Role Of Glial Cell Line-derived Neurotrophic Factor In Painful Diabetic Rats

Background.Diabetes mellitus(DM) is a common disorder and has a worldwide prevalence of6-7%. The neuropathies are among the most common of the long-time complications,affecting up to 50% patients with DM. Between 16% and 26% of diabetic patientsexperience chronic pain. This may be referred to as diabetic neuropathic pain (DNP)or painful diabetic neuropathy (PDN). Given that depression and other co-morbiditiesare commonly associated with pain, a broad approach to management is essential. Themechanisms of neuropathic pain are complex and the management is still quitedifficult. Optimisation of glycaemic control is recommended as initial step inmanagement. Tricyclic antidepressant, anticonvulsants, selective serotoninnoradrenaline re-uptake inhibitor are thought to be effective, together with opioidagonist. Irrespective of which treatment is offered, only about one third of patients arelikely to achieve more than 50% pain and many patients only achieve partial relieffrom therapy relief. Further research is needed to improve the diagnosis andmanagement of DPN.Neurotrophic factors may play key roles in pathophysiological mechanisms ofhuman neuropathies. GDNF, Glial cell line-derived neurotrophic factor, was found to have potent survival-promoting effects on various types of neurons including primarysensory neurons. Immunohistochemical studies have revealed the existence of GDNFin the superficial layers of spinal cord, an area closely related to pain transmission.GDNF also reversed sensory abnormalities that developed in neuropathic pain models,without affecting pain-related behavior in normal animals, possibly through theregulation of sodium-channel subunits expression in DRG (dorsal root ganglion),reducing ectopic discharge of unmyelinated primary afferents, and preventing DRGneuron daeth. GDNF has been proved to play an important role in the modulation ofnociceptive signals. However, it is not clear whether and how endogenous GDNFcould be involved in the diabetic neuropathic pain model.Partâ… . Expression changes of glial cell line-derivedneurotrophie factor in DRG of streptozotocin-induced diabeticratsObjective: To observe changes in the expressions of GDNF (glial cellline-derived neurotrophic factor) in STZ (streptozotocin) induced diabetic rat modelsof neuropathic pain.Methods: Forty-eight male Sprague-Dawley rats were randomly divided into2 groups: diabetes was induced in 36 rats with a single intraperitoneal injection ofstreptozotocin (60 mg/kg), another 12 rats were selected as controls. Diabetes wasconfirmed 5 days after injection by measurement of blood glucose levels. Tactileallodynia was determined by measuring paw withdrawal in response to probing with aseries of von Frey filaments. The expression of GDNF was examined by Western blotanalysis. The time points of analysis were selected as 2, and 4 weeks after STZinjection. At each time point, six animals of each group were used for every analysis.Results: Five days after administration of STZ, glucose level of 79%animals increased up to 16.7mmol/L and remained high after 4 weeks. The weight of DM rats became significantly lower than that of controls by day 5 and did not changesignificantly up to week 4. The thresholds of paw withdrawal in response to themechanical stimulus began to decrease at day 5 and further decreased for more than 4weeks. Two weeks following STZ injection, the GDNF contents in DRG weremarkedly decreased and stayed at lower levels in the following two weeks.Conclusions: The present results suggested that the changes of GDNF inthe nociceptive afferent system might contribute to the development and/ormaintenance of painful diabetic neuropathy.Partâ…¡. Changes of expression of GDNF in DRG ofpainful diabetic rats treated with gabapentinObjective: To investigate changes of expression of GDNF in DRG aftergabapentin was administered in STZ-induced diabetic neuropathic pain rats.Methods: Painful diabetic neuropathic rats were randomly divided into fourgroups and treated intraperitoneally with gabapentin (30, 60 and 120 mg/kg) or salinerespectively. The withdrawal threshold was measured for the next 4 hours. Then therats were treated twice with gabapentin (30, 60 and 120 mg/kg) or saline respectivelyevery day. And tactile sensitivity was measured every week using von Freymonofilaments following treatment with gabapentin (30, 60 and 120 mg/kg) or saline.Three weeks after gabapentin administration, Rats were sacrificed and Western Blot(n=6 in each group) analyses were used to observe the changes of GDNF expression.Results: Gabapentin (60 and 120 mg/kg) produced significant dose-dependentanti-hyperalgesia or anti-allodynia in painful diabetic rats. After treated withGabapentin (60 and 120 mg/kg), the withdrawal threshold of rats was significantlyincreased an hour after injection, and lasted for about 4 hours. Saline and Gabapentin (30 mg/kg) injection had no significant effect on the withdrawal threshold. Comparedto salines controls, rats treated twice daily with gabapentin (60 and 120 mg/kg) hadsignificantly higher von Frey thresholds on day 14 and stayed at higher level until day21. The expressions of GDNF in DRG of rats with gabapentin (60 and 120mg/kg)were markedly higher than that of rats treated with gabapentin30mg/kg orsaline.Conclusions: While the hyperalgeia and allodynia of diabetic rats werecompletely reversed by treatment with gabapentin, expression of GDNF in DRGincreased markedly, which indicated the correlation between GDNF and gabapentinein their anti-nociceptive effect.