Repeated activation of delta opioid receptors counteracts nerve injury-induced TNF-? up-regulation in the sciatic nerve of rats with neuropathic pain: A possible correlation with delta opioid receptors-mediated antiallodinic effect

Despite mu opioid receptor agonists are the cornerstones of moderate-to-severe acute pain treatment, their effectiveness in chronic pain conditions is controversial. In contrast to mu opioid receptor agonists, a number of studies have reported the effectiveness of delta opioid receptor agonists on neuropathic pain strengthening the idea that delta opioid receptors gain importance when chronic pain develops. Among other effects, it has been shown that delta opioid receptor activation in optic nerve astrocytes inhibits tumor necrosis factor-alpha-mediated inflammation in response to severe hypoxia. Considering the involvement of tumor necrosis factor-alpha in the development and maintenance of neuropathic pain, with this study we sought to correlate the effect of delta opioid receptor agonist on the development of mechanical allodynia to tumor necrosis factor-alpha expression at the site of nerve injury in rats subjected to chronic constriction injury of the sciatic nerve. To this aim, we measured the levels of tumor necrosis factor-alpha in the sciatic nerve of rats with neuropathic pain after repeated injections with a delta opioid receptor agonist. Results obtained demonstrated that repeated administrations of the delta opioid receptor agonist SNC80 (10 mg/kg, i.p. for seven consecutive days) significantly inhibited the development of mechanical allodynia in rats with neuropathic pain and that the improvement of neuropathic symptom was timely related to the reduced expression of tumor necrosis factor-alpha in the rat sciatic nerve. We demonstrated also that when treatment with the delta opioid receptor agonist was suspended both allodynia and tumor necrosis factor-alpha up-regulation in the sciatic nerve of rats with neuropathic pain were restored. These results show that persistent delta opioid receptor activation significantly attenuates neuropathic pain and negatively regulates sciatic nerve tumor necrosis factor-a expression in chronic constriction injury rats.