REDUCED NORADRENERGIC EXCITABILITY IN THE LOCUS COERULEUS COMPROMISES NOCICEPTIVE INHIBITION IN A DIABETIC MOUSE MODEL

The locus coeruleus (LC) contains numerous noradrenergic (NA) neurons that play an essential role in the regulation of cognitive function as well as in the control of nociceptive transmission by a widespread descending pathway to the spinal cord and the spinal trigeminal nucleus (Sp5C). The present work examines the LC activity in isoflurane anesthetized control mice and in streptozotocin-induced diabetic (STZ-diabetic) mice which display neuropathic pain. Using unit recordings, we examined the effect of formalin injection in the vibrissal pad (nociceptive stimulus) on LC activity. Formalin induced a sustained increase of the firing rate as well as the response to Sp5C electrical stimulation in control mice. 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 and systemic injection of IGF-I increased LC excitability. 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.