Supraspinal Modulation of Neuropathic Pain

Aim #1 tests the hypothesis that neuronal signals arising from the Locus Coeruleus (LC) are required for the expression of behavioral signs of neuropathic pain. The Year 1 progress report described preliminary results indicating that animals receiving anti- DBH saporin reduced behavioral signs of pain throughout the month-long period of behavioral testing. There was no effect of control saporin. The Year 2 progress report provided Fig 1, showing our success with confirmation of lesion placement. We also provide Fig 2, showing the final behavioral results of these studies; treatment could be turning off pain facilitation, and thus reduce allodynia. These results strongly support the hypothesis of Aim #1; that noradrenergic neurons in the LC contribute to allodynia. Aim #2 tests the hypothesis that the LC facilitates spinal nociceptive processing after nerve injury. The Yl progress report indicated that we are able to successfully induce Fos expression in the spinal cord with manual rubbing of the paw in animals with nerve injury. The Y2 progress reported provided Fig 3, illustrating that we are able to successfully induce Fos expression in the LC in animals with nerve injury, in contrast, Fos expression is much lower in uninjured animals. This result supports our hypothesis that the allodynia associated with peripheral nerve injury is associate with activation of the LC. During Y3, we completed quantification of changes in Fos expression, and have also evaluated the expression of pCREB, another marker of pain-related transcriptional activation. The Fos and pCREB results are similar; we show the pCREB results in Fig 4.