HCN channels (also known as Ih or If) are important for regulating neural pacemaker rhythm and influencing resting membrane potential, among many other functions. In the past few years, several groups, including ours, have shown that HCN channels are critically involved in chronic pain, possibly by driving ectopic discharges derived from DRG neurons and injured peripheral nerve sites (1-6).
To date, most of the previous work on HCN channels primarily focused on larger DRG neurons, which are known for their role in mechanical sensation. There is a good reason for this: HCN channels (in particular, HCN1) are predominantly expressed in larger DRG neurons (2). Surprisingly, however, previous work from Dr. McNaughton’s team found that HCN1 knockout (KO) mice only exhibited subtle changes in chronic pain behaviors compared with wild-type (WT) mice (7). In this study, the same group turned their attention to another subtype, HCN2, and elegantly showed that HCN2 in a subset of small DRG neurons is essential for both inflammatory and neuropathic pain. They specifically knocked out HCN2 in NaV1.8-expressing DRG neurons (nociceptive sensory neurons) and found that pain behaviors are largely relieved in NaV1.8-HCN2 KO mice. Their data further pinpoint that the role of HCN2 in chronic pain is mediated through driving action potential firings in NaV1.8-expressing nociceptors. It once again confirms the importance of HCN channels in pain. In retrospect, it is perhaps not surprising that HCN2 is important for inflammatory pain, because HCN2 is more sensitive to intracellular cAMP concentration than is HCN1. Therefore, many factors (e.g., prostaglandin E2) released during inflammation can positively regulate HCN currents by upregulating intracellular cAMP, and thus make the nociceptors more excitable. What is fascinating about this paper is that HCN2 in a subset of nociceptors can have such dramatic effects on chronic pain!
As pointed out in the paper, from the results of the present paper, researchers could expect that HCN2 may be a target of analgesics for chronic pain.
Accumulating evidence suggests that certain subsets of nociceptive neurons serve as sensors of certain noxious stimuli, for example, μ opioid receptor- and transient receptor potential (TRP) channel-containing nociceptors for thermal pain; δ opioid receptor- and cannabinoid receptor subtype 1-containing neurons for mechanical pain, and so on (8-11). It is also confirmed that acute and chronic pain share some similar mechanisms, but not all. For example, central sensitization seems to contribute more to the development of chronic pain than acute pain. Here, Emery et al. established an amazingly painless animal model to either acute or chronic stimuli/injury without showing other abnormalities by knockout of HCN2 channels in a small subset of DRG neurons (mostly in peripheral pain pathways). This, indeed, challenged the specificity theory. It will be interesting to know how HCN2 channels, or interaction of HCN2 and NaV1.8 channels, or any other physio- or pathological mechanisms involving HCN2 channels in this specific subset of DRG neurons, contribute so critically to the transmission and/or development of all kinds of pain.
Many ion channels and neuropeptides are confirmed to be expressed in certain groups of DRG neurons, especially nociceptive neurons (10). The TTX-resistant NaV1.8 channel is one of the well-accepted markers for nociceptors. This work picked up an even smaller group of DRG neurons that express both NaV1.8 and HCN2 channels, and comprise presumably 40 percent of small DRG neurons (Fig. S5 in Emery et al.), to study their role in pain transmission, and suggested that they are critical to both inflammatory and neuropathic pain. This interesting finding seems to narrow down the group of neurons that are responsible for pain transmission. If this is the case, hopefully it will give pain researchers a relatively more specific target to study pain mechanisms and discover more efficient and specific analgesics. In addition, interactions between HCN2 and other ion channels, better in NaV1.8-expressiing nociceptive neurons, will be of great interest.
An interesting paper always leads to many questions. This paper is no exception. For example, while the work in this study suggests that HCN2-driven action potentials in NaV1.8-expressing nociceptors cause pain behaviors, it remains possible that HCN2 channels expressed in central terminals of primary sensory fibers in spinal dorsal horn may also have a role (12-14).
Another major implication of this study is that HCN2 could potentially be a good drug target to combat chronic pain. However, many obstacles remain to be solved. For instance, a first challenge would be to develop the blocker that is selective to HCN2. To our knowledge, such a blocker is still not available. Even if it is available, side effects will be a major concern, as HCN2 is widely expressed in numerous regions and has many physiological functions. In particular, as demonstrated in this paper, global HCN2 KO mice are unable to live for a very long time. Nevertheless, this study, as stated by the authors, provides a valuable target to treat chronic pain.
