pattismith
Senior Member
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This is an important drug for ME/CFS patients, especially for those with POTS.
But its ability to block pain could make it one of the favorite drug for ME/CFS/Fibro.
HCN Channels: New Therapeutic Targets for Pain Treatment (2018)
….
HCN channels are activated by intracellular cyclic nucleotides [5,6], including guanosine-30,50-cyclic monophosphate (cGMP) and adenosine-30,50-cyclic monophosphate (cAMP), while the modulation of Ih (Ih = HCN current) is similar for both cyclic nucleotides, with the same efficacy at least in mammalians, the apparent affinities of Ih are 10–100 fold higher for cAMP than for cGMP [7].
….However, this cyclic nucleotide modulatory effect depends on each HCN subunit [9,10], with the cAMP sensitivity higher for HCN2 and HCN4, weaker in HCN1, and absent in HCN3 [11,12].
The cGMP has a similar efficacy to cAMP, but with a lower apparent affinity [13].
….
However, the Na+/K+ permeability ratio in HCN channels is ~1/4 and also displays asmall but significant permeability to Ca2+ ions[23]. Forinstance, at2.5mMof externalCa2+,the Ca2+ current in the native HCN current (Ih) as well as in the expression system, where channels HCN2 and HCN4 are expressed, is about 0.5% [23,24]. This Ca2+ current of HCN channels is relatively small (0.47% in HCN2 and 0.6% in HCN4 channels) compared with the fractional Ca2+ currents in other ion channels, such as the nicotinic acetylcholine receptor (2.5%) [25], glutamate receptor (10% for NMDA, N-methyl-D-aspartic acid) [26], AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors (0.5–5%) [27], CNG channels (10–80%) [28], and calcium channels (100%) [29].
However, this Ca2+ current through HCN channels may be enough to modulate Ca2+-dependent cellular functions [23,24].
...
The HCN channels are widely expressed in peripheral sensory neurons, neurons in the central nervous system [38], and cardiac tissues [2,3,39–41].
The HCN channels generate inward current (Ih)—a Na+/K+ current when the membrane potential is hyperpolarized, producing rhythmic electrical activity in specialized neurons of the brain [39,41,42] and in cardiac sinoatrial node cells [43].
Diverse functions have been attributed to Ih currents, including the determination of resting membrane potential (RMP), action potential (AP) firing rate, dendritic integration, and synaptic transmission [44].
HCN channel activity plays important roles in behavior and physiological process such as sleep and arousal, learning and memory, and anesthesia [38,45–47].
Misregulation of HCN channel activity has been shown to contribute to neurological and psychological disorders including pain, epilepsy, addiction, and anxiety [48–52].
….
In addition to cAMP, HCN channels are also allosterically regulated by other molecules, such as phosphatidylinositol 4,5-biphosphate, cholesterol, H+, and Cl− ions [31], and modulated by several post-translational modifications, such as phosphorylation (e.g., Src, mitogen-activated protein serine/threonine kinase [p38-MAPK], protein kinase C [PKC], and Ca2+/calmodulin-dependent protein kinase II) [54–57].
...
Diabetic patients develop a painful diabetic neuropathy (PDN)—a chronic pain condition induced by nerve damage [86]. The molecular mechanism of chronic pain in diabetes is poorly understood, and even at present there are no effective treatments [87]. Tsantoulas and colleagues [86] investigated the role of HCN2 as drivers of diabetic pain using mouse models (for diabetes type 1 and 2). The HCN2 channel activity blockade in small nociceptive neurons suppressed the diabetes-associated allodynia and prevented the nociceptive pathway in the spinal cord in mice [86].
Also, the pharmacological blockade with ivabradine, an HCN inhibitor, reduced chronic pain in mice with diabetes. These results suggest that selective HCN2 inhibitors might be a valuable treatment strategy for diabetic neuropathies [86].
In addition, Tsantoulas and colleagues [86] found that intracellular cAMP is increased in somato sensory neurons in an animal model of painful diabetes. This increased intracellular cAMP drives the diabetes-associated pain by facilitating the HCN2 activation with the consequent promotion of firing in primary nociceptive nerve fibers [86].
Nociceptive pain involves the transduction, conduction, transmission, modulation, and perception of noxious signals to the brain[95], which are then converted into an electrical signal[96]. The electrical signal is relayed to the dorsal horn,and then to the brain via spinal projections where the information is assessed, and the appropriate response is generated[96,97].
