["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend We tested the hypothesis that cAMP binding to HCN2 channels in nociceptors is a causal driver of neuropathic pain by using TRIP8bnano, a synthetic peptide we previously developed as a selective antagonist of cAMP in HCN channels. TRIP8bnano effectively abolishes cAMP potentiation of HCN2 currents in small‐diameter DRG neurons and alleviates pain behaviors in a rat model of neuropathic pain. These findings provide direct evidence that cAMP binding to HCN2 channels drives pathological pain and suggest a new therapeutic target.\n\n\n\n\n\n\n\n\n\nAbstract\nHyperpolarization‐activated cyclic nucleotide‐gated 2 (HCN2) channels regulate action potential firing in nociceptors and are critical mediators of neuronal hyperexcitability in response to inflammation and nerve injury. These channels are activated by membrane hyperpolarization and potentiated by direct cAMP binding to their C‐terminal cyclic nucleotide‐binding domain (CNBD). Although a role for cAMP in modulating HCN2 activity and contributing to neuropathic pain has been hypothesized, direct evidence has been lacking. To test this causal link, here we employ TRIP8bnano, comprising a minimal peptide derivative from the brain protein TRIP8b that selectively antagonizes cAMP binding to HCN channels. TRIP8bnano effectively abolished cAMP‐mediated potentiation of HCN2 currents in small‐diameter dorsal root ganglion (DRG) neurons, validating its utility as a functional inhibitor. In a rat model of neuropathic pain, DRG‐targeted expression of TRIP8bnano significantly reduced mechanical and thermal hypersensitivity. These findings provide the first direct evidence that cAMP binding to HCN2 channels drives nociceptor hyperexcitability and neuropathic pain and establishes disruption of this interaction as a promising therapeutic strategy.\n\n\n\n\n\n\n\n\n\nKey points\n\nActivation of HCN2 channels is potentiated by cAMP binding to their cyclic nucleotide binding domain (CNBD).\nTRIP8bnano abolishes cAMP binding to CNBD, thus inhibiting potentiation of HCN2 currents in both HEK 293T cells and rat DRG neurons.\nTRIP8bnano reduces mechanical and thermal hypersensitivity in a rat model of neuropathic pain.\nOur findings confirm a direct role of cAMP–HCN2 signalling in neuropathic pain and suggest a new therapeutic target.\n\n\n"]