Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy

Christoforos Tsantoulas; Sergio Lainez; Sara Wong; Ishita Mehta; Bruno Vilar; Peter A. McNaughton

doi:10.1126/scitranslmed.aam6072

Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy

Christoforos Tsantoulas, Sergio Lainez, Sara Wong, Ishita Mehta, Bruno Vilar, Peter A. McNaughton^*

^*Corresponding author for this work

Wolfson SPaRC

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Abstract

Diabetic patients frequently suffer from continuous pain that is poorly treated by currently available analgesics. We used mouse models of type 1 and type 2 diabetes to investigate a possible role for the hyperpolarizationactivated cyclic nucleotide-gated 2 (HCN2) ion channels as drivers of diabetic pain. Blocking or genetically deleting HCN2 channels in small nociceptive neurons suppressed diabetes-Associated mechanical allodynia and prevented neuronal activation of second-order neurons in the spinal cord in mice. In addition, we found that intracellular cyclic adenosine monophosphate (cAMP), a positive HCN2 modulator, is increased in somatosensory neurons in an animal model of painful diabetes. We propose that the increased intracellular cAMP drives diabetes-Associated pain by facilitating HCN2 activation and consequently promoting repetitive firing in primary nociceptive nerve fibers. Our results suggest that HCN2 may be an analgesic target in the treatment of painful diabetic neuropathy.

Original language	English
Article number	eaam6072
Number of pages	13
Journal	Science Translational Medicine
Volume	9
Issue number	409
Early online date	27 Sept 2017
DOIs	https://doi.org/10.1126/scitranslmed.aam6072
Publication status	Published - 27 Sept 2017

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10.1126/scitranslmed.aam6072

Hyperpolarization-activated cyclic nucleotide_TSANTOULAS_Acc6Sep2017Epub27Sep2017_GREEN AAMAccepted author manuscript, 2.31 MB

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720342/

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abstract = "Diabetic patients frequently suffer from continuous pain that is poorly treated by currently available analgesics. We used mouse models of type 1 and type 2 diabetes to investigate a possible role for the hyperpolarizationactivated cyclic nucleotide-gated 2 (HCN2) ion channels as drivers of diabetic pain. Blocking or genetically deleting HCN2 channels in small nociceptive neurons suppressed diabetes-Associated mechanical allodynia and prevented neuronal activation of second-order neurons in the spinal cord in mice. In addition, we found that intracellular cyclic adenosine monophosphate (cAMP), a positive HCN2 modulator, is increased in somatosensory neurons in an animal model of painful diabetes. We propose that the increased intracellular cAMP drives diabetes-Associated pain by facilitating HCN2 activation and consequently promoting repetitive firing in primary nociceptive nerve fibers. Our results suggest that HCN2 may be an analgesic target in the treatment of painful diabetic neuropathy.",

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AU - Vilar, Bruno

AU - McNaughton, Peter A.

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Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy

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