Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain

Healey, Shannon A Bernard; Scholtes, Ingrid; Abrahams, Mark; McNaughton, Peter A.; Menon, David; Lee, Michael C.

doi:10.1097/pr9.0000000000000967

Cited by 11 publications

(5 citation statements)

References 43 publications

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“…Nevertheless, clinical studies of painful DPN targeting these channels have been launched. 98 Several mechanisms of ion channel-mediated hyperexcitability and pain can occur (Figure 4C-D). 83 Increased ion channel expression increases conduction in unmyelinated C fiber nociceptors, intensifying impulse transmission to the CNS.…”

Section: Dpn Pain Mechanismsmentioning

confidence: 99%

Towards prevention of diabetic peripheral neuropathy: clinical presentation, pathogenesis, and new treatments

Elafros

Andersen²,

Bennett³

et al. 2022

The Lancet Neurology

136

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Section: Dpn Pain Mechanismsmentioning

confidence: 99%

Towards prevention of diabetic peripheral neuropathy: clinical presentation, pathogenesis, and new treatments

Elafros

Andersen²,

Bennett³

et al. 2022

The Lancet Neurology

136

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“…Another alternative to the vascular theory of migraine induction by K ATP channel opening is the involvement of HCN channels in the trigeminal nervous system [ 164 ]. Sustained hyperpolarization of neurons may engage HCN channels, and blockage of these have been suggested as therapeutic targets in diabetic neuropathy [ 166 ] and neuropathic [ 167 ] and inflammatory pain [ 168 ]. The proposed mechanism is that K ATP channel openers lead to the long-lasting hyperpolarization of trigeminal nerves, in turn activating HCN channels that leads to augmented neuronal excitability and firing of the neurons [ 169 , 170 ].…”

Section: Discussionmentioning

confidence: 99%

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Clement

Guo

Jansen‐Olesen

et al. 2022

Cells

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Globally, migraine is a leading cause of disability with a huge impact on both the work and private life of affected persons. To overcome the societal migraine burden, better treatment options are needed. Increasing evidence suggests that ATP-sensitive potassium (KATP) channels are involved in migraine pathophysiology. These channels are essential both in blood glucose regulation and cardiovascular homeostasis. Experimental infusion of the KATP channel opener levcromakalim to healthy volunteers and migraine patients induced headache and migraine attacks in 82-100% of participants. Thus, this is the most potent trigger of headache and migraine identified to date. Levcromakalim likely induces migraine via dilation of cranial arteries. However, other neuronal mechanisms are also proposed. Here, basic KATP channel distribution, physiology, and pharmacology are reviewed followed by thorough review of clinical and preclinical research on KATP channel involvement in migraine. KATP channel opening and blocking have been studied in a range of preclinical migraine models and, within recent years, strong evidence on the importance of their opening in migraine has been provided from human studies. Despite major advances, translational difficulties exist regarding the possible anti-migraine efficacy of KATP channel blockage. These are due to significant species differences in the potency and specificity of pharmacological tools targeting the various KATP channel subtypes.

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“…Because the HCN2 channel subtype is mainly expressed in neurons as opposed to other excitable tissues ( 302 ), HCN2 blockers abrogate DRG hyperexcitability without affecting the HCN1 channels that control cardiac rhythmicity ( 303 ). In the clinic, the non-selective HCN blocker, ivabradine which is approved for treatment of heart failure, has a beneficial effect in painful diabetic neuropathy but only a weak effect in other forms of neuropathic pain ( 304 ).…”

Section: Neuroinflammation and The Actions Of Primary Mediators On Pr...mentioning

confidence: 99%

Neuropathic pain; what we know and what we should do about it

Smith

2023

Front. Pain Res.

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Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve injury promotes Schwann cell activation and invasion of immunocompetent cells into the site of injury, spinal cord and higher sensory structures such as thalamus and cingulate and sensory cortices. Various cytokines, chemokines, growth factors, monoamines and neuropeptides effect two-way signalling between neurons, glia and immune cells. This promotes sustained hyperexcitability and spontaneous activity in primary afferents that is crucial for onset and persistence of pain as well as misprocessing of sensory information in the spinal cord and supraspinal structures. Much of the current understanding of pain aetiology and identification of drug targets derives from studies of the consequences of peripheral nerve injury in rodent models. Although a vast amount of information has been forthcoming, the translation of this information into the clinical arena has been minimal. Few, if any, major therapeutic approaches have appeared since the mid 1990's. This may reflect failure to recognise differences in pain processing in males vs. females, differences in cellular responses to different types of injury and differences in pain processing in humans vs. animals. Basic science and clinical approaches which seek to bridge this knowledge gap include better assessment of pain in animal models, use of pain models which better emulate human disease, and stratification of human pain phenotypes according to quantitative assessment of signs and symptoms of disease. This can lead to more personalized and effective treatments for individual patients. Significance statement: There is an urgent need to find new treatments for neuropathic pain. Although classical animal models have revealed essential features of pain aetiology such as peripheral and central sensitization and some of the molecular and cellular mechanisms involved, they do not adequately model the multiplicity of disease states or injuries that may bring forth neuropathic pain in the clinic. This review seeks to integrate information from the multiplicity of disciplines that seek to understand neuropathic pain; including immunology, cell biology, electrophysiology and biophysics, anatomy, cell biology, neurology, molecular biology, pharmacology and behavioral science. Beyond this, it underlines ongoing refinements in basic science and clinical practice that will engender improved approaches to pain management.

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Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain

Abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel receptors mediate neuropathic pain in preclinical models. Here, exploratory analysis reveals a dose-dependent reduction in pain with HCN blockade in patients with neuropathic pain.

Cited by 11 publications

References 43 publications

Towards prevention of diabetic peripheral neuropathy: clinical presentation, pathogenesis, and new treatments

Towards prevention of diabetic peripheral neuropathy: clinical presentation, pathogenesis, and new treatments

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

Neuropathic pain; what we know and what we should do about it

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