INTRATHECAL SOMATOSTATIN, SOMATOSTATIN ANALOGS, SUBSTANCE-P ANALOG AND DYNORPHIN-A CAUSE COMPARABLE NEUROTOXICITY IN RATS

Rats chronically implanted with intrathecal catheters received intrathecal injections (10-mu-l followed by 10-mu-l saline flush) of either saline (n = 5), somatostatin (100-mu-g, n = 10), the somatostatin analog BIM 23003 (100-mu-g, n = 5), the somatostatin analog SMS 201-995 (100-mu-g, n = 5), the substance P analog [D-Pro2, D-Trp7,9] SP (10-mu-g, n = 10), or dynorphin A (1-17) (20 nmol, n = 8). These doses (somatostatin, substance P and dynorphin A) were selected based on previous studies in which they caused significant motor deficits. Effects on thermal cutaneous nociception, behavior, motor function and spinal cord histopathology were evaluated. All peptides caused severe neurotoxicity, evidenced by flaccid hind leg paralysis and lumbar spinal neuronal degeneration, which was accompanied by an inflammatory reaction in meninges and spinal gray matter. Histopathological changes had developed within 24 h after injection of somatostatin, substance P analog and dynorphin A, showing mild to severe neuronal degeneration and mild inflammatory responses in spinal cord and meninges. Significant antinociceptive effects, due to severe neurotoxic effects, were only observed following intrathecal injection of SMS 201-995 and the substance P analog. Potential neurotoxic mechanisms of the different peptides are discussed.