This comment was coauthored by Qian Sun, Yu-Qiu Jiang, and Huiyin Tu, Neuroscience Research Institute, Peking University.
2. Hyperpolarization-activated, cyclic nucleotide-gated cation channels: roles in the differential electrophysiological properties of rat primary afferent neurons. Tu H, Deng L, Sun Q, Yao L, Han JS, Wan Y. J Neurosci Res 2004; 76(5):713-22.
3. Inhibition of hyperpolarization-activated current by ZD7288 suppresses ectopic discharges of injured dorsal root ganglion neurons in a rat model of neuropathic pain. Sun Q, Xing GG, Tu HY, Han JS, Wan Y. Brain Res 2005; 1032(1-2):63-9.
4. Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat. Luo L, Chang L, Brown SM, Ao H, Lee DH, Higuera ES, Dubin AE, Chaplan SR. Neuroscience 2007; 144(4):1477-85.
5. Axonal accumulation of hyperpolarization-activated cyclic nucleotide-gated cation channels contributes to mechanical allodynia after peripheral nerve injury in rat. Jiang YQ, Xing GG, Wang SL, Tu HY, Chi YN, Li J, Liu FY, Han JS, Wan Y. Pain 2008; 137(3):495-506.
12. Hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 ion channels modulate synaptic transmission from nociceptive primary afferents containing substance P to secondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn. Papp I, Szucs P, Holló K, Erdélyi F, Szabó G, Antal M. Eur J Neurosci 2006; 24(5):1341-52.
13. Plasticity of hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 expression in the spinal dorsal horn in inflammatory pain. Papp I, Holló K, Antal M. Eur J Neurosci 2010; 32(7):1193-201.
14. Spinal hyperpolarization-activated cyclic nucleotide-gated cation channels at primary afferent terminals contribute to chronic pain. Takasu K, Ono H, Tanabe M. Pain 2010; 151(1):87-96.
This exciting work indicates that modulation of HCN2 channel activity in Nav1.8-expressing sensory neurons represents a point of convergence for both inflammatory and neuropathic pain. The underlying mechanisms proposed for HCN2 channel contributions to development of hyperalgesia were not directly tested and remain an interesting direction for future study. Regardless of the underlying mechanisms, however, this and earlier work showing that non-selective inhibitors of HCN channels can blunt these forms of pain suggests that targeting nociceptor HCN2 channels may prove a useful therapeutic avenue in treatment of chronic inflammatory and neuropathic pain.
It is hard work to understand. I have some questions:.
Why were global HCN2-/- , not Nav1.8-HCN2-/-DRG neurons used in Fig 1 and Fig 2 (except Fig 2F)?
Fig1A: HCN2-/-can not abolish Ih current, “showing that another HCN isoform must also be expressed.” But in Fig 1C, in HCN2-/-neuron, the membrane potential cannot be affected by FSK or ZD7288, so is there “another HCN isoform” not sensitive to cAMP (ZD7288) or is it a hyperpolarized-activated K+ channel?
As we know, the amplitude of Ih current is bigger in the large DRG neuron than in the small DRG neuron. But in Fig2A, the Ih current is same in small and large DRG neuron. Furthermore, after HCN2 deletion, Ih amplitude is not changed, does that means other HCN subtype compensates?
Fig 2F, there are half of Nav1.8-HCN-/-DRG neuron sensitive to FSK, the other not. In Fig S5, small HCN2-/- DRG neuron is not sensitive to FSK, but 40% small Nav1.8-HCN-/- DRG neurons are still sensitive to FSK. Is there HCN2 expression in some small Nav1.8-HCN2-/- DRG neurons?
Comments
You Wan, Peking University
HCN channels (also known as
HCN channels (also known as Ih or If) are important for regulating neural pacemaker rhythm and influencing resting membrane potential, among many other functions. In the past few years, several groups, including ours, have shown that HCN channels are critically involved in chronic pain, possibly by driving ectopic discharges derived from DRG neurons and injured peripheral nerve sites (1-6).
