Abstract: Background and Objective: Adrenomedullin (AM) belongs to calcitonin gene-related peptide (CGRP) family. The pain peptide plays a role in pathological pain. This study investigated the possible involvement of AM in bone cancer pain. Methods: Carcinoma cells were injected into the medullary cavity of tibia in rats. Agent was administered intrathecally (i.t.). Nociceptive behaviors were assessed. Neurochemicals in the spinal dorsal horn and dorsal root ganglia (DRG) were assayed by immunohistochemistry and real-time PCR. Results: Carcinoma cells inoculated into the medullary cavity of right tibia induced a reduction of mechanical withdrawal threshold in the hind paw. This was accompanied by an increase in AM expression in small but not medium sized neurons in dorsal root ganglia (DRG). mRNA expression analysis showed that AM was upregulated in the spinal dorsal horn and DRG. Intrathecal (i.t.) administration of the selective AM receptor antagonist AM22-52 (10 nmol) on day 14 postinoculation attenuated bone cancer induced mechanical allodynia and inhibited the increase of AM protein and mRNA in the spinal cord and/or DRG. Bone cancer increased the expression of CGRP mRNA in the DRG but not in the spinal dorsal horn. Cancer cell inoculation induced an increase in neuronal nitric oxide synthesis (nNOS) expression in small but not medium sized neurons in DRG. Furthermore, the increase of CGRP mRNA and nNOS protein in DRG was abolished by i.t. AM22-52 (10 nmol).Conclusion: The present study suggests that the pronociceptive mediator AM was upregulated in autocrine and/or paracrine manners and involved in the pathogenesis of bone cancer pain. The enhanced AM bioactivity can facilitate the expression of nNOS and CGRP mRNA in DRG in bone cancer. Targeting AM receptors should be considered as a novel therapy to treat bone cancer pain.