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Papers of the Week

Papers: 16 Dec 2023 - 22 Dec 2023

2023 Dec 18

J Neurosci


Opioid-induced hyperalgesia and tolerance are driven by HCN ion channels.


Han X, Pinto LG, Vilar B, McNaughton PA


Prolonged exposure to opioids causes an enhanced sensitivity to painful stimuli (opioid-induced hyperalgesia, OIH) and a need for increased opioid doses to maintain analgesia (opioid-induced tolerance, OIT), but the mechanisms underlying both processes remain obscure. We found that pharmacological block or genetic deletion of HCN2 ion channels in primary nociceptive neurons of male mice completely abolished OIH but had no effect on OIT. Conversely, pharmacological inhibition of central HCN channels alleviated OIT but had no effect on OIH. Expression of C-FOS, a marker of neuronal activity, was increased in second-order neurons of the dorsal spinal cord by induction of OIH, and the increase was prevented by peripheral block or genetic deletion of HCN2, but block of OIT by spinal block of HCN channels had no impact on C-FOS expression in dorsal horn neurons. Collectively, these observations show that OIH is driven by HCN2 ion channels in peripheral nociceptors, while OIT is driven by a member of the HCN family located in the CNS. Induction of OIH caused increased cAMP in nociceptive neurons, and a consequent shift in the activation curve of HCN2 caused an increase in nociceptor firing. The shift in HCN2 was caused by expression of an aberrant constitutively active μ-opioid receptor (MOR) and was reversed by MOR antagonists. We identified the aberrant MOR as a 6-transmembrane splice variant, and we show that it increases cAMP by coupling constitutively to G HCN2 ion channels therefore drive OIH, and may be a novel therapeutic target for the treatment of OIH. Chronic opioid treatment causes opioid-induced hyperalgesia (OIH) and opioid-induced tolerance (OIT), both important drivers of opioid addiction. Here we show that an ion channel named HCN2 causes OIH, because blocking or genetically deleting HCN2 suppresses OIH. The activity of HCN2 is enhanced by chronic opioid exposure, resulting in increased excitability of peripheral nociceptive (pain-sensing) neurons. The enhanced HCN2 activity is caused by expression of an aberrant alternatively-spliced μ-opioid receptor that increases intracellular cAMP, which binds to and directly activates HCN2 ion channels. Conversely, we find that a member of the HCN ion channel family in the CNS drives OIT, probably by a similar mechanism. HCN channels are therefore potential therapeutic targets for the treatment of both OIH and OIT.