To date, most of the previous work on HCN channels primarily focused on larger DRG neurons, which are known for their role in mechanical sensation. There is a good reason for this: HCN channels (in particular, HCN1) are predominantly expressed in larger DRG neurons (2). Surprisingly, however, previous work from Dr. McNaughton’s team found that HCN1 knockout (KO) mice only exhibited subtle changes in chronic pain behaviors compared with wild-type (WT) mice (7). In this study, the same group turned their attention to another subtype, HCN2, and elegantly showed that HCN2 in a subset of small DRG neurons is essential for both inflammatory and neuropathic pain. They specifically knocked out HCN2 in NaV1.8-expressing DRG neurons (nociceptive sensory neurons) and found that pain behaviors are largely relieved in NaV1.8-HCN2 KO mice. Their data further pinpoint that the role of HCN2 in chronic pain is mediated through driving action potential firings in NaV1.8-expressing nociceptors. It once again confirms the importance of HCN channels in pain. In retrospect, it is perhaps not surprising that HCN2 is important for inflammatory pain, because HCN2 is more sensitive to intracellular cAMP concentration than is HCN1. Therefore, many factors (e.g., prostaglandin E2) released during inflammation can positively regulate HCN currents by upregulating intracellular cAMP, and thus make the nociceptors more excitable. What is fascinating about this paper is that HCN2 in a subset of nociceptors can have such dramatic effects on chronic pain!
As pointed out in the paper, from the results of the present paper, researchers could expect that HCN2 may be a target of analgesics for chronic pain.
Accumulating evidence suggests that certain subsets of nociceptive neurons serve as sensors of certain noxious stimuli, for example, μ opioid receptor- and transient receptor potential (TRP) channel-containing nociceptors for thermal pain; δ opioid receptor- and cannabinoid receptor subtype 1-containing neurons for mechanical pain, and so on (8-11). It is also confirmed that acute and chronic pain share some similar mechanisms, but not all. For example, central sensitization seems to contribute more to the development of chronic pain than acute pain. Here, Emery et al. established an amazingly painless animal model to either acute or chronic stimuli/injury without showing other abnormalities by knockout of HCN2 channels in a small subset of DRG neurons (mostly in peripheral pain pathways). This, indeed, challenged the specificity theory. It will be interesting to know how HCN2 channels, or interaction of HCN2 and NaV1.8 channels, or any other physio- or pathological mechanisms involving HCN2 channels in this specific subset of DRG neurons, contribute so critically to the transmission and/or development of all kinds of pain.
Many ion channels and neuropeptides are confirmed to be expressed in certain groups of DRG neurons, especially nociceptive neurons (10). The TTX-resistant NaV1.8 channel is one of the well-accepted markers for nociceptors. This work picked up an even smaller group of DRG neurons that express both NaV1.8 and HCN2 channels, and comprise presumably 40 percent of small DRG neurons (Fig. S5 in Emery et al.), to study their role in pain transmission, and suggested that they are critical to both inflammatory and neuropathic pain. This interesting finding seems to narrow down the group of neurons that are responsible for pain transmission. If this is the case, hopefully it will give pain researchers a relatively more specific target to study pain mechanisms and discover more efficient and specific analgesics. In addition, interactions between HCN2 and other ion channels, better in NaV1.8-expressiing nociceptive neurons, will be of great interest.
An interesting paper always leads to many questions. This paper is no exception. For example, while the work in this study suggests that HCN2-driven action potentials in NaV1.8-expressing nociceptors cause pain behaviors, it remains possible that HCN2 channels expressed in central terminals of primary sensory fibers in spinal dorsal horn may also have a role (12-14).
Another major implication of this study is that HCN2 could potentially be a good drug target to combat chronic pain. However, many obstacles remain to be solved. For instance, a first challenge would be to develop the blocker that is selective to HCN2. To our knowledge, such a blocker is still not available. Even if it is available, side effects will be a major concern, as HCN2 is widely expressed in numerous regions and has many physiological functions. In particular, as demonstrated in this paper, global HCN2 KO mice are unable to live for a very long time. Nevertheless, this study, as stated by the authors, provides a valuable target to treat chronic pain.
This comment was coauthored by Qian Sun, Yu-Qiu Jiang, and Huiyin Tu, Neuroscience Research Institute, Peking University.
References
1. Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. Chaplan SR, Guo HQ, Lee DH, Luo L, Liu C, Kuei C, Velumian AA, Butler MP, Brown SM, Dubin AE. J Neurosci 2003; 23(4):1169-78.
2. Hyperpolarization-activated, cyclic nucleotide-gated cation channels: roles in the differential electrophysiological properties of rat primary afferent neurons. Tu H, Deng L, Sun Q, Yao L, Han JS, Wan Y. J Neurosci Res 2004; 76(5):713-22.
