Pain without Nociceptors? Nav1.7-Independent Pain Mechanisms

Minett, Michael S.; Falk, Sarah; Santana-Varela, Sonia; Bogdanov, Yury; Nassar, Mohammed A.; Heegaard, Anne‐Marie; Wood, John N.

doi:10.1016/j.celrep.2013.12.033

Cited by 156 publications

(166 citation statements)

References 64 publications

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“…16 Following intraplantar injection of CFA in the left hind paw, inflammation develops in the affected (ipsilateral) hind paw. On day 2 after CFA administration, mice received an ip dose of either test compound 3 (as Na-salt 3a) or the vehicle.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na_V1.7 with Efficacy in Rodent Pain Models

Focken

Liu

Chahal

et al. 2016

ACS Med. Chem. Lett.

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ABSTRACT:We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNa V 1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNa V 1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of Na V 1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNa V 1.7 as a drug target for the treatment of pain. KEYWORDS: Sodium channel, Na V 1.7, Na V 1.5, pain, aryl sulfonamide, formalin model, cold allodynia T he sodium channel Na V 1.7 belongs to a family of transmembrane voltage gated sodium channels, which consists of nine isoforms in mammals (Na V 1.1 to Na V 1.9).1−4 Na V 1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Na V 1.7 and its encoding SCN9A gene to painful disorders in humans. Gain-of-function mutations in the SCN9A gene result in painful conditions such as inherited erythromelalgia, paroxysmal extreme pain disorder, and idiopathic small fiber neuropathies. In contrast, loss-of-function mutations in the SCN9A gene were found to be the genetic cause of a rare disorder called congenital insensitivity to pain, characterized by a complete loss of the ability to sense painful stimuli. It is noteworthy that no significant side effects have been reported in people lacking Na V 1.7, such as cognitive, motor, or non-nociceptive sensory impairments other than anosmia, giving further support to the concept of Na V 1.7 antagonists as analgesics.1−4 The predominant expression of the Na V 1.7 isoform in the PNS may offer a pathway to limit CNS-related adverse effects by developing compounds that do not cross the blood−brain barrier. Combined, these observations and findings have made Na V 1.7 a promising target for drug development for the treatment of pain. Indeed, there has been tremendous interest in the development of small molecule Na V 1.7 inhibitors as analgesics, particularly isoform-selective inhibitors, and coverage of the progress has been the subject of several excellent reviews. 1−7 In recent years, a series of aryl sulfonamides as Na V inhibitors have been reported that appear to be highly selective for Na V 1.7 over the cardiac ion channel Na V 1.5. [4][5][6]8 Since block of the Na V 1.5 channel may lead to arrhythmia and thus limit the therapeutic potential of nonselective Na V 1.7 inhibitors, isoform-selective inhibitors have attracted considerable interest due to their potential to avoid these adverse events.3,5 An example is aryl sulfonamide PF-04856264 ( Figure 1), which selectively blocks Na V 1.7 over Na V 1.5 and Na V 1.3.

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na_V1.7 with Efficacy in Rodent Pain Models

Focken

Liu

Chahal

et al. 2016

ACS Med. Chem. Lett.

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“…These receptors, such as the P2X3 receptor 37,38 and TRPV1 receptor, 39 have an effect on the overall pain behaviour; however, a recent study has demonstrated that we might have to think beyond the traditional classification of nociceptive neurons and sensory processing to effectively target cancer-induced bone pain. 40 Traditionally, the nociceptors have been classified based on expression of specific ion channels and receptors, such as the Nav1.7 and Nav1.8, and it is generally accepted that more than 90% of the nociceptors express Nav1.8. However, in the study by Minett et al, 40 it was demonstrated that the normal function of the Nav1.7-and Nav1.8-positive neurons was not critical for the development of pain behaviour in a mouse model of cancerinduced bone pain despite the fact that these Navs are highly essential for many other pain phenotypes.…”

Section: Peripheral Pain Mechanismsmentioning

confidence: 99%

Cancer pain physiology

Falk

Bannister

Dickenson

2014

British Journal of Pain

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Mechanisms of inflammatory and neuropathic pains have been elucidated and translated to patient care by the use of animal models of these pain states. Cancer pain has lagged behind since early animal models of cancer-induced bone pain were based on the systemic injection of carcinoma cells. This precluded systematic investigation of specific neuronal and pharmacological alterations that occur in cancer-induced bone pain. In 1999, Schwei et al. described a murine model of cancer-induced bone pain that paralleled the clinical condition in terms of pain development and bone destruction, confined to the mouse femur. This model prompted related approaches, and we can now state that cancer pain may include elements of inflammatory and neuropathic pains but also unique changes in sensory processing. Cancer-induced bone pain results in progressive bone destruction, elevated osteoclast activity and distinctive nocifensive behaviours (indicating the triad of ongoing, spontaneous and movement-induced hyperalgesia). In addition, cancer cells induce an inflammatory infiltrate and release growth factors, cytokines, interleukins, chemokines, prostanoids and endothelins, resulting in a reduction of pH to below 5 and direct deformation of primary afferents within bone. These peripheral changes, in turn, drive hypersensitivity of spinal cord sensory neurons, many of which project to the parts of the brain involved in the emotional response to pain. Within the spinal cord, a unique neuronal function reorganization within segments of the dorsal horn of the spinal cord receiving nociceptive input from the bone are discussed. Changes in certain neurotransmitters implicated in brain modulation of spinal function are also altered with implications for the affective components of cancer pain. Treatments are described in terms of mechanistic insights and in the case of opioids, which modulate pain transmission at spinal and supraspinal sites, their use can be compromised by opioid-induced hyperalgesia. We discuss evidence for how this comes about and how it may be treated.

