Hyperpolarization-Activated, Cation-Nonselective, Cyclic Nucleotide-Modulated Channel Blockade Alleviates Mechanical Allodynia and Suppresses Ectopic Discharge in Spinal Nerve Ligated Rats

Lee, Doo H.; Chang, Leon; Sorkin, Linda S.; Chaplan, Sandra R.

doi:10.1016/j.jpain.2005.02.002

Cited by 66 publications

(57 citation statements)

References 45 publications

(34 reference statements)

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“…Third, increased densities of I h were found in large-and/or medium-sized DRG neurons after experimentally induced injuries (80,206,432). Fourth, low concentrations of the I h blocker ZD7288 reverse both pain behavior and the spontaneous discharges in injured nerve fibers (80,220,380). Taken together, these findings strongly suggest that upregulation of I h that leads to an increased excitability of the cell is causative to the generation of ectopic firing.…”

Section: Peripheral Neuropathic Painmentioning

confidence: 81%

Hyperpolarization-Activated Cation Channels: From Genes to Function

Biel

Wahl‐Schott²,

Michalakis³

et al. 2009

Physiological Reviews

856

974

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises four members (HCN1-4) that are expressed in heart and nervous system. The current produced by HCN channels has been known as Ih (or If or Iq). Ih has also been designated as pacemaker current, because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. Extensive studies over the last decade have provided convincing evidence that Ih is also involved in a number of basic physiological processes that are not directly associated with rhythmicity. Examples for these non-pacemaking functions of Ih are the determination of the resting membrane potential, dendritic integration, synaptic transmission, and learning. In this review we summarize recent insights into the structure, function, and cellular regulation of HCN channels. We also discuss in detail the different aspects of HCN channel physiology in the heart and nervous system. To this end, evidence on the role of individual HCN channel types arising from the analysis of HCN knockout mouse models is discussed. Finally, we provide an overview of the impact of HCN channels on the pathogenesis of several diseases and discuss recent attempts to establish HCN channels as drug targets.

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Section: Peripheral Neuropathic Painmentioning

confidence: 81%

Hyperpolarization-Activated Cation Channels: From Genes to Function

Biel

Wahl‐Schott²,

Michalakis³

et al. 2009

Physiological Reviews

856

974

View full text Add to dashboard Cite

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“…IVA 5 mg/kg of administered in vehicle þ vehicle group did not alter the pain threshold in control animals. For sake of comparison, we also tested the effect of another pan HCN blocker, ZD7288, which has been proved to exert anti-hypersensitivity effects in neuropathic pain models (Lee et al, 2005;Smith et al, 2015) (Fig. 4B, top).…”

Section: Anti-hyperalgesic Efficacy Of Pan Hcn Blockers In An Animal mentioning

confidence: 99%

Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy

et al. 2018

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a b s t r a c tChemotherapy-Induced Peripheral Neuropathy (CIPN) is the most frequent adverse effect of pharmacological cancer treatments. The occurrence of neuropathy prevents the administration of fully-effective drug regimen, affects negatively the quality of life of patients, and may lead to therapy discontinuation. CIPN is currently treated with anticonvulsants, antidepressants, opioids and non-opioid analgesics, all of which are flawed by insufficient anti-hyperalgesic efficacy or addictive potential. Understandably, developing new drugs targeting CIPN-specific pathogenic mechanisms would dramatically improve efficacy and tolerability of anti-neuropathic therapies. Neuropathies are associated to aberrant excitability of DRG neurons due to the alteration in the expression or function of a variety of ion channels. In this regard, Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are overexpressed in inflammatory and neuropathic pain states, and HCN blockers have been shown to reduce neuronal excitability and to ameliorate painful states in animal models. However, HCN channels are critical in cardiac action potential, and HCN blockers used so far in pre-clinical models do not discriminate between cardiac and non-cardiac HCN isoforms. In this work, we show an HCN current gain of function in DRG neurons from oxaliplatin-treated rats. Biochemically, we observed a downregulation of HCN2 expression and an upregulation of the HCN regulatory beta-subunit MirP1. Finally, we report the efficacy of the selective HCN1 inhibitor MEL57A in reducing hyperalgesia and allodynia in oxaliplatin-treated rats without cardiac effects. In conclusion, this study strengthens the evidence for a disease-specific role of HCN1 in CIPN, and proposes HCN1-selective inhibitors as new-generation pain medications with the desired efficacy and safety profile.

