Abstract
Neuroimmune interactions underlying the development of pain sensitization in models of neuropathic pain have been widely studied. In this study, we evaluated the development of allodynia and its reduction associated with peripheral antineuroinflammatory effects induced by a dexamethasone-loaded biodegradable implant. Chronic constriction injury (CCI) of the sciatic nerve was performed in Wistar rats. The electronic von Frey test was applied to assess mechanical allodynia. The dexamethasone-loaded implant was placed perineurally at the moment of CCI or 12 days after surgery. Dorsal root ganglia (DRG; L4-L5) were harvested and nuclear extracts were assayed by Western blot for detection of nuclear factor (NF)-κB p65/RelA translocation. Dexamethasone delivered from the implant delayed the development of allodynia for approximately three weeks in CCI rats when the implantation was performed at day 0, but allodynia was not reversed when the implantation was performed at day 12. NF-κB was activated in CCI rat DRG compared with naive or sham animals (day 15), and dexamethasone implant inhibited p65/ RelA translocation in CCI rats compared with control. This study demonstrated that the dexamethasoneloaded implant suppresses allodynia development and peripheral neuroinflammation. This device can reduce the potential side effects associated with oral anti-inflammatory drugs.
Highlights
Dexamethasone, a potent anti-inflammatory and immunosuppressant drug, inhibits fibrovascular tissue formation around sutures, infiltration of inflammatory cells, and thermal hyperalgesia when administered intraperitoneally before and after chronic constriction injury (CCI) in rats (Clatworthy et al, 1995)
Taking into account the importance of nuclear factor (NF)-κB for the expression of several inflammatory mediators and the well-known effects induced by steroidal anti-inflammatory drug (SAID) on nuclear factor κB (NF-κB) activation, we investigated the association between the prevention of allodynia development and peripheral antineuroinflammatory effect
We showed that a perineural implant containing dexamethasone, placed at the moment of CCI, delays the development of mechanical allodynia in rats
Summary
Dexamethasone, a potent anti-inflammatory and immunosuppressant drug, inhibits fibrovascular tissue formation around sutures, infiltration of inflammatory cells, and thermal hyperalgesia when administered intraperitoneally before and after chronic constriction injury (CCI) in rats (Clatworthy et al, 1995). It is tempting to associate the antiallodynic effect induced by a steroidal anti-inflammatory drug (SAID) with its anti-inflammatory actions on the peripheral nervous. A variety of peripheral immune cells, including mast cells, macrophages, and lymphocytes, are resident in nerves and/or recruited to sites of peripheral nerve injury. Inflammatory mediators that sensitize or directly activate peripheral neurons to generate action potentials, leading to peripheral and central sensitization. To further study the peripheral antineuroinflammatory actions of SAIDs, in the present study we investigated the ability of a dexamethasone-loaded biodegradable implant to prevent the mechanical allodynia induced by sciatic injury in rats and its possible association with an effect on NF-κB activation in DRG. Biodegradable implants may be an effective dosage form since they may promote a controlled drug release at therapeutic levels for a prolonged period of time without frequent doses, avoiding undesirable targeting of healthy tissues and harmful side effects, as lower concentrations of drugs are administered when compared to oral formulations (Dash, Cudworth 2nd., 1998; Langer, 1998)
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