Botulinum toxin type A reduces pain supersensitivity in experimental diabetic neuropathy: Bilateral effect after unilateral injection

We investigated antinociceptive activity of botulinum toxin type A (BTX-A) in a model of diabetic neuropathic pain in rats. Male Wistar rats were made diabetic by a single intraperitoneal injection of streptozotocin (80 mg/kg). Sensitivity to mechanical and thermal stimuli was measured with the paw-pressure and hot-plate test, respectively. The formalin test was used to measure sensitivity to chemical stimuli. Diabetic animals with pain thresholds lower for at least 25% compared to the non-diabetic group were considered neuropathic and were injected with BTX-A either subcutaneously (3, 5 and 7 U/kg) or intrathecally (1 U/kg). Mechanical and thermal sensitivity was measured at several time-points. After peripheral application, BTX-A (5 and 7 U/kg) reduced mechanical and thermal hypersensitivity not only on ipsilateral, but on contralateral side, too. The antinociceptive effect started 5 days following BTX-A injection and lasted at least 15 days. Formalin-induced hypersensitivity in diabetic animals was abolished as well. When applied intrathecally, BTX-A (1 U/kg) reduced diabetic hyperalgesia within 24 h supporting the assumption of retrograde axonal transport of BTX-A from the peripheral site of injection to central nervous system. The results presented here demonstrate the long-lasting pain reduction after single BTX-A injection in the animals with diabetic neuropathy. The bilateral pain reduction after unilateral toxin application and the effectiveness of lower dose with the faster onset after the intrathecal injection suggest the involvement of the central nervous system in the antinociceptive action of BTX-A in painful diabetic neuropathy.