3. Inhibition of hyperpolarization-activated current by ZD7288 suppresses ectopic discharges of injured dorsal root ganglion neurons in a rat model of neuropathic pain. Sun Q, Xing GG, Tu HY, Han JS, Wan Y. Brain Res 2005; 1032(1-2):63-9.
4. Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat. Luo L, Chang L, Brown SM, Ao H, Lee DH, Higuera ES, Dubin AE, Chaplan SR. Neuroscience 2007; 144(4):1477-85.
5. Axonal accumulation of hyperpolarization-activated cyclic nucleotide-gated cation channels contributes to mechanical allodynia after peripheral nerve injury in rat. Jiang YQ, Xing GG, Wang SL, Tu HY, Chi YN, Li J, Liu FY, Han JS, Wan Y. Pain 2008; 137(3):495-506.
6. Characteristics of HCN channels and their participation in neuropathic pain. Jiang YQ, Sun Q, Tu HY, Wan Y. Neurochem Res 2008; 33(10):1979-89.
7. Role of the hyperpolarization-activated current Ih in somatosensory neurons. Momin A, Cadiou H, Mason A, McNaughton PA. J Physiol 2008; 586 (Pt 24):5911-29.
8. Transient receptor potential channels: targeting pain at the source. Patapoutian A, Tate S, Woolf CJ. Nat Rev Drug Discov 2009; 8(1):55-68.
9. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, Rubino T, Michalski CW, Marsicano G, Monory K, Mackie K, Marian C, Batkai S, Parolaro D, Fischer MJ, Reeh P, Kunos G, Kress M, Lutz B, Woolf CJ, Kuner R. Nat Neurosci 2007; 10(7):870-9.
10. Nociceptors--noxious stimulus detectors. Woolf CJ, Ma Q. Neuron 2007; 55(3):353-64.
11. Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Scherrer G, Imamachi N, Cao YQ, Contet C, Mennicken F, O'Donnell D, Kieffer BL, Basbaum AI. Cell 2009; 137(6):1148-59.
12. Hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 ion channels modulate synaptic transmission from nociceptive primary afferents containing substance P to secondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn. Papp I, Szucs P, Holló K, Erdélyi F, Szabó G, Antal M. Eur J Neurosci 2006; 24(5):1341-52.
13. Plasticity of hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 expression in the spinal dorsal horn in inflammatory pain. Papp I, Holló K, Antal M. Eur J Neurosci 2010; 32(7):1193-201.
14. Spinal hyperpolarization-activated cyclic nucleotide-gated cation channels at primary afferent terminals contribute to chronic pain. Takasu K, Ono H, Tanabe M. Pain 2010; 151(1):87-96.
Douglas Bayliss, University of Virginia
This exciting work indicates
This exciting work indicates that modulation of HCN2 channel activity in Nav1.8-expressing sensory neurons represents a point of convergence for both inflammatory and neuropathic pain. The underlying mechanisms proposed for HCN2 channel contributions to development of hyperalgesia were not directly tested and remain an interesting direction for future study. Regardless of the underlying mechanisms, however, this and earlier work showing that non-selective inhibitors of HCN channels can blunt these forms of pain suggests that targeting nociceptor HCN2 channels may prove a useful therapeutic avenue in treatment of chronic inflammatory and neuropathic pain.
Huiyin Tu, University of Nebraska Medical Center
It is hard work. Some
It is hard work to understand. I have some questions:.
Why were global HCN2-/- , not Nav1.8-HCN2-/-DRG neurons used in Fig 1 and Fig 2 (except Fig 2F)?
Fig1A: HCN2-/-can not abolish Ih current, “showing that another HCN isoform must also be expressed.” But in Fig 1C, in HCN2-/-neuron, the membrane potential cannot be affected by FSK or ZD7288, so is there “another HCN isoform” not sensitive to cAMP (ZD7288) or is it a hyperpolarized-activated K+ channel?
As we know, the amplitude of Ih current is bigger in the large DRG neuron than in the small DRG neuron. But in Fig2A, the Ih current is same in small and large DRG neuron. Furthermore, after HCN2 deletion, Ih amplitude is not changed, does that means other HCN subtype compensates?
Fig 2F, there are half of Nav1.8-HCN-/-DRG neuron sensitive to FSK, the other not. In Fig S5, small HCN2-/- DRG neuron is not sensitive to FSK, but 40% small Nav1.8-HCN-/- DRG neurons are still sensitive to FSK. Is there HCN2 expression in some small Nav1.8-HCN2-/- DRG neurons?