Painful diabetic peripheral neuropathy (PDPN) is a common complication of diabetes mellitus [1]. The painful symptom becomes a major factor in decreased quality of life for patients with diabetes, while it is lack of effective treatments. The aim of the present study is to investigate the changes of pain thresholds in the early stage of diabetes in db/db mice, an animal model of type 2 diabetes mellitus [2], and the underlying mechanisms. Diabetic mice (db/db) and non-diabetic littermates (wild type, WT) of C57BLKS strain were used in present study. Body weight, blood glucose and behavioral responses to various stimuli were measured every week in db/db mice and the non-diabetic littermates mice (WT) at 4-12 weeks of age. The mechanical and thermal threshold was measured by probing von Frey hairs (von Frey, Stoelting, USA) and Hargreaves’ tests, respectively [3]. Western blot was used to measure the expression of phosphorylated and total ERK1 and ERK2, GAPDH as well. Mice were deeply anesthetized by 25% urethane (1.5g/ kg body weight) before tissue collection for Western blot analysis. We found that (1) db/db mice, with a leptin receptor null mutation, are characterized by obese and hyperglycaemic; (2) db/db mice were hypersensitivity to mechanical and thermal stimuli at early stage of diabetes; (3) phosphorylations of ERK1 and pERK2, but not total ERK in the spinal cord from db/db mice are significantly increased as compared with that from wild-type mice; (4) at the age of 8 weeks, db/db mice showed increased pain hypersensitivity in the formalin test. In parallel, the expressions of pERK1 and pERK2 were largely increased in the ipsilateral spinal cord of diabetes after formalin injection. Our results indicated that activation of ERK may be a potential molecular mechanism involving in the pain hypersensitivity in type 2 diabetes. Keywords:painful diabetic peripheral neuropathy (PDPN); db/db mice, pain hypersensitivity, extracellular signal-regulated kinases (ERK)