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 microliters followed by 10 microliters saline flush) of either saline (n = 5), somatostatin (100 micrograms, n = 10), the somatostatin analog BIM 23003 (100 micrograms, n = 5), the somatostatin analog SMS 201-995 (100 micrograms, n = 5), the substance P analog [D-Pro2, D-Trp7,9] SP (10 micrograms, 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.
Gaumann
D M
DM
Department of Anesthesiology and Medicine, Mayo Clinic, Rochester, MN 55905.
Grabow
T S
TS
Yaksh
T L
TL
Casey
S J
SJ
Rodriguez
M
M
D000818:Animals; D004399:Dynorphins / Q000008:administration & dosage / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009498:Neurotoxins; D015282:Octreotide / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000503:physiopathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012640:Seizures / Q000139:chemically induced; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D013239:Stereotyped Behavior / Q000187:drug effects*; D013373:Substance P / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
D009498:Neurotoxins; D010446:Peptide Fragments; C069371:BIM 23003; D013373:Substance P; D013004:Somatostatin; D004399:Dynorphins; C032132:substance P, prolyl(2)-tryptophan(7,9)-; D015282:Octreotide