The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors

Wieskopf, Jeffrey S.; Mathur, Jayanti; Limapichat, Walrati; Post, Michael R.; Alqazzaz, Mona; Sorge, Robert E.; Martin, Loren J.; Zaykin, Dmitri V.; Smith, Shad B.; Freitas, Kelen; Austin, Jean-Sébastien; Dai, Feng; Zhang, Jie; Marcovitz, Jaclyn; Tuttle, Alexander H.; Slepian, P. Maxwell; Clarke, Sarah E. Dixon; Drenan, Ryan M.; Janes, Jeff; Sharari, Shakir Al; Segall, Samantha K.; Aasvang, Eske Kvanner; Lai, Weike; Bittner, R.; Richards, Christopher I.; Slade, Gary D.; Kehlet, Henrik; Walker, John R.; Maskos, Uwe; Changeux, Jean Pierre; Devor, Marshall; Maixner, William; Diatchenko, Luda; Belfer, Inna; Dougherty, Dennis A.; Su, Andrew I.; Lummis, Sarah C. R.; Damaj, M. Imad; Lester, Henry A.; Patapoutian, Ardem; Mogil, Jeffrey S.

doi:10.1126/scitranslmed.3009986

Cited by 72 publications

(76 citation statements)

References 81 publications

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“…That nAChRs subunits have a role on nocifensive behavior and on the antinociceptive effects of nicotine has also been previously shown (Bagdas et al, 2015; Damaj et al, 1999; Freitas et al, 2015; Saika et al, 2015; Wieskopf et al, 2015; Xanthos et al, 2015; Yalcin et al, 2011). In studies using nAChR agonists and antagonists as well as mice with nAChR subunits null mutations, researchers have shown that nAChRs containing α3, α4, α5, α6, α7, β2, and β4 subunits are involved in modulating nocifensive behaviors in response to acute noxious thermal stimuli (Damaj et al, 2007; Damaj et al, 1999; Marubio et al, 1999) and in response to inflammatory and neuropathic processes (AlSharari et al, 2012; Bagdas et al, 2015; Damaj et al, 1999; Freitas et al, 2015; Saika et al, 2015; Wieskopf et al, 2015; Xanthos et al, 2015; Yalcin et al, 2011).…”

Section: Discussionmentioning

confidence: 57%

“…In studies using nAChR agonists and antagonists as well as mice with nAChR subunits null mutations, researchers have shown that nAChRs containing α3, α4, α5, α6, α7, β2, and β4 subunits are involved in modulating nocifensive behaviors in response to acute noxious thermal stimuli (Damaj et al, 2007; Damaj et al, 1999; Marubio et al, 1999) and in response to inflammatory and neuropathic processes (AlSharari et al, 2012; Bagdas et al, 2015; Damaj et al, 1999; Freitas et al, 2015; Saika et al, 2015; Wieskopf et al, 2015; Xanthos et al, 2015; Yalcin et al, 2011). Others have also shown that mice with null mutations of α4, α5, or β2 have decreased response to the analgesic effects of nicotine, but intact response to the antinociceptive effects of morphine (Damaj et al, 2007; Marubio et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

et al. 2016

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Caretakers and clinicians alike have long recognized that individuals with autism spectrum disorder (ASD) can have altered sensory processing, which can contribute to its core symptoms. However, the pathobiology of sensory alterations in ASD is poorly understood. Here we examined nocifensive behavior in ASD mouse models, the BTBR T+Itpr3tf/J (BTBR) and the fragile-X mental retardation-1 knockout (Fmr1-KO) mice. We also examined the effects of nicotine on nocifensive behavior given that nicotine, a nicotinic cholinergic receptor (nAChR) agonist that has antinociceptive effects and was shown to improve social deficits and decrease repetitive behaviors in BTBR mice. Compared to respective controls, both BTBR and Fmr1-KO had hyporesponsiveness to noxious thermal stimuli and electrical stimulation of C-sensory fibers, normal responsiveness to electrical stimulation of Aβ- and Aδ-fiber, and hyperresponsiveness to visceral pain after acetic acid intraperitoneal injection. In BTBR, nicotine at lower doses increased, whereas at higher doses, it decreased hotplate latency compared to vehicle. In a significantly different effect pattern, in control mice, nicotine had antinociceptive effects to noxious heat only at the high dose. Interestingly, these nocifensive behavior alterations and differential responses to nicotine antinociceptive effects in BTBR mice were associated with significant downregulation of α3, α4, α5, α7, β2, β3, and β4 nAChR subunits in several cerebral regions both, during embryonic development and adulthood. Taken together, these findings further implicate nAChRs in behaviors alterations in the BTBR model and lend support to the hypothesis that nAChRs may be a target for treatment of behavior deficits and sensory dysfunction in ASD.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

