title: Demethylating drugs as novel analgesics for cancer pain.
abstract: OBJECTIVE
  In this study, we evaluated the analgesic potential of demethylating drugs on oral cancer pain. Although demethylating drugs could affect expression of many genes, we focused on the mu-opioid receptor (OPRM1) gene pathway, because of its role in pain processing. We determined the antinociceptive effect of OPRM1 re-expression in a mouse oral cancer model.
  
  
  METHODS
  Using a mouse oral cancer model, we determined whether demethylating drugs produced antinociception through re-expression of OPRM1. We then re-expressed OPRM1 with adenoviral transduction and determined if, and by what mechanism, OPRM1 re-expression produced antinociception. To determine the clinical significance of OPRM1 on cancer pain, we quantified OPRM1 methylation in painful cancer tissues and nonpainful contralateral normal tissues of patients with oral cancer, and nonpainful dysplastic tissues of patients with oral dysplasia.
  
  
  RESULTS
  We demonstrated that OPRM1 was methylated in cancer tissue, but not normal tissue, of patients with oral cancer, and not in dysplastic tissues from patients with oral dysplasia. Treatment with demethylating drugs resulted in mechanical and thermal antinociception in the mouse cancer model. This behavioral change correlated with OPRM1 re-expression in the cancer and associated neurons. Similarly, adenoviral-mediated OPRM1 re-expression on cancer cells resulted in naloxone-reversible antinociception. OPRM1 re-expression on oral cancer cells in vitro increased β-endorphin secretion from the cancer, and decreased activation of neurons that were treated with cancer supernatant.
  
  
  CONCLUSIONS
  Our study establishes the regulatory role of methylation in cancer pain. OPRM1 re-expression in cancer cells produces antinociception through cancer-mediated endogenous opioid secretion. Demethylating drugs have an analgesic effect that involves OPRM1.
authors: Department of Oral Maxillofacial Surgery, New York University, New York, NY, United States.|Bluestone Center for Clinical Research, New York University, NY, United States.
authors: Chi T
authors: CT
authors: Viet
authors: Department of Oral Maxillofacial Surgery, New York University, New York, NY, United States.|Bluestone Center for Clinical Research, New York University, NY, United States.
authors: Dongmin
authors: D
authors: Dang
authors: Department of Oral Maxillofacial Surgery, New York University, New York, NY, United States.|Bluestone Center for Clinical Research, New York University, NY, United States.
authors: Yi
authors: Y
authors: Ye
authors: Department of Oral Maxillofacial Surgery, New York University, New York, NY, United States.|Bluestone Center for Clinical Research, New York University, NY, United States.
authors: Kentaro
authors: K
authors: Ono
authors: Department of Oral Maxillofacial Surgery, New York University, New York, NY, United States.|Bluestone Center for Clinical Research, New York University, NY, United States.
authors: Ronald R
authors: RR
authors: Campbell
authors: Department of Oral Maxillofacial Surgery, New York University, New York, NY, United States.|Bluestone Center for Clinical Research, New York University, NY, United States.
authors: Brian L
authors: BL
authors: Schmidt
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000150:complications*; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation; D000077209:Decitabine; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D009062:Mouth Neoplasms / Q000150:complications*; D009474:Neurons / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D017450:Receptors, Opioid, mu / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D012668:Trigeminal Ganglion / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D000970:Antineoplastic Agents; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D003562:Cytidine; D000077209:Decitabine; C009131:pyrimidin-2-one beta-ribofuranoside; D001374:Azacitidine