Nerve growth factor- and neurotrophin-3-induced changes in nociceptive threshold 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 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 microM), but not CGP 36742 (100 microM), 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.
Malcangio
M
M
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.
Garrett
N E
NE
Cruwys
S
S
Tomlinson
D R
DR
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005071:Evoked Potentials / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D006987:Hypesthesia / Q000139:chemically induced / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D020933:Neurotrophin 3; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects*; D010477:Perfusion; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D012636:Secretory Rate / Q000187:drug effects; D016037:Single-Blind Method; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*
D000700:Analgesics; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D009292:Narcotic Antagonists; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D009943:Organophosphorus Compounds; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D013373:Substance P; D009270:Naloxone; D002211:Capsaicin