Guanfacine Normalizes Presynaptic Alpha-2 Adrenoceptors Enrichment and Ameliorates Neuropathic Pain in Type 1 Diabetic Rats

Diabetes is associated with several complications, including neuropathic pain, which is challenging to manage with currently available drugs. Descending noradrenergic neurons possess anti-nociceptive activity; however their involvement in diabetic neuropathic pain remains to be explored. To infer the regulatory role of this system, we examined in the pons, a part of the brainstem, lumbar nerves of the spinal cord and dorsal root ganglia of streptozotocin (STZ) -treated rats, a model for type 1 diabetes (T1D) , the localization (immunofluorescence) and the mRNA (qRT-PCR) and protein (Western blotting) expression of alpha-2A adrenoceptor (ADRA2A) . The data revealed that presynaptic SNAP-25 labeled ADRA2A in the central and peripheral nervous system of STZ diabetic rats were up-regulated both at the mRNA and protein levels. Interestingly, the levels of PSD-95 labeled postsynaptic neuronal ADRA2A remain unaltered as a function of diabetes. These biochemical abnormalities in the noradrenergic system of diabetic animals were associated with increased pain sensitivity as typified by the presence of hyperalgesia and cold/mechanical allodynia. The latter pain-related behaviors were assessed using Hargreaves apparatus, cold-plate and dynamic plantar aesthesiometer. Chronically administered guanfacine, a selective ADRA2A agonist, to diabetic animals downregulated the upregulation of neuronal presynaptic ADRA2A and ameliorated the hyperalgesia and the cold/mechanical allodynia in these animals. Together, these findings demonstrate that guanfacine may function as a potent analgesic and highlight ADRA2A, a key component of the descending neuronal autoinhibitory pathway as a potential therapeutic target in the treatment of diabetic neuropathic pain.