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“…At the same time, oxaliplatin-induced neuropathic pain, a condition that exhibits mechanical and cold allodynia, was not alleviated by Na V 1.7 knockout even when Na V 1.7 was also removed from sympathetic neurons 186 . Cancer-induced bone pain and resultant gait abnormalities were also not significantly affected by Na V 1.7 knockout in all peripheral neurons 186 . There are also pain conditions that are only partially alleviated by Na V 1.7 knockout in Na V 1.8-positive neurons, such as allodynia following a burn injury 187 .…”

Section: Na V 17mentioning

confidence: 81%

“…While global Na V 1.7 knockout in mice was shown to be non-responsive to a range of neuropathic pain conditions and demonstrated deficiencies in acute pain sensing 175 , it is now evident that Na V 1.7 is not responsible for all that is painful 2,178,186 , dashing the hopes that the Na V 1.7 channel may be a panacea for all pain. The subsequent surging interest in the role of Na V channels in pain have revealed that other Na V isoforms, in particular Na V 1.6 and Na V 1.8, also play a major part in noxious sensing 2,186,197,198,205,207,349,350 , suggesting that further understanding of Na V 1.6 and Na V 1.8 may help us to decipher the pathophysiological mechanisms of pain.…”

Section: Chapter 6 -Overall Conclusionmentioning

confidence: 99%

“…Neuronal injury models, such as chronic constriction injury and spinal nerve transection injury, were only alleviated when Na V 1.7 was knocked out in all DRG neurons or knocked out in sympathetic peripheral neurons, and were not affected in mice with Na V 1.7 knocked out only in Na V 1.8-positive C-fibres 186 . At the same time, oxaliplatin-induced neuropathic pain, a condition that exhibits mechanical and cold allodynia, was not alleviated by Na V 1.7 knockout even when Na V 1.7 was also removed from sympathetic neurons 186 . Cancer-induced bone pain and resultant gait abnormalities were also not significantly affected by Na V 1.7 knockout in all peripheral neurons 186 .…”

Section: Na V 17mentioning

confidence: 99%

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A pharmacological and transcriptomic approach to exploring novel pain targets

Yin¹

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Ever since the discovery that mutations in the voltage-gated sodium channel 1.7 protein are responsible for human congenital insensitivity to pain, the voltage-gated sodium channel (Na V ) family of ion channels has been the subject of intense research with the hope of discovering novel analgesics. We now know that Na V 1.7 deletion in select neuronal populations yield different phenotypes, with the deletion of Na V 1.7 in all sensory neurons being successful at abolishing mechanical and heat-induced pain. However, it is rapidly becoming apparent that a number of pain syndromes are not modulated by Na V 1.7 at all, such as oxaliplatin-mediated neuropathy. It is particularly interesting to note that the loss of Na V 1.7 function is also associated with the selective inhibition of pain mediated by specific stimuli, such as that observed in burn-induced pain where Na V 1.7 gene knockout abolished thermal allodynia but did not affect mechanical allodynia. Accordingly, significant interests exist in delineating the contribution of other Na V isoforms in modality-specific pain pathways. Two other isoforms, Na V 1.6 and Na V 1.8, are now specifically implicated in some Na V 1.7-independent conditions such as oxaliplatin-induced cold allodynia. Such selective contributions of specific ion channel isoforms to pain highlight the need to discover other putative protein targets involved in mediating nociception.The aim of my work is therefore to discover selective molecular inhibitors of Na V 1.6 and Na V 1.8, to find useful cell models for peripheral nociceptors, to investigate the roles of Na V 1.6 and Na V 1.8 in an animal model of burn-induced pain, and to screen for putative new targets for analgesia in burn-related pain.Chapter 2 of this thesis describes activity-guided discovery of novel Na V 1.6 and Na V 1.8-modulting peptides from crude spider venoms. Crude venom from Poecilotheria metallica successfully reduced Na V 1.8-mediated voltage changes in HEK293-expressing cells. A new Na V 1.8-inhibitory peptide was sequenced from the venom and named Pme1a. However, Pme1a exhibited TRPV1 agonist activity and induced nocifensive behaviours, such as paw licking, after injection into the hind paws of mice, indicating the peptide was not a selective Na V 1.8 modulator and was unsuitable as a tool for Na V 1.8 investigation.iii With the unsuccessful exploration of spider venoms for new specific inhibitors, I then investigated in vitro cell models as tools to research specific nociceptor subtypes that express Na V 1.6 or Na V 1.8. In Chapter 3, I provide the first complete transcriptome of three common in vitro neuronal cell lines (SH-SY5Y, F-11, and ND7/23) to examine whether they were appropriate for investigating the functions of Na V 1.6 and Na V 1.8, and to identify if the cell lines resemble in vivo dorsal root ganglion (DRG) neuronal subclasses. The three cell lines examined all expressed proteins belonging to similar pathways and of similar proportions to native DRG neurons. However, they did not express any ce...

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Pain without Nociceptors? Nav1.7-Independent Pain Mechanisms

Cited by 156 publications

References 64 publications

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na_V1.7 with Efficacy in Rodent Pain Models

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na_V1.7 with Efficacy in Rodent Pain Models

Cancer pain physiology

A pharmacological and transcriptomic approach to exploring novel pain targets

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Pain without Nociceptors? Nav1.7-Independent Pain Mechanisms

Cited by 156 publications

References 64 publications

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models

Cancer pain physiology

A pharmacological and transcriptomic approach to exploring novel pain targets

Contact Info

Product

Resources

About

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na_V1.7 with Efficacy in Rodent Pain Models

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na_V1.7 with Efficacy in Rodent Pain Models