DIABETE E DOLORE: EFFETTO TERAPEUTICO DEI METABOLITI DEL TESTOSTERONE

Abstract

Diabetic neuropathy one of important complications of diabetes, is associated with neuropathic pain in about 50% of diabetic subjects. Clinical management of neuropathic pain is complex and so far unsatisfactory. To this aim in rats rendered diabetic by streptozotocin injection we have analyzed the effects of the testosterone metabolites, dihydrotestosterone (DHT) and 5α- androstane-3α,17β-diol (3α-diol), on nociceptive and allodynia thresholds. Moreover, molecular and functional parameters in the spinal cord related with pain modulation, such as the levels of glutamate, the expression and phosphorylation of synaptic proteins, the expression of substance P, neuroinflammatory markers and translocator protein, as well as the number of GFAP immunoreactive astrocytes have been analyzed. Finally, the levels of DHT and 3α-diol have been evaluated in spinal cord of steroid treated and untreated animals. Diabetes resulted in a significant decrease in DHT levels in the spinal cord that was reverted by DHT or 3α-diol treatments. In addition, 3α-diol treatment resulted in a significant increase in 3α-diol in the spinal cord over control values. Both steroids show analgesic properties on diabetic neuropathic pain. Interestingly, they exert their effects affecting different pain parameters and possibly by different mechanisms of action. Indeed, DHT treatment counteract the effect of diabetes on mechanical nociceptive threshold, pre- and post-synaptic components, glutamate release, astrocyte immunoreactivity and expression of interleukin-1β, while 3α-diol treatment was effective on tactile allodynia threshold, glutamate release, astrocyte immunoreactivity and the expression of substance P, toll-like receptor 4, tumor necrosis factor-α, transforming growth factor β-1, interleukin-1β and translocator protein. Moreover a DRG primary cell colture experiment was performed in order to demonstrate the 3α-diol specific effect GABA-A-mediated on substance P expression. Altogether these results suggest that testosterone metabolites are potential agents for the treatment of diabetic neuropathic pain.