PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-8 (8)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Pain without Nociceptors? Nav1.7-Independent Pain Mechanisms 
Cell Reports  2014;6(2):301-312.
Summary
Nav1.7, a peripheral neuron voltage-gated sodium channel, is essential for pain and olfaction in mice and humans. We examined the role of Nav1.7 as well as Nav1.3, Nav1.8, and Nav1.9 in different mouse models of chronic pain. Constriction-injury-dependent neuropathic pain is abolished when Nav1.7 is deleted in sensory neurons, unlike nerve-transection-related pain, which requires the deletion of Nav1.7 in sensory and sympathetic neurons for pain relief. Sympathetic sprouting that develops in parallel with nerve-transection pain depends on the presence of Nav1.7 in sympathetic neurons. Mechanical and cold allodynia required distinct sets of neurons and different repertoires of sodium channels depending on the nerve injury model. Surprisingly, pain induced by the chemotherapeutic agent oxaliplatin and cancer-induced bone pain do not require the presence of Nav1.7 sodium channels or Nav1.8-positive nociceptors. Thus, similar pain phenotypes arise through distinct cellular and molecular mechanisms. Therefore, rational analgesic drug therapy requires patient stratification in terms of mechanisms and not just phenotype.
Graphical Abstract
Highlights
•Phenotypically identical pain models have different underlying molecular mechanisms•Nav1.7 expression is required for sympathetic sprouting after neuronal damage•Oxaliplatin and cancer-induced bone pain are both Nav1.7-independent•Deleting Nav1.7 in adult mice reverses nerve damage-induced neuropathic pain
Wood and colleagues describe two pain syndromes that occur in the absence of Nav1.7, a sodium channel considered to be essential for pain perception and olfaction in humans. They provide evidence that pain phenotypes such as cold and mechanical allodynia can arise through distinct cell and molecular mechanisms after nerve injury in mouse peripheral sensory neurons. The existence of redundant mechanistically distinct peripheral pain mechanisms may help to explain recent difficulties with the development of new analgesic drugs.
doi:10.1016/j.celrep.2013.12.033
PMCID: PMC3969273  PMID: 24440715
2.  Sodium channels and mammalian sensory mechanotransduction 
Molecular Pain  2012;8:21.
Background
Members of the degenerin/epithelial (DEG/ENaC) sodium channel family are mechanosensors in C elegans, and Nav1.7 and Nav1.8 voltage-gated sodium channel knockout mice have major deficits in mechanosensation. β and γENaC sodium channel subunits are present with acid sensing ion channels (ASICs) in mammalian sensory neurons of the dorsal root ganglia (DRG). The extent to which epithelial or voltage-gated sodium channels are involved in transduction of mechanical stimuli is unclear.
Results
Here we show that deleting β and γENaC sodium channels in sensory neurons does not result in mechanosensory behavioural deficits. We had shown previously that Nav1.7/Nav1.8 double knockout mice have major deficits in behavioural responses to noxious mechanical pressure. However, all classes of mechanically activated currents in DRG neurons are unaffected by deletion of the two sodium channels. In contrast, the ability of Nav1.7/Nav1.8 knockout DRG neurons to generate action potentials is compromised with 50% of the small diameter sensory neurons unable to respond to electrical stimulation in vitro.
Conclusion
Behavioural deficits in Nav1.7/Nav1.8 knockout mice reflects a failure of action potential propagation in a mechanosensitive set of sensory neurons rather than a loss of primary transduction currents. DEG/ENaC sodium channels are not mechanosensors in mouse sensory neurons.
doi:10.1186/1744-8069-8-21
PMCID: PMC3378430  PMID: 22449024
Mechanotransduction; Sodium channels; Pain; Nav1.7; Nav1.8; ENaCs
3.  GRK2: a Novel Cell Specific Regulator of Severity and Duration of Inflammatory Pain 
Chronic pain associated with inflammation is a common clinical problem and the underlying mechanisms have only begun to be unravelled. GRK2 regulates cellular signalling by promoting G protein-coupled receptor (GPCR) desensitization and direct interaction with downstream kinases including p38. The aim of this study was to determine the contribution of GRK2 to regulation of inflammatory pain and to unravel the underlying mechanism. GRK2+/− mice with ~50% reduction in GRK2 developed increased and markedly prolonged thermal hyperalgesia and mechanical allodynia after carrageenan-induced paw inflammation or after intraplantar injection of the GPCR-binding chemokine CCL3. The effect of reduced GRK2 in specific cells was investigated using CRE-Lox technology. Carrageenan or CCL3-induced hyperalgesia was increased but not prolonged in mice with decreased GRK2 only in Nav1.8-nociceptors. In vitro, reduced neuronal GRK2 enhanced CCL3-induced TRPV1 sensitisation. In vivo, CCL3-induced acute hyperalgesia in GRK2+/− mice was mediated via TRPV1.
