Opioid-Induced Hyperalgesia and Tolerance Are Driven by HCN Ion Channels

Long-term use of opioid medications can lead to increased sensitivity to pain (opioid-induced hyperalgesia, or OIH) and a decreased response to the drug (opioid-induced tolerance, or OIT). The study found that OIH is linked to HCN2 ion channels in pain-sensing neurons located outside the central nervous system. Blocking or removing these HCN2 channels in mice eliminated OIH, but it did not affect OIT. Conversely, blocking HCN channels in the central nervous system reduced OIT but had no effect on OIH. The researchers discovered that OIH causes increased levels of cAMP in pain-sensing neurons, leading to changes in HCN2 channel activity and increased neuron firing. This effect is caused by a specific type of opioid receptor that increases cAMP levels. These findings suggest that HCN2 channels could be a target for new treatments for addiction.

• 1
  Peripheral HCN2 ion channels drive opioid-induced hyperalgesia (OIH). Blocking or genetically deleting HCN2 in primary nociceptive neurons abolishes OIH.
• 2
  Central HCN channels drive opioid-induced tolerance (OIT). Pharmacological inhibition of central HCN channels alleviates OIT but has no effect on OIH.
• 3
  A constitutively active μ-opioid receptor (MOR) splice variant increases cAMP in nociceptive neurons, shifting the activation curve of HCN2 and increasing nociceptor firing, driving OIH.