There are compelling evidence supporting the involvement of HCN1–2 subunits in the transmission of electrical signals and the induction of peripheral pain [77,84,98–101].
Evidence suggests that the inhibition of HCN channels function results in an interruption of electrical signals; therefore, blocking HCN channels can have analgesic effects and reduces pain sensation.
For instance, the nonselective HCN channel blocker ZD-7288 (Figure 2) suppresses mechanical and thermal hypersensitivity in different models of neuropathic pain [77,84,98,99,102]. Dysfunction of HCN channel activity is associated with the development and maintenance of chronic pain and inhibition of HCN channel activity produces the anti-nociceptive effect [82,103,104].
….
However, there is also evidence that the infusion of HCN blockers in the central nervous system also generates anti-nociceptive effect.
….
Additionally, further studies where the HCN channel inhibitors ivabradine and gabapentin were used (the latter is a gold standard for neuropathic pain treatment; Figure 2), corroborated the anti-nociceptive effect [82,107]. Gabapentin, which acts by blocking voltage-gated calcium channels, also showed an upregulated activity of the HCN channels [108]. However, the gabapentin binding mechanism and how it modulates HCN channels remains unclear.
..... a wide range of volatile anesthetics (e.g.,enflurane isoflurane, halothane[129–133],and xenon[134]),intravenous(e.g.,pentobarbital[135], ketamine [136,137], and propofol [45,47,138]) agents, and adjuncts including loperamide (µ-opiate receptor agonist) [139,140] and α2-receptor agonists (e.g., clonidine and dexmedetomidine [141–143]) inhibit HCN channel activity [144], and thereby prevent membrane depolarization.
The general anesthetic propofol (2,6-di-isopropylphenol) (Figure 4) selectively inhibits HCN1 channels versus HCN2, 3, and 4 [45,138].
... Ketamine, a drug with anesthetic, analgesic, and psychotropic effects, also inhibits the HCN1 subunit in cortical pyramidal neurons (Figure 4), and its effects are attenuated in HCN1 knockout mice [136,146].
On the other hand, the local anesthetic lidocaine (Figure 4) inhibits HCN1, HCN2, and HCN4 subunits, as well as heteromeric HCN1–HCN2 channels acting in a dose-dependent manner over a concentration range relevant for systemic use.
.....
But its ability to block pain could make it one of the favorite drug for ME/CFS/Fibro.
HCN Channels: New Therapeutic Targets for Pain Treatment (2018)
….
HCN channels are activated by intracellular cyclic nucleotides [5,6], including guanosine-30,50-cyclic monophosphate (cGMP) and adenosine-30,50-cyclic monophosphate (cAMP), while the modulation of Ih (Ih = HCN current) is similar for both cyclic nucleotides, with the same efficacy at least in mammalians, the apparent affinities of Ih are 10–100 fold higher for cAMP than for cGMP [7].
….However, this cyclic nucleotide modulatory effect depends on each HCN subunit [9,10], with the cAMP sensitivity higher for HCN2 and HCN4, weaker in HCN1, and absent in HCN3 [11,12].
The cGMP has a similar efficacy to cAMP, but with a lower apparent affinity [13].
….
However, the Na+/K+ permeability ratio in HCN channels is ~1/4 and also displays asmall but significant permeability to Ca2+ ions[23]. Forinstance, at2.5mMof externalCa2+,the Ca2+ current in the native HCN current (Ih) as well as in the expression system, where channels HCN2 and HCN4 are expressed, is about 0.5% [23,24]. This Ca2+ current of HCN channels is relatively small (0.47% in HCN2 and 0.6% in HCN4 channels) compared with the fractional Ca2+ currents in other ion channels, such as the nicotinic acetylcholine receptor (2.5%) [25], glutamate receptor (10% for NMDA, N-methyl-D-aspartic acid) [26], AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors (0.5–5%) [27], CNG channels (10–80%) [28], and calcium channels (100%) [29].
However, this Ca2+ current through HCN channels may be enough to modulate Ca2+-dependent cellular functions [23,24].
...
The HCN channels are widely expressed in peripheral sensory neurons, neurons in the central nervous system [38], and cardiac tissues [2,3,39–41].
The HCN channels generate inward current (Ih)—a Na+/K+ current when the membrane potential is hyperpolarized, producing rhythmic electrical activity in specialized neurons of the brain [39,41,42] and in cardiac sinoatrial node cells [43].