Reduced GRK2 in microglia/monocytes only was required and sufficient to transform acute carrageenan- or CCL3-induced hyperalgesia into chronic hyperalgesia. Chronic hyperalgesia in GRK2+/− mice was associated with ongoing microglial activation and increased phospho-p38 and TNF-α in the spinal cord. Inhibition of spinal cord microglial, p38, or TNF-α activity by intrathecal administration of specific inhibitors reversed ongoing hyperalgesia in GRK2+/− mice. Microglia/macrophage GRK2 expression was reduced in the lumbar ipsilateral spinal cord during neuropathic pain, underlining the patho-physiological relevance of microglial GRK2.
Thus, we identified completely novel cell-specific roles of GRK2 in regulating acute and chronic inflammatory hyperalgesia.
doi:10.1523/JNEUROSCI.5752-09.2010
PMCID: PMC3129713  PMID: 20147541
inflammatory hyperalgesia; G protein-coupled receptor kinase; microglia; p38; TNF; TRPV1; CCL3
4.  Nociceptor-expressed ephrin-B2 regulates inflammatory and neuropathic pain 
Molecular Pain  2010;6:77.
Background
EphB receptors and their ephrin-B ligands play an important role in nervous system development, as well as synapse formation and plasticity in the adult brain. Recent studies show that intrathecal treatment with EphB-receptor activator ephrinB2-Fc induced thermal hyperalgesia and mechanical allodynia in rat, indicating that ephrin-B2 in small dorsal root ganglia (DRG) neurons and EphB receptors in the spinal cord modulate pain processing. To examine the role of ephrin-B2 in peripheral pain pathways, we deleted ephrin-B2 in Nav1.8+ nociceptive sensory neurons with the Cre-loxP system. Sensory neuron numbers and terminals were examined using neuronal makers. Pain behavior in acute, inflammatory and neuropathic pain models was assessed in the ephrin-B2 conditional knockout (CKO) mice. We also investigated the c-Fos expression and NMDA receptor NR2B phosphorylation in ephrin-B2 CKO mice and littermate controls.
Results
The ephrin-B2 CKO mice were healthy with no sensory neuron loss. However, pain-related behavior was substantially altered. Although acute pain behavior and motor co-ordination were normal, inflammatory pain was attenuated in ephrin-B2 mutant mice. Complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia was halved. Formalin-induced pain behavior was attenuated in the second phase, and this correlated with diminished tyrosine phosphorylation of N-methyl-D-aspartic acid (NMDA) receptor subunit NR2B in the dorsal horn. Thermal hyperalgesia and mechanical allodynia were significantly reduced in the Seltzer model of neuropathic pain.
Conclusions
Presynaptic ephrin-B2 expression thus plays an important role in regulating inflammatory pain through the regulation of synaptic plasticity in the dorsal horn and is also involved in the pathogenesis of some types of neuropathic pain.
doi:10.1186/1744-8069-6-77
PMCID: PMC2992507  PMID: 21059214
5.  RET Signaling is Required for Survival and Normal Function of Non-Peptidergic Nociceptors 
Small unmyelinated sensory neurons classified as nociceptors are divided into two subpopulations based on phenotypic differences including expression of neurotrophic factor receptors. Approximately half of unmyelinated nociceptors express the NGF receptor TrkA and half express the GDNF Family Ligand (GFL) receptor Ret. The function of NGF/TrkA signaling in the TrkA population of nociceptors has been extensively studied and NGF/TrkA signaling is a well established mediator of pain. The GFLs are analgesic in models of neuropathic pain emphasizing the importance of understanding the physiological function of GFL/Ret signaling in nociceptors. However, perinatal lethality of Ret-null mice has precluded the study of the physiological role of GFL/Ret signaling in the survival, maintenance and function of nociceptors in viable mice. We deleted Ret exclusively in nociceptors by crossing nociceptor-specific Nav1.8 Cre and Ret conditional mice to produce Ret-Nav1.8 conditional knock out (CKO) mice. Loss of Ret exclusively in nociceptors results in a reduction in nociceptor number and size indicating Ret signaling is important for the survival and trophic support of these cells. Ret-Nav1.8 CKO mice exhibit reduced epidermal innervation, but normal central projections. In addition, Ret-Nav1.8 CKO mice have increased sensitivity to cold and increased formalin-induced pain, demonstrating that Ret signaling modulates the function of nociceptors in vivo. Enhanced inflammation-induced pain may be mediated by decreased Prostatic Acid Phosphatase (PAP) as PAP levels are markedly reduced in Ret-Nav1.8 CKO mice. The results of this study identify the physiological role of endogenous Ret signaling in the survival and function of nociceptors.
