Increased oxidative stress is a mechanism that probably plays a major role in the development of diabetic complications, including peripheral neuropathy. However, because of the unclear mechanism there is no effective drug for DPN. Lack of neurotrophic support has been proposed as a contributing factor in the etiology of diabetic neuropathy based on studies in animal models of Type I diabetes. Here, the developmental origin, injury-induced changes, and mature myelinating and nonmyelinating phenotypes of Schwann cells are reviewed prior to a description of nerve fiber pathology and consideration of pathogenic mechanisms in human and experimental diabetic neuropathy. For pain relief, several types of drugs may be used, notably antidepressants (e.g. Chemotherapy induced peripheral neuropathy (CIPN) remains one of the major limitations in oncology clinics due to increasing number of cancer patients, lack of effective treatment strategy, relapse of disease . www.clincaltrials.gov NCT01906008).
On the contrary, VFX administered for 21 days prior to MRF significantly decreased the analgesic action of MRF; this effect was augmented only after YOH pretreatment. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00070.x, 2010). These alterations in gene expression modulate critical components of metabolite pathways and the electron transport chain associated with the neuronal mitochondrion. The dose of STZ required for inducing diabetes depends on the animal species, age of animal, route of administration, weight of animal, nutritional status  and different responses to xenobiotics. Callaghan, A. Diabetogenic doses vary with species and the optimal doses that have been reported to produce maximum diabetic conditions in various species are: rats (50 to 75 mg/kg ip(intraperitoneal) [14, 25, 34, 45, 46], mice (175 to 200 mg/kg ip or iv (intravenous) ; dogs (15 mg/kg for 3 days) . At lower doses, STZ-induced diabetes is not stable, since spontaneous recovery occurs.
Carrington AL, Litchfield JE. , they reported that a single high dose of 130 or 150 mg/kg bwt or multiple doses of 40 mg/kg bwt produced hyperglycemia similar to type I diabetes and three administrations of multiple low dose generated mild hyperglycemia (250–450 mg/dl), that is similar to type II diabetes in experimental mice. When administered intravenously, the binding of STZ to its target site is completed within a short time and plasma levels of STZ rapidly decrease within 15 minutes and concentrate in the liver and kidneys [47, 48]. The interneurons modulate the synapse between the first-order neuron and the second-order neuron by releasing gamma amino butyric acid (GABA), an inhibitory neurotransmitter. Thus the biochemical changes observed after 15 minutes of STZ induction are secondary changes and not due to a direct effect of STZ . During feet side-side configuration, postural mechanisms have been reported (12) to be under ankle mechanism in AP direction, whereas hip abductors/adductors motor activities are associated with ML control. Some authors  described a triphasic response in blood glucose after streptozotocin administration.
According to their study, in the first two hours of STZ challenge, blood glucose rises. This transient hyperglycemia is due to sudden breakdown of liver glycogen. The second phase, starting at about 6 hours after STZ dosing, is a hypoglycemic one, which may be severe enough to lead to death. Akude E, Zherebitskaya E, Roy CSK, Girling K, Fernyhough P. Structural alterations in pancreatic beta cells (total degranulation) occur within 48 h after the administration of streptozocin and last for up to four months . However, in the study carried out by Eleazu et al.  and Adeghate and Ponery , they reported that the destruction of the insulin secreting β-cells starts three days post STZ administration, reaching its peak at 2 to 4 weeks in rats, leaving less active cells that result in a diabetic state.
In clinical research studies investigating the ameliorating actions of some medicinal plants in diabetic animals induced with STZ, its best to commence administration of the test plants about two weeks post STZ induction or about 11 days after initial hyperglycemic levels since some animals have the ability to return to normoglycemic levels even after initial hyperglycemic levels. Thus if such measures are not taken, one will not know if the transformation to normoglycemic level is as a result of the test plants administered or the animal’s ability to withstand the initial STZ challenge. Researchers using diabetic animals for research employ 16–24 hours fasting, but this fasting brings about important changes. These changes tend to affect internal cellular biochemistry and one should therefore expect differences in the effects of preparations on isolated cells, tissue or organs removed from animals that have, or have not been fasted. Fasting has pronounced effects on clinical chemistry analysts and hematology in diabetic animal models. Hypoglycaemia for instance, is more pronounced in fasted animals, therefore STZ should be administered to fed animals to avoid mortalities . Although, one major reason for subjecting laboratory animals to fasting before blood collection is to reduce variability of some clinical chemistry parameters between feeding and fasting conditions, intestinal physiologic functions and drug-metabolizing enzymes may have some difference under feeding and fasting conditions.
Thus, the fasting in animals should be decided on a case by case basis, rather than made uniform for every study. Injection of STZ (45 and 55 mg kg-1 intraperitoneally) after 2 weeks of dietary manipulation has been reported to cause hyperglycemia both in rats fed both normal pellet diet (NPD) and high fat diet . Such rats were reported to be insulin-deficient as compared to the normal rats and exhibited a drastic reduction in the body weight and some of them died within 2 weeks of STZ administration. In addition, insulinotropic (glipizide) and insulin-sensitizing (pioglitazone) agents failed to alter the PGL in these fat-fed/STZ (45 and 55 mg kg-1) diabetic rats. Thus, these fat-fed rats with high dose of STZ (45 and 55 mg kg-1) resembled more like type I diabetes. The materialization of the disease pattern was achieved by combining the feeding of HFD which produced insulin resistance and low dose of STZ treatment that caused the initial beta cell dysfunction and subsequently the frank hyperglycemia (pre-diabetic state) in non-genetic, out-bred Sprague–Dawley rats. The rats fed with high-fat diet developed obesity, hyperinsulinemia, and insulin resistance, thus limiting the screening of agents on controlling the blood glucose level .
Interestingly, the intraperitoneal dose of STZ (35 mg/kg) that produced frank hyperglycemia in HFD-fed rats failed to produce the same in NPD-fed rats. The HFD rat model with low dose of STZ (35 mg kg-1) was therefore considered by the authors to represent the pathophysiological state of type 2 diabetes as it was accompanied by marginal increase in body weight in contrast to the catabolic loss of body weight, characteristic of diabetic condition produced by high dose of STZ. Neuropathy is the most common chronic complication of diabetes mellitus. One of the most elusive symptoms in diabetic neuropathy is pain, characterized by mechanical and thermal hyperalgesia . Hypernociception induced by systemic STZ administration has been widely used as an animal model of diabetic neuropathy. 11. To provide information on underlying mechanisms and to evaluate potential therapies, experimental research on diabetic neuropathy is usually carried out using genetic or chemically induced diabetic animal models.
A systemic administration of STZ has been reported to induce hyperalgesia to thermal, mechanical and chemical stimuli . STZ induced hyperalgesia is frequently associated with hyperglycemia because in some studies its development was prevented by insulin treatment [57, 58]. STZ induced hyperalgesia is frequently associated with hyperglycemia because in some studies its development was prevented by insulin treatment [58, 59]. Although these studies suggest that STZ induces painful diabetic neuropathy, it is important to point out that the majority of studies evaluating STZ-induced hyperalgesia only include animals rendered hyperglycemic . In the study carried out by Cunha and colleagues , they reported that administration of high dose (40 mg/kg bwt) and low dose (10 or 20 mg/kg bwt) of Streptozotocin produced mechanical hypernociception in all the STZ challenged rats whereas the low dose failed to produce hyperglycemia, suggesting that some other factor other than hyperglycemia could be involved in STZ-induced mechanical hypernociception.