Peripheral and central mechanisms of NGF-induced hyperalgesia.
Mechanisms underlying the hyperalgesia induced by a single systemic injection of nerve growth factor (NGF) in adult rats were studied in vivo. A single dose of NGF initiated a prolonged thermal hyperalgesia to a radiant heat source within minutes that lasted for days. Animals which had been pretreated with the mast cell degranulating compound 48/80 or either one of two specific 5-hydroxytryptamine receptor antagonists (ICS 205-930 and methiothepin) also developed an NGF-induced thermal hyperalgesia, but onset was delayed by more than 3 h. In the presence of ICS 205-930 or methiothepin the early component NGF-induced hyperalgesia was reversed and the animals responded with an initial hypoalgesia to the thermal stimuli. Whereas these results indicate a peripheral mechanism for the initial thermal hyperalgesia, the later phase (7 h-4 days after NGF) appeared to be centrally maintained, since it could be selectively blocked by the non-competitive NMDA receptor antagonist MK-801. In contrast to the almost immediate thermal hyperalgesia following a single injection of NGF, a significant mechanical hyperalgesia began only after a 7 h latency. This NGF-induced mechanical hyperalgesia was not blocked by any of the treatments that attenuated the thermal hyperalgesia, indicating that a separate mechanism may be involved. Additional electrophysiological experiments showed that NGF-induced hyperalgesia was not maintained by an increased amount of spontaneous activity in C-fibres. A final result showed that endogenous release of NGF in a model of acute inflammation (complete Freund's adjuvant-induced inflammation) may be involved in the development of thermal hyperalgesia, since it could be blocked by concomitant treatment with anti-NGF antisera. These data indicate that NGF-induced thermal and mechanical hyperalgesia are mediated by different mechanisms. The rapid onset component of thermal hyperalgesia is due to a peripheral mechanism involving the degranulation of mast cells, whereas the late component involves central NMDA receptors. In contrast, the NGF-induced mechanical hyperalgesia seems to be independent of mast cell degranulation or central NMDA receptor sites.
Lewin
G R
GR
Department of Neurobiology and Behavior, SUNY at Stony Brook 11794.
Rueff
A
A
Mendell
L M
LM
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000503:physiopathology*; D004594:Electrophysiology; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D008407:Mast Cells / Q000502:physiology; D009412:Nerve Fibers / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D017933:Peripheral Nervous System / Q000187:drug effects / Q000503:physiopathology*; D010812:Physical Stimulation; D051381:Rats; D011921:Rats, Inbred WKY; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D009414:Nerve Growth Factors; D016194:Receptors, N-Methyl-D-Aspartate; D017366:Serotonin Receptor Agonists; D003189:p-Methoxy-N-methylphenethylamine