doi:10.1523/JNEUROSCI.5930-09.2010
PMCID: PMC2850282  PMID: 20237269
Ret; neurotrophic factor; GDNF; pain; inflammation; nociceptor
6.  Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice 
Molecular Pain  2006;2:33.
Changes in sodium channel activity and neuronal hyperexcitability contribute to neuropathic pain, a major clinical problem. There is strong evidence that the re-expression of the embryonic voltage-gated sodium channel subunit Nav1.3 underlies neuronal hyperexcitability and neuropathic pain.
Here we show that acute and inflammatory pain behaviour is unchanged in global Nav1.3 mutant mice. Surprisingly, neuropathic pain also developed normally in the Nav1.3 mutant mouse. To rule out any genetic compensation mechanisms that may have masked the phenotype, we investigated neuropathic pain in two conditional Nav1.3 mutant mouse lines. We used Nav1.8-Cre mice to delete Nav1.3 in nociceptors at E14 and NFH-Cre mice to delete Nav1.3 throughout the nervous system postnatally. Again normal levels of neuropathic pain developed after nerve injury in both lines. Furthermore, ectopic discharges from damaged nerves were unaffected by the absence of Nav1.3 in global knock-out mice. Our data demonstrate that Nav1.3 is neither necessary nor sufficient for the development of nerve-injury related pain.
doi:10.1186/1744-8069-2-33
PMCID: PMC1630424  PMID: 17052333
7.  Neuropathic pain develops normally in mice lacking both Nav1.7 and Nav1.8 
Molecular Pain  2005;1:24.
Two voltage gated sodium channel α-subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain. Mis-expression of voltage-gated sodium channels by damaged sensory neurons has also been implicated in the development of neuropathic pain, but the role of Nav1.7 and Nav1.8 is uncertain. Here we show that deleting Nav1.7 has no effect on the development of neuropathic pain. Double knockouts of both Nav1.7 and Nav1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds. These studies demonstrate that, in contrast to the highly significant role for Nav1.7 in determining inflammatory pain thresholds, the development of neuropathic pain does not require the presence of either Nav1.7 or Nav1.8 alone or in combination.
doi:10.1186/1744-8069-1-24
PMCID: PMC1215513  PMID: 16111501
8.  Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons 
Nature Communications  2012;3:791-.
Human acute and inflammatory pain requires the expression of voltage-gated sodium channel Nav1.7 but its significance for neuropathic pain is unknown. Here we show that Nav1.7 expression in different sets of mouse sensory and sympathetic neurons underlies distinct types of pain sensation. Ablating Nav1.7 gene (SCN9A) expression in all sensory neurons using Advillin-Cre abolishes mechanical pain, inflammatory pain and reflex withdrawal responses to heat. In contrast, heat-evoked pain is retained when SCN9A is deleted only in Nav1.8-positive nociceptors. Surprisingly, responses to the hotplate test, as well as neuropathic pain, are unaffected when SCN9A is deleted in all sensory neurons. However, deleting SCN9A in both sensory and sympathetic neurons abolishes these pain sensations and recapitulates the pain-free phenotype seen in humans with SCN9A loss-of-function mutations. These observations demonstrate an important role for Nav1.7 in sympathetic neurons in neuropathic pain, and provide possible insights into the mechanisms that underlie gain-of-function Nav1.7-dependent pain conditions.
Sodium channel Nav1.7 is essential for acute human pain but its role in chronic neuropathic pain is unclear. Minett and colleagues show that Nav1.7 expression specifically in sympathetic neurons, rather than sensory neurons, is required for the development of chronic neuropathic pain after injury.
doi:10.1038/ncomms1795
PMCID: PMC3337979  PMID: 22531176

Results 1-8 (8)