for analgesic development.
... We found that three genes coding subunits for nicotinic acetylcholine receptors, chrna1, chrna2b and chrna6, are downregulated in enteric neurons in absence of chd8. Mutations in CHRNA1, and CHRNA6 have been implicated in fast-channel congenital myasthenic syndrome (MIM#608930) characterized by early-onset progressive muscle weakness, and chronic pain 53,54 . Of . ...
Gastrointestinal complaints in autism are common and impact the quality of life of affected individuals, yet the underlying mechanisms are understudied. We have found that individuals with mutations in CHD8 present with gastrointestinal disturbances. We have shown that loss of chd8, the sole ortholog of CHD8 in zebrafish, leads to reduced number of enteric neurons and decreased intestinal mobility. However, it remains unclear how chd8 acts during the development of the enteric nervous system and whether CHD8-associated gastrointestinal complaints are solely due to impaired neuronal function in the intestine. Here, utilizing a stable chd8 mutant zebrafish model, we found that the loss of chd8 leads to reduced number of vagal neural crest cells (NCCs), enteric neural progenitors, emigrating from the neural tube and their early migration capability was altered. At later stages, although the intestinal colonization by the NCCs was complete, we found decreased numbers of both NCC-derived serotonergic neurons and serotonin-producing enterochromaffin cells, suggesting an intestinal hyposerotonemia in absence of chd8. Moreover, transcriptomic analyses revealed altered expression of key receptors and enzymes in serotonin and acetylcholine signaling pathways. Next, tissue examination of chd8 mutants revealed thinner intestinal epithelium accompanied by accumulation of neutrophils and decreased numbers of goblet cells and eosinophils. Last, single-cell sequencing of whole mid- and posterior intestines showed a global disruption of the immune balance with perturbed expression of inflammatory interleukins and changes in immune cell clusters. Our findings propose a causal developmental link between chd8, serotonergic pathway, intestinal homeostasis, and autism-associated gastrointestinal complaints.
... Another pharmacologically important a6containing receptor is a diheteromer containing the b4 subunit that occurs in the sensory neurons of dorsal root ganglia (58). BARP and IRE1a are needed to reconstitute a6b4 receptors, which are curiously not affected by NACHO (59). ...
... Unfortunately, ABT-594 had unacceptable adverse effects (88), and its therapeutic nAChR target was unknown. Subsequently, a genomics screen of dorsal root ganglion tissue from outbred mouse strains identified that a6 nAChR subunit mRNA levels inversely correlate with pain responses in a spared nerve injury model (58). Accordingly, analgesic effects of nicotine after both inflammatory and neuropathic injuries are absent in a6 KO mice. ...
... Accordingly, analgesic effects of nicotine after both inflammatory and neuropathic injuries are absent in a6 KO mice. Furthermore, human postoperative pain and temporomandibular disorder are affected by a polymorphism in the CHRNA6 (a6) promoter (58). ...
Accessory proteins and nicotinic receptors
Acetylcholine was the first neurotransmitter identified, and nicotinic acetylcholine receptors (nAChRs) were the first neurotransmitter receptors isolated. Recent studies have identified a multitude of molecules and mechanisms that regulate nAChRs in different tissues. In a review, Matta et al . discuss these discoveries and their implications for the cell biology and medicinal pharmacology of nACHRs. Many accessory factors promote the assembly and function of diverse nAChRs. Some factors are small molecules, some are proteins, some control receptor biogenesis, and some regulate channel gating. These protein chaperones and auxiliary subunits elucidate the pharmacological and physiological processes regulated by acetylcholine. —PRS
... On the other side, the reduced expression of β2 could contribute to the allodoynic phenotype of cuff mice, as we have previously shown that β2-knock out mice have a decreased mechanical threshold (Yalcin et al., 2011b). This is reminiscent of the negative correlation observed between the mRNA level of the α6 nAChR subunit (variable across inbred mice strains) and the amount of allodynia the mice develop after spare-nerve injury (Wieskopf et al., 2015). In contrast with our results, a study in rats using a peripheral axotomy model found an increase in the mRNA levels for α5 and β2 in the axotomy dorsal horn vs. control (Yang et al., 2004). ...
Endogenous acetylcholine (ACh) is an important modulator of nociceptive sensory processing in the spinal cord. An increased level of spinal ACh induces analgesia both in humans and rodents while interfering with cholinergic signaling is allodynic, demonstrating that a basal tone of spinal ACh modulates nociceptive responses in naïve animals. The plasticity undergone by this cholinergic system in chronic pain situation is unknown, and the mere presence of this tone in neuropathic animals is controversial. We have addressed these issues in mice through behavioral experiments, histology, electrophysiology and molecular biology, in the cuff model of peripheral neuropathy. Our behavior experiments demonstrate the persistence, and even increased impact of the analgesic cholinergic tone acting through nicotinic receptors in cuff animals. The neuropathy does not affect the number or membrane properties of dorsal horn cholinergic neurons, nor specifically the frequency of their synaptic inputs. The alterations thus appear to be in the neurons receiving the cholinergic signaling, which is confirmed by the fact that subthreshold doses of acetylcholinesterase (AChE) inhibitors in sham animals become anti-allodynic in cuff mice and by the altered expression of the β2 nicotinic receptor subunit. Our results demonstrate that endogenous cholinergic signaling can be manipulated to relieve mechanical allodynia in animal models of peripheral neuropathy. Until now, AChE inhibitors have mainly been used in the clinics in situations of acute pain (parturition, post-operative). The fact that lower doses (thus with fewer side effects) could be efficient in chronic pain conditions opens new avenues for the treatment of neuropathic pain.
Significance statement
Chronic pain continues to be the most common cause of disability that impairs the quality of life, accruing enormous and escalating socio-economic costs. A better understanding of the plasticity of spinal neuronal networks, crucially involved in nociceptive processing, could help designing new therapeutic avenues. We here demonstrate that chronic pain modifies the spinal nociceptive network in such a way that it becomes more sensitive to cholinergic modulations. The spinal cholinergic system is responsible for an analgesic tone that can be exacerbated by acetylcholinesterase inhibitors, a property used in the clinic to relief acute pain (child birth, post-op). Our results suggest that lower doses of acetylcholinesterases, with even fewer side effects, could be efficient to relieve chronic pain.
