The involvement of HCN2 ion channels in opioid-induced hyperalgesia and tolerance

Student thesis: Doctoral ThesisDoctor of Philosophy


Opioid-induced hyperalgesia (OIH) and tolerance (OIT) counteract opioid analgesia and drive dose escalation, thereby producing adverse effects on patients. Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are constitutive membrane proteins which function as nonselective cation nonselective voltage-dependence cation channels. HCN2 ion channels, that are sensitive to cAMP, play a critical role in excitability in peripheral nociceptor neurons. Prolonged opioid administration has long been considered to result in an elevation of cAMP concentration. Therefore, the activation of HCN2 via the cAMP pathway is suggested to drive the development of OIH and possible OIT. Here we showed that inhibiting or genetically deleting peripheral HCN2 in nociceptors abolishes hyperalgesia induced by chronic morphine treatment, while inhibition of central HCN channels alleviates OIT. The expression of C-FOS, a marker of neuronal activity, in second-order neurons of the dorsal spinal cord was increased in OIH mice and was reversed by blocking or genetically deleting HCN2 whereas they were unchanged by inhibiting central HCN channels in OIT mice. Long-term morphine administration caused an increase in firing frequencies of action potential in sensory neurons as a result of the increased cAMP levels, indicating the existence of peripheral neuronal hyperexcitability. We showed that this was due to a depolarizing shift in the voltage-dependence of activation of HCN2, caused by increased expression of aberrant 6TM μ opioid receptors and a consequent Gs-driven activation of cAMP signalling pathways. These experiments support the idea that OIH is caused by enhanced neuronal excitability in the periphery, driven by a potentiated activity of HCN2 ion channels. This hypothesis may provide a new therapeutic target for the treatment of OIH.
Date of Award1 Jul 2023
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorPeter McNaughton (Supervisor) & Kirsty Bannister (Supervisor)

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