et al. 2016

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“…We calculated that 51%–77% of human eGenes are also expressed in mouse DRGs. From microarray data, we found 3rd quartile gene expression above 1st quartile overall expression for 333 (77%) out of 432 matched eGenes (Figure S5a, GEO set GSE65997) (Wieskopf et al, 2015). From single-cell mouse RNA-Seq data, we found expression of 3rd quartile above zero for 376 (51%) out of 731 matched eGenes (Usoskin et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…AK092568 is not the gene suggested by the original publication, which speculated on the role of chaperonin-containing-TCP1-complex-5 gene ( CCT5 , P=1.83e-01) and/or family with sequence similarity 173, member B ( FAM173B , P=4.36e-01). Interestingly, AK092568 is situated within death-associated protein ( DAP ) gene, which is a positive mediator of programmed cell death induced by interferon-gamma, and can potentially regulate expression of DAP , which can be found in mouse DRG (GEO set GSE65997 (Wieskopf et al, 2015)), in both neuronal and non-neuronal DRG cell types (2.5 and 1.0 rpkM respectively (Usoskin et al, 2015), Figure S5c). As such, the potential role of AK092568 in pain is at least as likely as CCT5 or FAM173B .…”

Section: Resultsmentioning

confidence: 99%

Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes

et al. 2017

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SUMMARY Dorsal root ganglia (DRG) relay sensory information to the brain, giving rise to the perception of pain, disorders of which are prevalent and burdensome. Here, we mapped expression quantitative trait loci (eQTLs) in a collection of human DRGs. DRG eQTLs were enriched within untranslated regions of coding genes of low abundance, with some overlapping with other brain regions and blood cell cis-eQTLs. We confirm functionality of identified eQTLs through their significant enrichment within open chromatin and highly deleterious SNPs, particularly at the exon level, suggesting substantial contribution of eQTLs to alternative splicing regulation. We illustrate pain-related genetic association results explained by DRG eQTLs, with the strongest evidence for contribution of the human leukocyte antigen (HLA) locus, confirmed using a mouse inflammatory pain model. Finally, we show that DRG eQTLs are found among hits in numerous genome-wide association studies, suggesting that this dataset will help address pain components of non-pain disorders.

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“…α6 subunits are also expressed by a subset of retinal ganglion cells, a sparse population of neurons in the dorsal lateral geniculate nucleus of the thalamus, and are widely expressed in several layers of superior colliculus (Mackey et al, 2012). α6 subunits are also expressed in medial habenula to interpeduncular nucleus pathway (Henderson et al, 2014, Shih et al, 2014), and have recently been shown to play an important role in nociception via their expression in spinal cord (Wieskopf et al, 2015). Although the DA system is the most logical candidate to mediate nicotine-elicited locomotor activation, several of these areas also have a plausible link to the locomotor system.…”

Section: Discussionmentioning

confidence: 99%

α6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity

et al. 2015

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Acetylcholine acts through nicotinic and muscarinic acetylcholine (ACh) receptors in ventral midbrain and striatal areas to influence dopamine (DA) transmission. This cholinergic control of DA transmission is important for processes such as attention and motivated behavior, and is manipulated by nicotine in tobacco products. Identifying and characterizing the key ACh receptors involved in cholinergic control of DA transmission could lead to small molecule therapeutics for treating disorders involving attention, addiction, Parkinson’s disease, and schizophrenia. α6-containing nicotinic acetylcholine receptors (nAChRs) are highly and specifically expressed in midbrain DA neurons, making them an attractive drug target. Here, we used genetic, pharmacological, behavioral, and biophysical approaches to study this nAChR subtype. For many experiments, we used mice expressing mutant α6 nAChRs (“α6L9S” mice) that increase the sensitivity of these receptors to agonists such as ACh and nicotine. Taking advantage of a simple behavioral phenotype exhibited by α6L9S mice, we compared the ability of full versus partial α6* nAChR agonists to activate α6* nAChRs in vivo. Using local infusions of both agonists and antagonists into brain, we demonstrate that neurons and nAChRs in the midbrain are sufficient to account for this behavioral response. To complement these behavioral studies, we studied the ability of in vivo α6* nAChR activation to support plasticity changes in midbrain DA neurons that are relevant to behavioral sensitization and addiction. By coupling local infusion of drugs and brain slice patch clamp electrophysiology, we show that activating α6* nAChRs in midbrain DA areas is sufficient to enhance glutamatergic transmission in VTA DA neurons. Together, these results from in vivo studies strongly suggest that α6* nAChRs expressed by VTA DA neurons are positioned to strongly influence both DA-mediated behaviors and the induction of synaptic plasticity by nicotine.

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The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors

Cited by 72 publications

References 81 publications

Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes

α6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity

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