Genetic studies have identified the voltage-gated sodium channel 1.7 (Na1.7) as pain target. Due to the ineffectiveness of small molecules and monoclonal antibodies as therapeutics for pain, single-domain antibodies (VHs) are developed against the human Na1.7 (hNa1.7) using a novel antigen presentation strategy. A 70 amino-acid peptide from the hNa1.7 protein is identified as a target antigen. A recombinant version of this peptide is grafted into the complementarity determining region 3 (CDR3) loop of an inert VH in order to maintain the native 3D conformation of the peptide. This antigen is used to isolate one VH able to i) bind hNa1.7, ii) slow the deactivation of hNa1.7, iii) reduce the ability of eliciting action potentials in nociceptors, and iv) reverse hyperalgesia in in vivo rat and mouse models. This VH exhibits the potential to be developed as a therapeutic capable of suppressing pain. This novel antigen presentation strategy can be applied to develop biologics against other difficult targets such as ion channels, transporters and GPCRs.