Mus musculus
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ABSTRACT:
PROVIDER: PRJNA260894 | ENA |
REPOSITORIES: ENA
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Project description:The molecular basis of analgesia in congenital insensitivity to pain associated with loss of Nav1.7 function
2015-08-06 | E-GEOD-61373 | ExpressionAtlas
Project description:Loss of function mutations in the SCN9a gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain (CIP) and anosmia in otherwise normal humans and mice, suggesting that this channel may be a good analgesic drug target. Surprisingly, potent selective antagonists of Nav1.7 are weak analgesics. We therefore investigated whether Nav1.7 , as well as contributing to electrical signalling may have an additional function. Here we report that Nav1.7 deletion has profound effects on the sensory neuron transcriptome, leading to dysregulation of a number of transcription factors as well as upregulation of enkephalin precursor PENK mRNA and down regulation of CEACAM10 mRNA, a protein involved in noxious thermosensation. PENK mRNA is transcriptionally upregulated in Nav1.7 null mutant female sensory neurons, resulting in increased enkephalin expression in the dorsal horn of the spinal cord. PENK expression is down-regulated by addition of the sodium ionophore monensin, suggesting that sodium may play a role as a second messenger. Application of the opioid antagonist naloxone strongly enhances noxious peripheral input into the spinal cord, and dramatically reduces analgesia in both male and female Nav1.7 null mutant mice, as well as in human Nav1.7 null mutants. These data show that loss of Nav1.7 expression increases opioid drive over the lifetime of mice and humans. They further suggest that Nav1.7 channel blockers alone may not replicate the phenotype of null mutant humans and mice, but should be potentiated with exogenous opioids. RNA was extracted from Dorsal Root Ganglia tissue from Nav1.7 Knock-Out, Nav1.8 KO and Nav1.9 KO mice (n = 3) and hybridised on Affymetrix Mouse Genome 430 2.0 Array (GPL1261)
2014-09-13 | E-GEOD-61373 | biostudies-arrayexpress
Project description:Current treatments for chronic pain rely largely on opioids despite their significant side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in NaV1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between NaV subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of NaV1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Towards this end, we first optimized the efficiency of NaV1.7 repression in vitro in Neuro2A cells, and then by the lumbar intrathecal route delivered both epigenome-engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain and BzATP-induced pain. Our results demonstrate: i) effective repression of NaV1.7 in lumbar dorsal root ganglia; ii) reduced thermal hyperalgesia in the inflammatory state; iii) decreased tactile allodynia in the neuropathic state; and iv) no changes in normal motor function. We anticipate this genomically scarless and non-addictive pain prevention and amelioration approach enabling Long-lasting Analgesia via Targeted in vivo Epigenetic Repression of NaV1.7, a methodology we dub pain LATER, will have significant therapeutic potential in management of persistent pain states.
2022-01-01 | GSE159818 | GEO
Project description:Loss of function mutations in the SCN9a gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain (CIP) and anosmia in otherwise normal humans and mice, suggesting that this channel may be a good analgesic drug target. Surprisingly, potent selective antagonists of Nav1.7 are weak analgesics. We therefore investigated whether Nav1.7 , as well as contributing to electrical signalling may have an additional function. Here we report that Nav1.7 deletion has profound effects on the sensory neuron transcriptome, leading to dysregulation of a number of transcription factors as well as upregulation of enkephalin precursor PENK mRNA and down regulation of CEACAM10 mRNA, a protein involved in noxious thermosensation. PENK mRNA is transcriptionally upregulated in Nav1.7 null mutant female sensory neurons, resulting in increased enkephalin expression in the dorsal horn of the spinal cord. PENK expression is down-regulated by addition of the sodium ionophore monensin, suggesting that sodium may play a role as a second messenger. Application of the opioid antagonist naloxone strongly enhances noxious peripheral input into the spinal cord, and dramatically reduces analgesia in both male and female Nav1.7 null mutant mice, as well as in human Nav1.7 null mutants. These data show that loss of Nav1.7 expression increases opioid drive over the lifetime of mice and humans. They further suggest that Nav1.7 channel blockers alone may not replicate the phenotype of null mutant humans and mice, but should be potentiated with exogenous opioids.
2014-09-13 | GSE61373 | GEO
Project description:Mice and humans who have lost the expression of functional sodium channel Nav1.7 are pain-free, but otherwise normal. This is the result of a loss of neurotransmitter release such as glutamate and Substance P from primary sensory neurons. The sensory neurons are otherwise normal apart from loss of neurotransmitter release. Adult gene deletion results in a loss of neuronal excitability with some analgesia that is not linked to opioid activity. Drugs that block Nav1.7 have lethal effects through action on the autonomic nervous system and the heart. But the embryonic null humans and mice are fine. Therefore there must be compensation for the embryonic loss of Nav1.7. This experiment compares the protein components of wild type normal mice and Nav1.7 embryonic deletion mice in order to identify compensatory mechanisms.
