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Transient Receptor Potential Melastatin 8 (TRPM8) ion channel is a nociceptor critically involved in such pathological processes. Direct blockade of TRPM8 exhibits significant analgesic effects but also incurs severe side effects such as hypothermia. To selectively target TRPM8 channels against cold allodynia, a cyclic peptide DeC\u20101.2 is de novo designed with the optimized hot\u2010spot centric approach. DeC\u20101.2 modality specifically inhibited the ligand activation of TRPM8 but not the cold activation as measured in single\u2010channel patch clamp recordings. 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