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“…First, in situ hybridization (Kouranova et al, 2008), immunohistochemical (Tu et al, 2004;Jiang et al, 2008;Kouranova et al, 2008), and electrophysiological (Mayer and Westbrook, 1983;Kouranova et al, 2008;Momin et al, 2008) data show that sensory neurons express HCN channels, and that injury causes altered HCN subunit trafficking (Chaplan et al, 2003;Jiang et al, 2008) and enhanced I H current amplitudes (Chaplan et al, 2003;Yao et al, 2003). Second, sensory cell hyperexcitability is inhibited by superfusion with N-ethyl-1,6-dihydro-1,2-dimethyl-6-(methylimino)-N-phenyl-4-pyrimidinamine hydrochloride (ZD7288) (Chaplan et al, 2003;Yao et al, 2003;Jiang et al, 2008), a selective pan-isoform inhibitor of HCN channels, and systemic, but not central, administration of ZD7288 alleviates mechanical allodynia (Chaplan et al, 2003;Lee et al, 2005). Third, HCN1 gene deletion partially blocks development of cold allodynia (Orio et al, 2009), and in a parallel fashion, targeted deletion of HCN2 prevents the development of neuropathic pain in response to chronic nerve constriction (Emery et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

Tibbs

Rowley

Sanford

et al. 2013

J Pharmacol Exp Ther

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Chronic pain after peripheral nerve injury is associated with afferent hyperexcitability and upregulation of hyperpolarizationactivated, cyclic nucleotide-regulated (HCN)-mediated I H pacemaker currents in sensory neurons. HCN channels thus constitute an attractive target for treating chronic pain. HCN channels are ubiquitously expressed; analgesics targeting HCN1-rich cells in the peripheral nervous system must spare the cardiac pacemaker current (carried mostly by HCN2 and HCN4) and the central nervous system (where all four isoforms are expressed). The alkylphenol general anesthetic propofol (2,6-diiso-propylphenol) selectively inhibits HCN1 channels versus HCN2-HCN4 and exhibits a modest pharmacokinetic preference for the periphery. Consequently, we hypothesized that propofol, and congeners, should be antihyperalgesic. Alkyl-substituted propofol analogs have different rank-order potencies with respect to HCN1 inhibition, GABA A receptor (GABA A -R) potentiation, and general anesthesia. Thus, 2,6-and 2,4-di-tertbutylphenol (2,6-and 2,4-DTBP, respectively) are more potent HCN1 antagonists than propofol, whereas 2,6-and 2,4-di-sec-butylphenol (2,6-and 2,4-DSBP, respectively) are less potent. In contrast, DSBPs, but not DTBPs, enhance GABA A -R function and are general anesthetics. 2,6-DTBP retained propofol's selectivity for HCN1 over HCN2-HCN4. In a peripheral nerve ligation model of neuropathic pain, 2,6-DTBP and subhypnotic propofol are antihyperalgesic. The findings are consistent with these alkylphenols exerting analgesia via non-GABA A -R targets and suggest that antagonism of central HCN1 channels may be of limited importance to general anesthesia. Alkylphenols are hydrophobic, and thus potential modifiers of lipid bilayers, but their effects on HCN channels are due to direct drug-channel interactions because they have little bilayer-modifying effect at therapeutic concentrations. The alkylphenol antihyperalgesic target may be HCN1 channels in the damaged peripheral nervous system.

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Hyperpolarization-Activated, Cation-Nonselective, Cyclic Nucleotide-Modulated Channel Blockade Alleviates Mechanical Allodynia and Suppresses Ectopic Discharge in Spinal Nerve Ligated Rats

Cited by 66 publications

References 45 publications

Hyperpolarization-Activated Cation Channels: From Genes to Function

Hyperpolarization-Activated Cation Channels: From Genes to Function

Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

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