Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons

Minett, Michael S.; Nassar, Mohammed A.; Clark, Anna K.; Passmore, Gayle M.; Dickenson, Anthony H.; Wang, Fan; Malcangio, Marzia; Wood, John N.

doi:10.1038/ncomms1795

Cited by 242 publications

(266 citation statements)

References 53 publications

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“…NGF-dependent heat hyperalgesia is also essentially absent in mice with a sensory neuron specific deletion of the SCN9A gene encoding Na V 1.7 channels (Nassar et al, 2004). Mechanical pain behavior is strongly attenuated in mice lacking Na V 1.7 in sensory neurons, which is consistent with a critical role for this channel in sustaining nociceptor AP propagation (Nassar et al, 2004;Minett et al, 2012). There is, however, as yet only little direct evidence that the primary consequence of Na V 1.7 loss is an attenuation of the ability of somatic Cfibers to conduct action potentials (Wilson et al, 2011).…”

Section: Mechanisms Of Ngf-dependent Mechanical Hyperalgesiamentioning

confidence: 69%

“…Na V 1.7 is an a important channel in olfactory sensory neurons (OSNs) and here it appears to be primarily required for the transfer of sensory information from OSN to second order neurons in the olfactory bulb (Weiss et al, 2011). This has led to speculation that the primary mechanism leading to the spectacular loss of pain phenotypes in humans lacking Na V 1.7 channels is a block of information transfer from primary afferent C-fibers at their central synapses in the dorsal horn (Black et al, 2012;Minett et al, 2012). If the expression or sub-cellular distribution of Na V 1.7 channels is controlled by NGF availability (Gould et al, 2000;Diss et al, 2008), then it is conceivable that anti-NGF drugs work in an Na V 1.7 dependent manner.…”

Section: Mechanisms Of Ngf-dependent Mechanical Hyperalgesiamentioning

confidence: 99%

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Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

Lewin

Lechner

Smith

2014

Handbook of Experimental Pharmacology

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Nerve growth factor (NGF) is central to the development and functional regulation of sensory neurons that signal the first events that lead to pain. These sensory neurons, called nociceptors, require NGF in the early embryo to survive and also for their functional maturation. The long road from the discovery of NGF and its roles during development to the realization that NGF plays a major role in the pathophysiology of inflammatory pain will be reviewed. In particular, we will discuss the various signaling events initiated by NGF that lead to long lasting thermal and mechanical hyperalgesia in animals and in man. It has been realized relatively recently that humanized, function blocking antibodies directed against NGF show remarkably analgesic potency in human clinical trials for painful conditions as varied as osteoarthritis, lower back pain and interstitial cystitis. Thus, anti-NGF medication has the potential to make a major impact on day-to-day pain treatment in the near future. It is therefore all the more important to understand the precise pathways and mechanisms that are controlled by NGF to initiate and sustain mechanical and thermal hyperalgesia. Recent work suggests that NGF-dependent regulation of the mechanosensory properties of sensory neurons that signal mechanical pain may open new mechanistic avenues to refine and exploit relevant molecular targets for novel analgesics.

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Section: Mechanisms Of Ngf-dependent Mechanical Hyperalgesiamentioning

confidence: 69%

Section: Mechanisms Of Ngf-dependent Mechanical Hyperalgesiamentioning

confidence: 99%

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

Lewin

Lechner

Smith

2014

Handbook of Experimental Pharmacology

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“…Ablation of Na V 1.7 in all mouse sensory neurons abolishes mechanical pain, inflammatory pain, and reflex withdrawal responses to heat, without affecting neuropathic pain. However, ablation of Na V 1.7 in both sensory and sympathetic neurons abolishes all pain sensations and recapitulates the pain-free phenotype seen in CIP patients (9). Thus, Na V 1.7 appears to be an attractive target for the development of novel analgesics for treating a wide range of pain pathologies.…”

Section: Discussionmentioning

confidence: 89%

“…Gain-of-function mutations in the SNC9A gene encoding the pore-forming α-subunit of Na V 1.7 cause severe episodic pain in inherited neuropathies, such as erythromelalgia and paroxysmal extreme pain disorder (7), whereas loss-of-function mutations in SCN9A result in a congenital indifference to pain (CIP) (8). The latter phenotype can be recapitulated in rodents via complete knockout of Na V 1.7 in all sensory and sympathetic neurons (9). Moreover, certain polymorphisms in SCN9A correlate with sensitivity to nociceptive inputs (10).…”

