ETHNOPHARMACOLOGICAL RELEVANCE: Calotropis procera (Ait.) R.Br. is one of an ancient traditional shrub, which has been used for the treatment of diabetes, pain and inflammation for thousands of years in India. The root extract of Calotropis procera has been widely used by the tribal׳s of district Udaipur, Rajasthan (India) for treatment of diabetes mellitus and its associated complications like diabetic neuropathy. The present study was performed to explore the protective effect of root, stem and leaf extracts of Calotropis procera in diabetes and diabetic neuropathy against tactile allodynia, mechanical hyperalgesia and thermal hyperalgesia in streptozotocin induced diabetic rats. MATERIALS AND METHODS: Diabetes and peripheral neuropathy were induced in Wistar rats by injection of streptozotocin (45 mg/kg/intraperitoneally). The roots, stem and leaves of Calotropis procera were sequentially extracted with petroleum ether, chloroform, ethyl acetate and methanol. All the extracts were assessed by oral administration at 100 and 250 mg/kg in streptozotocin diabetic rats. The following compounds were used as positive controls: insulin NPH (1 IU/kg/day), metformin (500 mg/kg/day), glibenclamide (2.5 mg/kg/day) and a combination of acarbose (20 mg/kg/day) with methylcobalamine (500 µg/kg/day). In contrast, the streptozotocin induced untreated diabetic rats termed as negative control. Thermal hyperalgesia, mechanical hyperalgesia and tactile allodynia were evaluated in all groups of streptozotocin diabetic rats to assess the extent of neuropathy by Eddy׳s hot plate, tail immersion, Randall-Selitto and Von Frey hair tests. The basal nociceptive thresholds were assessed in week 4 of post streptozotocin injection. All groups received their treatment on a regular basis from 28 to 42 days following a confirmation of diabetic neuropathy. The nociceptive thresholds were assessed in all groups in week 5 and 6. The histopathology of pancreas and biochemical estimations of plasma insulin and glycosylated haemoglobin (HbA1C%) levels were also performed in week 6 of post streptozotocin injection. RESULTS: The negative control rats developed diabetes and diabetic neuropathy after 6 week of streptozotocin administration distinguished by significant (p<0.01) hyperalgesia and tactile allodynia with enhanced HbA1C% level compared to normoglycemic rats. Chronic administration of root methanol, stem methanol and leaf ethyl-acetate extracts of Calotropis procera for 2 weeks at 100 and 250 mg/kg doses significantly (p<0.01) attenuated the diabetes induced mechanical hyperalgesia, thermal hyperalgesia, tactile allodynia and HbA1C% level in streptozotocin diabetic rats as compared to negative control rats. Further, the root methanol extract of Calotropis procera in 100mg/kg dose showed the regeneration capability of β cells in the histology of pancreas with significant (p<0.01) improvement in plasma insulin level in streptozotocin diabetic rats compared to negative control rats. CONCLUSION: Root methanol extract of Calotropis procera (100mg/kg) has shown ameliorative effect in diabetic neuropathy which may be attributed by its multiple actions including potent hypoglycemic and antioxidant.