Reduced Noradrenergic Excitability in the Locus Coeruleus Compromises Nociceptive Inhibition in a Diabetic Mouse Model

The locus coeruleus (LC) play an essential role in the regulation of nociceptive transmission by a widespread descending pathway to the spinal cord and the spinal trigeminal nucleus. We examined the effect of formalin injection in the vibrissal pad (nociceptive stimulus) on LC activity in isoflurane anesthetized control and in streptozotocin-induced diabetic (STZ-diabetic) mice which display neuropathic pain. Using unit recordings, we observed that formalin induced a sustained increase in the firing rate of LC neurons. In contrast, STZ-diabetic mice only showed an initial response, suggesting a reduced neuronal excitability. This finding was supported by a reduced c-Fos expression in comparison with control mice. We suggest that the reduction of LC excitability was due to a reduction of the insulin-like growth factor I (IGF-I) levels that occur in diabetes. In fact, immunohistochemistry studies showed that IGF-I receptors were diminished in STZ-diabetic mice. Treatment of STZ-diabetic mice with the IGF-I receptor sensitizer AIK3a305 restored LC activity. In conclusion, the lack of IGF-I in the brain of diabetic animals may be responsible for the reduced activity of LC neurons and, consequently, for the altered control of nociceptive transmission, facilitating chronic pain development in neuropathy diseases.