Diverse functions have been attributed to Ih currents, including the determination of resting membrane potential (RMP), action potential (AP) firing rate, dendritic integration, and synaptic transmission [44].
HCN channel activity plays important roles in behavior and physiological process such as sleep and arousal, learning and memory, and anesthesia [38,45–47].
Misregulation of HCN channel activity has been shown to contribute to neurological and psychological disorders including pain, epilepsy, addiction, and anxiety [48–52].
….
In addition to cAMP, HCN channels are also allosterically regulated by other molecules, such as phosphatidylinositol 4,5-biphosphate, cholesterol, H+, and Cl− ions [31], and modulated by several post-translational modifications, such as phosphorylation (e.g., Src, mitogen-activated protein serine/threonine kinase [p38-MAPK], protein kinase C [PKC], and Ca2+/calmodulin-dependent protein kinase II) [54–57].
...
Diabetic patients develop a painful diabetic neuropathy (PDN)—a chronic pain condition induced by nerve damage [86]. The molecular mechanism of chronic pain in diabetes is poorly understood, and even at present there are no effective treatments [87]. Tsantoulas and colleagues [86] investigated the role of HCN2 as drivers of diabetic pain using mouse models (for diabetes type 1 and 2). The HCN2 channel activity blockade in small nociceptive neurons suppressed the diabetes-associated allodynia and prevented the nociceptive pathway in the spinal cord in mice [86].
Also, the pharmacological blockade with ivabradine, an HCN inhibitor, reduced chronic pain in mice with diabetes. These results suggest that selective HCN2 inhibitors might be a valuable treatment strategy for diabetic neuropathies [86].
In addition, Tsantoulas and colleagues [86] found that intracellular cAMP is increased in somato sensory neurons in an animal model of painful diabetes. This increased intracellular cAMP drives the diabetes-associated pain by facilitating the HCN2 activation with the consequent promotion of firing in primary nociceptive nerve fibers [86].
Nociceptive pain involves the transduction, conduction, transmission, modulation, and perception of noxious signals to the brain[95], which are then converted into an electrical signal[96]. The electrical signal is relayed to the dorsal horn,and then to the brain via spinal projections where the information is assessed, and the appropriate response is generated[96,97].
There are compelling evidence supporting the involvement of HCN1–2 subunits in the transmission of electrical signals and the induction of peripheral pain [77,84,98–101].
Evidence suggests that the inhibition of HCN channels function results in an interruption of electrical signals; therefore, blocking HCN channels can have analgesic effects and reduces pain sensation.
For instance, the nonselective HCN channel blocker ZD-7288 (Figure 2) suppresses mechanical and thermal hypersensitivity in different models of neuropathic pain [77,84,98,99,102]. Dysfunction of HCN channel activity is associated with the development and maintenance of chronic pain and inhibition of HCN channel activity produces the anti-nociceptive effect [82,103,104].
….
However, there is also evidence that the infusion of HCN blockers in the central nervous system also generates anti-nociceptive effect.
….
Additionally, further studies where the HCN channel inhibitors ivabradine and gabapentin were used (the latter is a gold standard for neuropathic pain treatment; Figure 2), corroborated the anti-nociceptive effect [82,107]. Gabapentin, which acts by blocking voltage-gated calcium channels, also showed an upregulated activity of the HCN channels [108]. However, the gabapentin binding mechanism and how it modulates HCN channels remains unclear.
..... a wide range of volatile anesthetics (e.g.,enflurane isoflurane, halothane[129–133],and xenon[134]),intravenous(e.g.,pentobarbital[135], ketamine [136,137], and propofol [45,47,138]) agents, and adjuncts including loperamide (µ-opiate receptor agonist) [139,140] and α2-receptor agonists (e.g., clonidine and dexmedetomidine [141–143]) inhibit HCN channel activity [144], and thereby prevent membrane depolarization.
The general anesthetic propofol (2,6-di-isopropylphenol) (Figure 4) selectively inhibits HCN1 channels versus HCN2, 3, and 4 [45,138].
... Ketamine, a drug with anesthetic, analgesic, and psychotropic effects, also inhibits the HCN1 subunit in cortical pyramidal neurons (Figure 4), and its effects are attenuated in HCN1 knockout mice [136,146].
On the other hand, the local anesthetic lidocaine (Figure 4) inhibits HCN1, HCN2, and HCN4 subunits, as well as heteromeric HCN1–HCN2 channels acting in a dose-dependent manner over a concentration range relevant for systemic use.
.....