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confidence: 99%

Discovery of a selective Na _V 1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

Yang

Xiao

Kang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

163

151

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Loss-of-function mutations in the human voltage-gated sodium channel Na V 1.7 result in a congenital indifference to pain. Selective inhibitors of Na V 1.7 are therefore likely to be powerful analgesics for treating a broad range of pain conditions. Herein we describe the identification of μ-SLPTX-Ssm6a, a unique 46-residue peptide from centipede venom that potently inhibits Na V 1.7 with an IC 50 of ∼25 nM. μ-SLPTX-Ssm6a has more than 150-fold selectivity for Na V 1.7 over all other human Na V subtypes, with the exception of Na V 1.2, for which the selectivity is 32-fold. μ-SLPTX-Ssm6a contains three disulfide bonds with a unique connectivity pattern, and it has no significant sequence homology with any previously characterized peptide or protein. μ-SLPTX-Ssm6a proved to be a more potent analgesic than morphine in a rodent model of chemicalinduced pain, and it was equipotent with morphine in rodent models of thermal and acid-induced pain. This study establishes μ-SPTX-Ssm6a as a promising lead molecule for the development of novel analgesics targeting Na V 1.7, which might be suitable for treating a wide range of human pain pathologies.chronic pain | drug discovery | peptide therapeutic

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“…In Na v 1.7 cKO mice, Na v 1.7 is removed from cells in which Na v 1.8 has been expressed (i.e., Na v 1.8-Cre-driven cKO). It is likely that Na v 1.7 is still present where Na v 1.8 is not expressed, potentially in as many as 25% of DRG neurons (Black et al, 1996;Shields et al, 2012), as well as in the sympathetic nervous system (Sangameswaran et al, 1996;Toledo-Aral et al, 1997;Minett et al, 2012). In this context, the finding that mechanical hypersensitivity remains intact in Na v 1.7 cKO mice should not be overinterpreted as ruling out the involvement of Na v 1.7 in this process as well.…”

Section: Discussionmentioning

confidence: 99%

Sodium Channel Na_v1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

Shields

Cheng

Üçeyler³

et al. 2012

J. Neurosci.

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Marked hypersensitivity to heat and mechanical (pressure) stimuli develop after a burn injury, but the neural mechanisms underlying these effects are poorly understood. In this study, we establish a new mouse model of focal second-degree burn injury to investigate the molecular and cellular basis for burn injury-induced pain. This model features robust injury-induced behavioral effects and tissuespecific altered cytokine profile, but absence of glial activation in spinal dorsal horn. Three voltage-gated sodium channels, Na v 1.7, Na v 1.8, and Na v 1.9, are preferentially expressed in peripheral somatosensory neurons of the dorsal root ganglia (DRGs) and have been implicated in injury-induced neuronal hyperexcitability. Using knock-out mice, we provide evidence that Na v 1.7 selectively contributes to burn-induced hypersensitivity to heat, but not mechanical, stimuli. After burn model injury, wild-type mice display increased sensitivity to heat stimuli, and a normally non-noxious warm stimulus induces activity-dependent Fos expression in spinal dorsal horn neurons. Strikingly, both effects are absent in Na v 1.7 conditional knock-out (cKO) mice. Furthermore, burn injury increases density and shifts activation of tetrodotoxin-sensitive currents in a hyperpolarized direction, both pro-excitatory properties, in DRG neurons from wild-type but not Na v 1.7 cKO mice. We propose that, in sensory neurons damaged by burn injury to the hindpaw, Na v 1.7 currents contribute to the hyperexcitability of sensory neurons, their communication with postsynaptic spinal pain pathways, and behavioral thresholds to heat stimuli. Our results offer insights into the molecular and cellular mechanisms of modality-specific pain signaling, and suggest Na v 1.7-blocking drugs may be effective in burn patients.

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Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons

Cited by 242 publications

References 53 publications

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

Discovery of a selective Na _V 1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

Sodium Channel Na_v1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

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Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons

Cited by 242 publications

References 53 publications

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

Discovery of a selective Na V 1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

Sodium Channel Nav1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

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Discovery of a selective Na _V 1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

Sodium Channel Na_v1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury