Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Alles, Sascha R.A.; Smith, Peter A.

doi:10.3389/fpain.2021.750583

Cited by 36 publications

(36 citation statements)

References 495 publications

(833 reference statements)

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“…56 Although Na v 1.7, K v 7.2, Ca v 2.2, Ca v 3.2, and HCN2 channels have emerged as potential therapeutic targets for drug development, with the notable exception of gabapentinoid action on voltage-gated Ca 2þ channels, 9 pharmacological manipulation of these channels has failed to identify new therapeutic approaches. 57 The observation that peripherally generated pain is often not suppressed by rhizotomy 58 seems at odds with the idea that stimulus-independent spontaneous activity is required for pain maintenance. It is possible, however, that pain seen after rhizotomy is related to deafferentation.…”

Section: Structural Remodeling Of Injured Peripheral Nervesmentioning

confidence: 99%

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management

Smith

2023

Can. J. Neurol. Sci.

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Patients with neuropathic pain are heterogeneous in pathophysiology, etiology, and clinical presentation. Signs and symptoms are determined by the nature of the injury and factors such as genetics, sex, prior injury, age, culture, and environment. Basic science has provided general information about pain etiology by studying the consequences of peripheral injury in rodent models. This is associated with the release of inflammatory cytokines, chemokines, and growth factors that sensitize sensory nerve endings, alter gene expression, promote post-translational modification of proteins, and alter ion channel function. This leads to spontaneous activity in primary afferent neurons that is crucial for the onset and persistence of pain and the release of secondary mediators such as colony-stimulating factor 1 from primary afferent terminals. These promote the release of tertiary mediators such as brain-derived neurotrophic factor and interleukin-1β from microglia and astrocytes. Tertiary mediators facilitate the transmission of nociceptive information at the spinal, thalamic, and cortical levels. For the most part, these findings have failed to identify new therapeutic approaches. More recent basic science has better mirrored the clinical situation by addressing the pathophysiology associated with specific types of injury, refinement of methodology, and attention to various contributory factors such as sex. Improved quantification of sensory profiles in each patient and their distribution into defined clusters may improve translation between basic science and clinical practice. If such quantification can be traced back to cellular and molecular aspects of pathophysiology, this may lead to personalized medicine approaches that dictate a rational therapeutic approach for each individual.

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Section: Structural Remodeling Of Injured Peripheral Nervesmentioning

confidence: 99%

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management

Smith

2023

Can. J. Neurol. Sci.

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“…VGCCs are well-known pain signal mediators in primary afferent neurons [ 24 ]. Even though calcium channels have been studied as a possible therapeutic target for more than 20 years, these agents are not reported yet to be effective in clinical management of pain [ 25 ].…”

Section: Precision Medicine Targeting Orofacial Painmentioning

confidence: 99%

Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine

Raman

Ikutame

Okura

et al. 2023

JPM

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Orofacial pain (OFP) is a dental specialty that includes the diagnosis, management and treatment of disorders of the jaw, mouth, face, head and neck. Evidence-based understanding is critical in effectively treating OFPs as the pathophysiology of these conditions is multifactorial. Since OFP impacts the quality of life of the affected individuals, treating patients successfully is of the utmost significance. Despite the therapeutic choices available, treating OFP is still quite challenging, owing to inter-patient variations. The emerging trends in precision medicine could probably lead us to a paradigm shift in effectively managing the untreatable long-standing pain conditions. Precision medicine is designed based on the patient’s genetic profile to meet their needs. Several significant relationships have been discovered based on the genetics and genomics of pain in the past, and some of the notable targets are discussed in this review. The scope of this review is to discuss preclinical and clinical trials that include approaches used in targeted therapy for orofacial pain. Future developments in pain medicine should benefit from current trends in research into novel therapeutic approaches.

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“…It is, therefore, notable that nociceptor excitability is increased in many pathological pain conditions (11), and that the resulting increase in afferent activity may be necessary and sufficient to drive pathological pain (12)(13)(14). Neuronal excitability depends on the complex interplay between diverse ion channels (15)(16)(17) but some ion channels seem to be particularly important for pain. For instance, loss-or gain-of-function mutations in the gene SCN9A, which encodes the voltage-gated sodium channel Na V 1.7, cause loss of pain or painful neuropathies, respectively (18-21, for review see 22).…”

Section: Introductionmentioning

confidence: 99%

Equivalent excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

Xie

Yang

Ratté

et al. 2022

Preprint

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Nociceptive sensory neurons convey pain signals to the CNS. Nociceptor hyperexcitability amplifies those signals, causing pain hypersensitivity. Reducing nociceptor excitability should mitigate that hypersensitivity, consistent with the effects of loss-of-function mutations in voltage-gated sodium (NaV) channels like NaV1.7. Yet efforts to phenocopy such mutations pharmacologically have failed in clinical trials. This failure may stem from the degenerate nature of nociceptor excitability. Here, we show that nociceptors can achieve equivalent excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. If NaV1.3 and/or NaV1.8 levels are high enough to maintain nociceptor excitability, selectively blocking NaV1.7 (e.g. with PF-05089771) becomes inconsequential. We demonstrate shifts in drug efficacy by comparing neurons tested after different numbers of days in vitro (DIV): Nociceptor excitability relies on NaV1.8 at DIV0 but that responsibility shifts to NaV1.7 and NaV1.3 on DIV4-7. A similar shift in NaV-dependence occurs in vivo, following inflammation, and impacts the ability of PF-05089771 to modulate pain sensitivity. These results demonstrate that nociceptors are surprisingly flexible in using different NaV isoforms to regulate excitability. This flexibility poses a serious problem for subtype-selective drugs whose efficacy hinges on such vagaries. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.

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Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Cited by 36 publications

References 495 publications

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management

Targeted Therapy for Orofacial Pain: A Novel Perspective for Precision Medicine

Equivalent excitability through different sodium channels and implications for the analgesic efficacy of selective drugs

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