Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat

Luo, Ling; Chang, Leon; Brown, Sean M.; Ao, Hong; Lee, D.H.; Higuera, Emiliano S.; Dubin, Adrienne E.; Chaplan, Sandra R.

doi:10.1016/j.neuroscience.2006.10.048

Cited by 97 publications

(109 citation statements)

References 55 publications

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“…After more than 10 y, ZD7288 [4-(N-Ethyl-N-phenylamino)-1,2 dimethyl-6-(methylamino) pyrimidinium chloride ICI-D7288 N-Ethyl-1,6-dihydro-1,2-dimethyl-6-(methylimino)-N-phenyl-4-pyrimidinamine hydrochloride] was found to be a highly selective blocker of HCN. 2 ZD7288 reduces heart rate without impairing cardiac function, and it also mediates analgesia in neuropathic pain, 3 consistent with an action on HCN channels. Thus, ZD7288 has been widely used as a selective HCN inhibitor in physiological studies.…”

Section: Introductionsupporting

confidence: 53%

Is ZD7288 a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channel currents?

Liao

Liu

et al. 2012

Channels

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Section: Introductionsupporting

confidence: 53%

Is ZD7288 a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channel currents?

Liao

Liu

et al. 2012

Channels

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“…Moreover, prefrontal subregions have been shown to be involved in pain processing. For example, the ACC subdivision of the mPFC mediates the affective components of pain responses and is involved in pain-related learning associated with prediction and avoidance of noxious stimuli (Malin et al, 2007). Neuroimaging studies in humans have demonstrated that the ACC is the most consistently activated structure during pain stimulation (Rainville et al, 1997;Apkarian et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Neuroimaging studies in humans have demonstrated that the ACC is the most consistently activated structure during pain stimulation (Rainville et al, 1997;Apkarian et al, 2005). Accordingly, electrophysiological studies have reported that neurons in the ACC respond to noxious stimuli (Sikes and Vogt, 1992;Hutchison et al, 1999), exhibit enhanced spike frequency and intrinsic excitability after peripheral nerve injury (Metz et al, 2009;Gong et al, 2010;Blom et al, 2014), and can display synaptic long-term potentiation in rats following digit amputation (Wei and Zhuo, 2001). Therefore, strengthening of synaptic transmission and connections in supraspinal regions such as the ACC may underlie persistent pain (Zhuo, 2004).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Neuropathy Induces HCN Channel Dysfunction in Pyramidal Neurons of the Medial Prefrontal Cortex

2015

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Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its molecular basis. The cationic current I h mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels plays an important role in pain by facilitating ectopic firing and hyperexcitability in DRG neurons, however little is known regarding the role of I h in supraspinal pain pathways. The medial prefrontal cortex (mPFC), which is reported to be involved in the affective aspects of pain, exhibits high HCN channel expression. Using the spared nerve injury (SNI) model of neuropathic pain in Long-Evans rats and patch-clamp recordings in layer II/III pyramidal neurons of the contralateral mPFC, we observed a hyperpolarizing shift in the voltage-dependent activation of I h in SNI neurons, whereas maximal I h remained unchanged. Accordingly, SNI mPFC pyramidal neurons exhibited increased input resistance and excitability, as well as facilitated glutamatergic mGluR5-mediated persistent firing, compared with sham neurons. Moreover, intracellular application of bromo-cAMP abolished the hyperpolarizing shift in the voltage-dependent activation of I h observed in SNI neurons, whereas protein kinase A (PKA) inhibition further promoted this shift in both SNI and sham neurons. Behaviorally, acute HCN channel blockade by local injection of ZD7288 in the mPFC of SNI rats induced a decrease in cold allodynia. These findings suggest that changes in the cAMP/PKA axis in mPFC neurons underlie alterations to HCN channel function, which can influence descending inhibition of pain pathways in neuropathic conditions.

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“…Finally, a group of embryos, grown in culture as described above, received topical application of the bradycardic agent ZD7288. This drug blocks the I f cardiac pacemaker channels in the heart pacemaker, reducing heart rate without creating an inotropic cardiac effect (Yusuf and Camm 2003;Luo et al 2006).…”

Section: Experimental Design and Embryo Populationsmentioning

confidence: 99%

“…ZD7288, which blocks the I f cardiac pacemaker channels in the heart pacemaker, is widely regarded as a pure bradycardic drug that reduces f H without producing inotropic changes in heart performance (e.g., Yusuf and Camm 2003;Luo et al 2006). Acute dosing of ZD7288 at 30-, 250-, and 500-mM concentrations caused a bradycardia that was dependent on dose and time ( fig.…”

Section: Critique Of Zd7288 and Its Applicationmentioning

confidence: 99%

Reduced Heart Rate and Cardiac Output Differentially Affect Angiogenesis, Growth, and Development in Early Chicken Embryos (Gallus domesticus)

Branum

Yamada-Fisher

Burggren

2013

Physiological and Biochemical Zoology

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An increase in both vascular circumferential tension and shear stress in the developing vasculature of the chicken embryo has been hypothesized to stimulate angiogenesis in the developing peripheral circulation chorioallantoic membrane (CAM). To test this hypothesis, angiogenesis in the CAM, development, and growth were measured in the early chicken embryo, following acute and chronic topical application of the purely bradycardic drug ZD7288. At hour 56, ZD7288 reduced heart rate (f H ) by ∼30% but had no significant effect on stroke volume (∼ mL), collectively resulting in a significant fall in 0.19 ‫ע‬ 0.2 cardiac output (CO) from ∼ to mL min Ϫ1 . Mean 27 ‫ע‬ 3 ‫ע81‬ 2 f H at 72 h of development was similarly significantly lowered by acute ZD7288 treatment (250 mM) to beats min Ϫ1 , 128 ‫ע‬ 0.3 compared with and beats min Ϫ1 in con-174.5 ‫ע‬ 0.3 174.7 ‫ע‬ 0.8 trol and Pannett-Compton (P-C) saline-treated embryos, respectively. Chronic dosing with ZD7288-and the attendant decreases in f H and CO-did not change eye diameter or cervical flexion (key indicators of development rate) at 120 h but significantly reduced overall growth (wet and dry body mass decreased by 20%). CAM vessel density index (reflecting angiogenesis) measured 200-400 mm from the umbilical stalk was not altered, but ZD7288 reduced vessel numbers-and therefore vessel density-by 13%-16% more distally (500-600 mm from umbilical stalk) in the CAM. In the ZD7288-treated embryos, a decrease in vessel length was found within the second branch order (∼300-400 mm from the umbilical stock), while a decrease in vessel diameter was found closer to the umbilical stock, beginning in the first branch order (∼200-300 mm). Paradoxically, chronic application of P-C saline also reduced peripheral CAM vessel density index at 500 and 600 mm by 13% and 7%, respectively, likely from washout of local angiogenic factors. In summary, decreased f H with reduced CO did not slow development rate but reduced embryonic growth rate and angiogenesis in the CAM periphery. This study demonstrates for the first time that different processes in the ontogeny of the early vertebrate embryo (i.e., hypertrophic growth vs. development) have differential sensitivities to altered convective blood flow.

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Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat

Cited by 97 publications

References 55 publications

Is ZD7288 a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channel currents?

Is ZD7288 a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channel currents?

Peripheral Neuropathy Induces HCN Channel Dysfunction in Pyramidal Neurons of the Medial Prefrontal Cortex

Reduced Heart Rate and Cardiac Output Differentially Affect Angiogenesis, Growth, and Development in Early Chicken Embryos (Gallus domesticus)

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