2024-10-17 | PXD052513 | Pride
Project description:The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. As well as action potential propagation, NaV1.7 regulates neurotransmitter release, integrates depolarizing inputs over long periods and regulates transcription. In order to better understand these functions, we generated an epitope-tagged NaV1.7 mouse that showed normal NaV1.7 channel activity and normal pain behavior. Analysis of NaV1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 NaV1.7 associated proteins including known and novel interactors such as sodium channel β3 subunit (Scn3b) and collapsin response mediator protein (Crmp2). Selected NaV1.7 protein interactors, such as Crmp2, membrane-trafficking protein synapototagmin-2 (Syt2), G protein-regulated inducer of neurite outgrowth 1 (Gprin1), L-type amino acid transporter 1 (Lat1) and transmembrane P24 trafficking protein 10 (Tmed10) were validated using co-immunoprecipitation and functional assays. The information provided with this physiologically normal epitope-tagged mouse should provide useful insights into the downstream mechanisms associated with NaV1.7 channel function.
2018-01-15 | PXD005155 | Pride
Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.
2024-09-12 | GSE267265 | GEO
Project description:For over a millennium, mind-body interactions have fascinated scientists and doctors for their abilities to shape human perceptions of the external world 1,2. Placebo effects are striking demonstrations of mind-body interactions in which, in the absence of any treatment, a positive expectation of pain relief can reduce or even abolish the experience of pain 3–6. However, despite widespread recognition of the strength of placebo effects and their impact on everyday human experience and clinical trials for new analgesics, the neural circuit basis of the placebo effect has remained a mystery. Here, we show that analgesia from the expectation of pain relief is mediated by a distinct population of rostral anterior cingulate cortex (rACC) neurons that project to the pontine nuclei (rACC→Pn), a pair of brainstem pre-cerebellar nuclei with no established function in pain processing. To do this, we created a behavioral assay that models placebo analgesia by conditioning mice to expect pain relief when moving from a chamber with a heated floor to a second chamber. In this assay, an expectation of pain relief induces an analgesic effect that, like placebo analgesia in humans, is mediated by endogenous opioids. Calcium imaging of neural activity in freely moving mice and electrophysiological studies in cingulate cortical brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an unusual abundance of opioid receptors in these cells, further suggesting a role in pain modulation. Selective inhibition of either the rACC→Pn pathway or of opioid-receptor-expressing Pn neurons disrupted placebo analgesia and decreased pain thresholds. Finally, a subset of cerebellar Purkinje cells exhibits activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. Altogether, these findings elucidate longstanding mysteries surrounding the placebo effect by identifying a specific neural pathway that mediates expectation-based pain relief. This discovery opens the possibility of targeting this novel pathway with drugs or neurostimulation methods to treat pain. More broadly, our studies provide a framework for investigating the neural circuit basis of other mind-body interactions beyond those involving pain, and point to prefrontocortical-cerebellar communication as a potential basis for such effects.
2024-09-12 | GSE267264 | GEO
Project description:Voltage-gated sodium channels (Navs) 1.7, 1.8, and 1.9 are predominately expressed in peripheral sensory neurons and are critical for action potential propagation in nociceptors. Unexpectedly, we found that expression of SCN9A, SCN10A, SCN11A, and SCN2A, the alpha subunit of Nav1.7, Nav1.8, Nav1.9 and Nav1.2, respectively, are up-regulated in spinal dorsal horn (SDH) neurons of miR-96 knockout mice. These mice also have de-repression of CACNA2d1/2 in DRG and display heat and mechanical allodynia that could be attenuated by intrathecal or intraperitoneal injection of Nav1.7 or Nav1.8 inhibitors or Gabapentin. Moreover, Gad2::CreERT2 conditional miR-96 knockout mice phenocopied global knockout mice, implicating inhibitory neurons; nerve injury induced significant loss of miR-96 in SDH GABAergic and Glutamatergic neurons in mice which negative correlated to up-regulation of Nav1.7, Nav1.8, Nav1.9 and Scn2a, this dis-regulation of miR-96 and Navs in SDH neurons contributed to neuropathic pain which can be alleviated by intrathecal injection of Nav1.7 or Nav1.8 blockers. In conclusion, miR-96 is required to avoid allodynia through limiting the expression of VGCCs and Navs in DRG and Navs in SDH in naïve and nerve injury induced neuropathic pain mice. Our findings suggest that central nervous system penetrating Nav1.7 and Nav1.8 inhibitors may be efficacious for pain relief.
2021-07-06 | GSE144832 | GEO
Project description:Prdm12 is a key transcription factor in nociceptor neurogenesis. Mutations of Prdm12 cause Congenital Insensitivity to Pain (CIP) due to failure of nociceptor development. However, precisely how deletion of Prdm12 during development or adulthood affects nociception is unknown. Here, we employ tissue- and temporal-specific knockout mouse models to test the function of Prdm12 during development and in adulthood. We find that constitutive loss of Prdm12 causes deficiencies in proliferation during sensory neurogenesis. We also demonstrate that conditional knockout from dorsal root ganglia (DRGs) during embryogenesis causes defects in nociception. In contrast, we find that in adult DRGs, Prdm12 is dispensable for most pain sensation and injury-induced hypersensitivity. Using transcriptomic analysis, we found mostly unique changes in adult Prdm12 knockout DRGs compared to embryonic knockout, and that PRDM12 is likely a transcriptional activator in the adult. Overall, we find that the function of PRDM12 changes over developmental time.
2021-02-25 | GSE167468 | GEO