The use of neuropeptide-targeted cytotoxins to make selective neural lesions has achieved one noteworthy success in pain research to date, substance P-saporin. The general applicability of this first success in unknown, the present proposal seeks to extend this approach to target neurons that express the mu opiate receptor (MOR) using a targeted toxin composed of the mu opiate peptide, dermorphin, to target the ribosome inactivating protein, saporin, selectively into neurons expressing MOR. There are numerous locations with putative central nervous system pain circuits where neurons express MOR. The site chosen in the present proposal is the substantia gelatinosa of the spinal cord dorsal horn. The goals of the present proposal are to determine if dermorphin-saporin has the desired targeting capability, to destroy MOR-expressing neurons, and to determine the effect of intrathecal dermorphin-saporin on pain perception using two thermal algesia assays, one reflex and one operant. Toxin will be administered into the lumbar subarachnoid space, and anatomic studies will determine the extent and specificity of the lesion. Thermal algesia testing will determine if the lesion differentially affects responses to high and low intensity noxious heat and if the lesion affects the analgesic potency of intrathecal morphine. Results of these experiments will establish if dermorphin-saporin is effective and selective in vivo, and if selective destruction of lamina II MOR-expressing neurons alters pain perception or the analgesic effects of intrathecal morphine. Many valuable future experiments and clinical applications may be possible if dermorphin-saporin proves effective.
| Kline 4th, Robert H; Wiley, Ronald G (2008) Spinal mu-opioid receptor-expressing dorsal horn neurons: role in nociception and morphine antinociception. J Neurosci 28:904-13 |
