The heart‐rate‐reducing agent, ivabradine, reduces mechanical allodynia in a rodent model of neuropathic pain

Noh, Sun Up; Kumar, Naresh; Bukhanova, N.; Chen, Y.; Stemkowsi, P.L.; Smith, Peter A.

doi:10.1002/j.1532-2149.2014.00460.x

Cited by 26 publications

(37 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This altered activity results from changes in the properties and/or expression of various types of voltage-gated Na + , K + , and Ca 2+ channels (Waxman et al, 1999;Abdulla andSmith, 2001b, 2002;Cummins et al, 2001;Stemkowski and Smith, 2012b;Bourinet et al, 2014;Waxman and Zamponi, 2014;Daou et al, 2016). There are also changes in the function of Na + -K + ATPases (Venteo et al, 2016), intracellular Ca 2+ handling (Hogan et al, 2014;D'Arco et al, 2015;Yilmaz and Gold, 2016;Yilmaz et al, 2017), TRP channels (Basso and Altier, 2017), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Hogan and Poroli, 2008;Emery et al, 2011;Noh et al, 2014;Young et al, 2014).…”

Section: Mechanisms Of Neuropathic Pain and Potential Therapeuticmentioning

confidence: 99%

“…Changes in Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. HCN channels have emerged as a promising peripheral drug target for neuropathic as well as inflammatory pain (Chaplan et al, 2003;Emery et al, 2011Emery et al, , 2012Noh et al, 2014;Young et al, 2014;Tsantoulas et al, 2016). HCN2 is expressed in about half of small somatosensory neurons, which are mainly nociceptors, and plays an important role in the control of firing frequency in response to noxious stimuli (Emery et al, 2011).…”

Section: Role Of Ectopic Activity In Primary Afferent Fibersmentioning

confidence: 99%

“…a. HCN channels as therapeutic targets. A blocker of HCN channels, ivabradine, which is also used clinically to treat angina and heart failure, has been shown to be effective in treating signs of neuropathic pain in animal models through peripheral action on small sensory neurons and to decrease firing frequency in cultured DRG neurons from nerve-injured animals (Noh et al, 2014;Young et al, 2014). More recent work has focused on the search for selective HCN2 blockers (Sartiani et al, 2017) that may abrogate hyperexcitability of DRG neurons without affecting the HCN1 channels that are responsible for controlling cardiac rhythmicity .…”

Section: Role Of Ectopic Activity In Primary Afferent Fibersmentioning

confidence: 99%

See 2 more Smart Citations

Etiology and Pharmacology of Neuropathic Pain

Alles¹,

Smith²

2018

Pharmacol Rev

293

251

View full text Add to dashboard Cite

Section: Mechanisms Of Neuropathic Pain and Potential Therapeuticmentioning

confidence: 99%

Section: Role Of Ectopic Activity In Primary Afferent Fibersmentioning

confidence: 99%

Section: Role Of Ectopic Activity In Primary Afferent Fibersmentioning

confidence: 99%

See 1 more Smart Citation

Etiology and Pharmacology of Neuropathic Pain

Alles¹,

Smith²

2018

Pharmacol Rev

293

251

View full text Add to dashboard Cite

“…Although the analgesia produced by existing HCN blockers is robust and wide-ranging across several animal pain models, their clinical use is hampered by the induced bradycardia due to inhibition of HCN4-dependent pacemaking activity in the heart [65,118]. To circumvent this, it is imperative to clarify which HCN isoform(s) confer the analgesic effect and to selectively target those responsible.…”

Section: Hcn2 Is the Culpritmentioning

confidence: 99%

“…Ivabradine shows a lack of off-target effects and consistent antinociceptive efficacy in several chronic pain models [65,118]. Ivabradine shows a lack of off-target effects and consistent antinociceptive efficacy in several chronic pain models [65,118].…”

Section: Ivabradinementioning

confidence: 99%

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

Tsantoulas

Mooney

McNaughton

2016

Biochemical Journal

View full text Add to dashboard Cite

Nociception - the ability to detect painful stimuli - is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a 'pacemaker for pain', in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

show abstract

Central neural alterations predominate in an insect model of nociceptive sensitization

Tabuena

Solis

Geraldi

et al. 2016

J of Comparative Neurology

View full text Add to dashboard Cite

Many organisms respond to noxious stimuli with defensive maneuvers. This is noted in the hornworm, Manduca sexta, as a defensive strike response. After tissue damage, organisms typically display sensitized responses to both noxious or normally innocuous stimuli. To further understand this phenomenon, we used novel in situ and in vitro preparations based on paired extracellular nerve recordings and videography to identify central and peripheral nerves responsible for nociception and sensitization of the defensive behavior in M. sexta. In addition, we used the in vivo defensive strike response threshold assayed with von Frey filaments to examine the roles N-methyl-D-aspartate receptor (NMDAR) and hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels play in this nociceptive sensitization using the inhibitors MK-801 and AP5 (NMDAR), and ivabradine and ZD7288 (HCN). Using our new preparations, we found that afferent activity evoked by noxious pinch in these preparations was conveyed to central ganglia by axons in the anterior- and lateral-dorsal nerve branches, and that sensitization induced by tissue damage was mediated centrally. Furthermore, sensitization was blocked by all inhibitors tested except the inactive isomer L-AP5, and reversed by ivabradine both in vivo and in vitro. Our findings suggest that M. sexta’s sensitization occurs through central signal amplification. Due to the relatively natural sensitization method and conserved molecular actions, we suggest that M. sexta may be a valuable model for studying the electrophysiological properties of nociceptive sensitization and potentially related conditions such as allodynia and hyperalgesia in a comparative setting that offers unique experimental advantages.

show abstract

The heart‐rate‐reducing agent, ivabradine, reduces mechanical allodynia in a rodent model of neuropathic pain

Abstract: Because ivabradine is effective at an oral dose that produces only moderate pharmacological heart rate reduction, and this is known to be well tolerated in a clinical context, these results underline its possible use in neuropathic pain management.

Cited by 26 publications

References 43 publications

Etiology and Pharmacology of Neuropathic Pain

Etiology and Pharmacology of Neuropathic Pain

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

Central neural alterations predominate in an insect model of nociceptive sensitization

Contact Info

Product

Resources

About