Trends in Pharmacological Sciences
ReviewHCN2 ion channels: an emerging role as the pacemakers of pain
Section snippets
Types of pain
The ability to sense noxious stimuli is an essential protective mechanism that initiates effective behavioral responses in order to avoid damaging stimuli. The vital role this primeval sense plays in survival is illustrated by the cases of people suffering from congenital insensitivity to pain, a rare disorder in which individuals often die prematurely from accidental injuries [1]. Not all pain is advantageous, however, because pain can also manifest itself as a chronic, pathological state, in
Role for HCN ion channels in modulating action potential frequency
HCN ion channels carry an inward current (termed If in cardiac tissue and Ih in neurons) which is unusual because it is activated by membrane hyperpolarization between approximately –60 and –90 mV. In cardiac pacemaker tissue, the hyperpolarization following an action potential activates If, generating an inward membrane current and depolarizing the membrane to threshold for the next action potential 9, 10. A crucial property of If is that its range of activation is shifted towards more positive
In vivo experiments: HCN2 and inflammatory pain
Experiments in vivo are the ultimate test for any hypothesis relating ion channels to pain. Pharmacological blockade of HCN channels by the pan-HCN inhibitor, ZD-7288, gives significant analgesia in a variety of inflammatory tests in both rats and mice, including the PGE2, formalin, carrageenan and mild thermal injury models 20, 26, 27, 28. Although these observations support a role for one or more of the HCN ion channel isoforms in pain, they do not identify the isoforms involved. Off-target
In vivo experiments: HCN2 and neuropathic pain
There is little agreement about what causes neuropathic pain, apart from that the initiating factor is damage to peripheral nerves. Nerve damage causes an ongoing firing of action potentials in both large- and small-diameter afferent nerve fibers 34, 35, 36, 37, but it remains unresolved whether it is this ectopic firing or some other change that triggers neuropathic pain, nor whether ectopic firing in large- or small-diameter fibers is important. Altered gene expression in peripheral sensory
Bridging the gap between inflammatory and neuropathic pain
Inflammatory and neuropathic pain have traditionally been regarded as discrete entities, differing in their origins, which in the case of neuropathic pain are still enigmatic. This view is also reflected in how these conditions are treated. Inflammatory pain is in general well-treated with NSAIDs and opioid analgesics, albeit with many side effects. By contrast, current treatments for neuropathic pain are frequently ineffective and carry with them a substantial burden of side effects.
Concluding remarks
The work discussed in this review supports a central role for HCN2 ion channels in both inflammatory and neuropathic pain. One striking difference between the two is that inflammatory pain usually disappears as the injury heals, whereas neuropathic pain often continues long after inflammation associated with the nerve injury has, at least apparently, completely disappeared. Whether HCN channels remain important in long-term neuropathic pain is still unclear and will form an interesting topic
Acknowledgments
Work in the authors’ lab was supported by a grant from the UK Biotechnology and Biological Sciences Research Council (BBSRC) to P.A.M., a European Commission Marie Curie fellowship, and a BBSRC CASE PhD studentship (part-funded by Organon Inc.) to E.C.E.
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2021, Neuroscience ResearchCitation Excerpt :These results indicated that Shank3 had a significant role in the development of neuropathic pain. HCN2 initiates neuronal excitability following nerve injury in neuropathic pain (Du et al., 2013; Emery et al., 2011, 2012). It has been previously shown that reduction of Shank3 blocked the SNI-dependent increase of HCN2 in rats subjected to SNI and that activation of HCN2 played a key role in neuropathic pain by rewiring synaptic connections in the dorsal horn (Emery et al., 2012).
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2021, Trends in Pharmacological SciencesCitation Excerpt :It is possible that prolonged hyperpolarization can activate HCN channels. Both cAMP and cGMP can activate these channels [88] and lead to increases in the open probability, resulting in augmented neuronal excitability and firing of the neurons [89] because these channels are expressed in the TG [90]. If the HCN channels are activated in the peripheral synapses, the nodes of Ranvier, or on neuronal soma, this might induce triggering of spontaneous firing and generation of an action potential.