The Effects of Agrin Isoforms on Diabetic Neuropathic Pain in a Rat Streptozotocin Model

BACKGROUND: Diabetes mellitus affects 9.3% of the US population and increases risks of surgery and complications. Diabetic neuropathic pain (DNP), one of the main consequences of diabetes mellitus, is extremely difficult to treat. Current medications yield limited benefits and/or have severe adverse effects. Therefore, new, effective treatment is needed.

METHODS: Streptozotocin at 55 mg/kg was injected intraperitoneally in rats to induce diabetes mellitus. Diabetic rats exhibiting neuropathic pain underwent intrathecal injection of purified agrin proteins at various doses and were then tested for tactile allodynia to evaluate whether DNP was inhibited. The agrin effects were also analyzed with patch-clamp recording on spinal cord slices.

RESULTS: Fifty-kilo Dalton agrin (Agr50) at 0.2 and 2 ng suppressed DNP when given intrathecally, while 25- and 75-kDa agrin (Agr25, Agr75) had little effect. The suppressive effect of Agr50 lasted 4 hours after a single bolus injection. The difference in effects of Agr50 on mean withdrawal threshold (4.6 ± 2.2 g before treatment to 26 ± 0 g after treatment) compared with that of Agr25 (4.9 ± 2.0 g to 4.9 ± 2.0 g) and Agr75 (5.3 ± 2.3 g to 9.2 ± 2.5 g) was highly significant (P < .01). On spinal cord slices, Agr50 increased spontaneous GABAergic current activities, suggesting increased spontaneous inhibitory postsynaptic currents and action potential firing rate from GABA neurons, whereas Agr25 and Agr75 had no such effect.

CONCLUSIONS: Agr50 had a potent suppressive effect on DNP and increased spontaneous inhibitory postsynaptic currents and action potential firing rate from GABA neurons. Therefore, Agr50 may provide a potential therapy for DNP.