Nociception — the ability to detect painful stimuli — is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a ‘pacemaker for pain’, in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.
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Cover Image
Cover Image
A merged immunofluorescence microscope image of meiotic chromosome spread from testes excised from wild-type male mice, stained with antibodies against phospho-gamma-H2AX (green) to detect DNA damage and Sycp3 (red) to determine the stage of progression of cells during synapsis. Cells were counter-stained with DAPI (blue). Images were visualized and taken using Zeiss AxioImager Z1 epifluorescence microscope with Zeiss AxioCam MRc5 at 63X objective (Zeiss Plan-APOCHROMAT, 63x/1.4 Oil DIC, ∞/0.17). Photo was taken by Joanna H.S. Lee and Philipp Kaldis, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore. Image kindly supplied by Philipp Kaldis. For further details see pages 2783–2798
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HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain
Christoforos Tsantoulas, Elizabeth R. Mooney, Peter A. McNaughton; HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain. Biochem J 15 September 2016; 473 (18): 2717–2736. doi: https://doi.org/10.1042/BCJ20160287
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