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Volume 17, Number 21, Issue of November 1, 1997 pp. 8459-8467
Copyright ©1997 Society for NeuroscienceNerve Growth Factor- and Neurotrophin-3-Induced Changes in Nociceptive Threshold and the Release of Substance P from the Rat Isolated Spinal Cord
Received April 25, 1997; revised July 30, 1997; accepted Aug. 11, 1997.
Marzia Malcangio, Neil E. Garrett, Simon Cruwys, and David R. Tomlinson Department of Pharmacology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London E1 4NS, United Kingdom
Acute superfusion of nerve growth factor (NGF; 1-100 ng/ml) through a naive rat spinal cord preparation did not alter basal or electrically evoked release of substance P-like immunoreactivity (SP-LI). In contrast, neurotrophin-3 (NT-3; 1-100 ng/ml), although not modifying SP-LI basal outflow, dose-dependently inhibited the electrically evoked, but not capsaicin (10 nM)-induced, release of the peptide. This NT-3 (10 ng/ml)-induced inhibition persisted even in the presence of 100 ng/ml NGF in the perfusion fluid and was still significant when the evoked release of SP-LI was enhanced by a prolonged in vivo treatment with NGF. Co-superfusion with naloxone (0.1 µM), but not CGP 36742 (100 µM), a GABAB antagonist, prevented NT-3 (10 ng/ml) inhibition of SP-LI release. Basal and electrically evoked release of SP-LI from the rat spinal cord in vitro was not modified 24 hr after single systemic injection of either NGF (1 mg/kg) or NT-3 (10 mg/kg). At these time intervals from administration, NGF had induced thermal and mechanical hyperalgesia in the rat hindpaw, and NT-3 had induced mechanical, but not thermal, hypoalgesia. NT-3 administered six times over a 2 week period (at 1 mg/kg) did not alter thermal threshold but significantly reduced electrically evoked release of SP-LI from the spinal cord. An identical treatment regimen with 1 mg/kg NGF induced a significant increase in evoked release of SP-LI. However, this was not associated with a significant hyperalgesia. Although finding that NGF-induced hyperalgesia does not clearly correlate with changes in the release of SP-LI in the spinal cord, this study shows that NT-3 is an inhibitor of SP-LI release and suggests that this mechanism may be responsible for NT-3-induced antinociception.
Key words: NGF; NT-3; hyperalgesia; hypoalgesia; substance P; spinal cord; adult rat; release
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