NERVE GROWTH FACTOR-AND NEUROTROPHIN-3-INDUCED CHANGES IN NOCICEPTIVETHRESHOLD AND THE RELEASE OF SUBSTANCE-P FROM THE RAT ISOLATED SPINAL-CORD

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 contra st, neurotrophin-3 (NT-3; 1-100 ng/ml), although not modifying SP-LI b asal outflow, dose-dependently inhibited the electrically evoked, but not capsaicin (10 nM)-induced, release of the peptide. This NT-3 (10 n g/ml)-induced inhibition persisted even in the presence of 100 ng/ml N GF in the perfusion fluid and was still significant when the evoked re lease of SP-LI was enhanced by a prolonged in vivo treatment with NGF. Co-superfusion with naloxone (0.1 mu M), but not CGP 36742 (100 mu M) , a GABA(B) antagonist, prevented NT-3 (10 ng/ml) inhibition of SP-LI release. Basal and electrically evoked release of SP-LI from the rat s pinal cord in vitro was not modified 24 hr after single systemic injec tion of either NGF (1 mg/kg) or NT-3 (10 mg/kg). At these time interva ls from administration, NGF had induced thermal and mechanical hyperal gesia in the rat hindpaw, and NT-3 had induced mechanical, but not the rmal, hypoalgesia. NT-3 administered six times over a 2 week period (a t 1 mg/kg) did not alter thermal threshold but significantly reduced e lectrically 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 signi ficant hyperalgesia. Although finding that NGF-induced hyperalgesia do es not clearly correlate with changes in the release of SP-LI in the s pinal cord, this study shows that NT-3 is an inhibitor of SP-LI releas e and suggests that this mechanism may be responsible for NT-3-induced antinociception.